Leaders in Pharmaceutical Business Intelligence (LPBI) Group

View on Amazon.com

https://www.amazon.com/dp/B0BRNRB6KB

since 1/3/2023

 

Audio y Texto

• NEW GENRE Volume Three: Milestones in Physiology & Discoveries in Medicine and Genomics

https://pharmaceuticalintelligence.com/audio-english-spanish-biomed-e-series/new-genre-audio-english-spanish-series-e-patient-centered-medicine-precision-medicine/new-genre-volume-three-milestones-in-physiology-discoveries-in-medicine-and-genomics-series-e-volume-3%ef%bf%bc/

 

• Original Volume Three: Milestones in Physiology & Discoveries in Medicine and Genomics

On Amazon.com since 12/27/2015

http://www.amazon.com/dp/B019VH97LU

 

• NEW GENRE Volume Three: Milestones in Physiology & Discoveries in Medicine and Genomics 

https://pharmaceuticalintelligence.com/audio-english-spanish-biomed-e-series/new-genre-audio-english-spanish-series-e-patient-centered-medicine-precision-medicine/new-genre-volume-three-milestones-in-physiology-discoveries-in-medicine-and-genomics-series-e-volume-3%ef%bf%bc/

 

This volume has the following three parts:

PART A: The eTOCs in Spanish in Audio format

PART B: The eTOCs in Bi-lingual format: Spanish and English in Text format

PART C: The Editorials of the original e-Books in English in Audio format

 

PART A:

The eTOCs in Spanish in Audio format

 

Serie E: Medicina centrada en el paciente

 

TERCER VOLUMEN

 

Hitos de la fisiología
Descubrimientos en medicina, genómica y terapéutica: Perspectiva centrada en el paciente

 

2015

Traducción a español

Montero Language Services

Disponible en Amazon.com desde el 27/12/2015

http://www.amazon.com/dp/B019VH97LU

 

Autor, redactor y editor

Larry H Bernstein, MD, FCAP

Director científico

Leaders in Pharmaceutical Business Intelligence

Larry.bernstein@gmail.com

 

Fuente de la imagen: Adaptado de Google Images

 

Aviva Lev-Ari, PhD, RN

Redactora jefe de la serie de libros electrónicos BioMed

Leaders in Pharmaceutical Business Intelligence, Boston

avivalev-ari@alum.berkeley.edu

 

 

 

Lista de colaboradores y sus biografías

 

Autor del volumen, redactor y editor

Larry H Bernstein, MD, FCAP

 

Autores invitados:

Stephen J Williams, PhD: 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 9.10

Aviva Lev-Ari, PhD, RN: 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 7.9, 7.10, 7.11

Tilda Barliya, PhD: 8.7, 8.8

Demet Sag, PhD: 8.9, 8.10, 8.11, 8.12

 

 

Los enlaces indicados llevan al contenido original en inglés

MD	Licenciado/a en medicina y cirugía (Estados Unidos)
PhD	Doctorado/a
RN	Enfermero/a titulado/a (National Board of Nursing Registration)
FCAP	Miembro distinguido (Fellow) del Colegio de Anatomopatólogos de los Estados Unidos
FDA	Food and Drug Administration (Administración de Alimentos y Medicamentos de los Estados Unidos)
IDO	Indolamina 2,3-dioxigenasa
TDD	Sistema de administración transdérmica de fármacos
LLC	Compañía de responsabilidad limitada (Limited Liability Company)
RNA	ARN

 

Indice de contenidos electrónico (IDCe)

 

Prefacio sobre fisiología, medicina, genómica y terapéutica

Larry H Bernstein, MD, FCAP

 

Capítulo 1:        Evolución de los fundamentos de las industrias de pruebas diagnósticas y productos farmacéuticos

 

Introducción

 

1.1     Resumen de los descubrimientos médicos realizados entre 1880 y 1980

https://pharmaceuticalintelligence.com/2014/12/03/outline-of-medical-discoveries-between-1880-and-1980/

Larry H Bernstein, MD, FCAP

 

1.2     La historia de las enfermedades infecciosas y la epidemiología a finales del siglo XIX y en el siglo XX

http://pharmaceuticalintelligence.com/2014/12/09/the-history-of-infectious-diseases-and-epidemiology-in-the-late-19th-and-20th-century/

Larry H Bernstein, MD, FCAP

 

1.3     La clasificación de la microbiota

http://pharmaceuticalintelligence.com/2015/01/17/an-overview-of-clinical-microbiology-classification-and-antimicrobial-resistance/

Larry H Bernstein, MD, FCAP

 

1.4     Principales aportaciones a la química entre 1880 y 1980

http://pharmaceuticalintelligence.com/2014/12/03/selected-contributions-to-chemistry-from-1880-to-1980/

Larry H Bernstein, MD, FCAP

 

1.5     La evolución de la química clínica en el siglo XX

http://pharmaceuticalintelligence.com/2014/12/13/the-evolution-of-clinical-chemistry-in-the-20th-century/

Larry H Bernstein, MD, FCAP

 

1.6     Hitos en la evolución de las pruebas diagnósticas en el sistema sanitario estadounidense: desde los años 20 hasta la pregenómica

http://pharmaceuticalintelligence.com/2014/11/16/milestones-in-the-evolution-of-diagnostics-in-the-us-healthcare-system-1920s-to-pre-genomics/

Larry H Bernstein, MD, FCAP

 

Resumen

 

Capítulo 2:        La búsqueda de la evolución de la función de las proteínas, las enzimas y los catalizadores metálicos en los procesos vitales

 

Introducción

 

2.1     La vida y obra de Allan Wilson

http://pharmaceuticalintelligence.com/2015/01/20/the-life-and-work-of-allan-wilson/

Larry H Bernstein, MD, FCAP

 

2.2     La evolución de la mioglobina y la hemoglobina

http://pharmaceuticalintelligence.com/2015/01/19/life-on-earth-is-traced-to-oxygen-binding/

Larry H Bernstein, MD, FCAP

 

2.3     Más complejidad en la evolución de las proteínas

http://pharmaceuticalintelligence.com/2015/01/18/more-complexity-in-protein-evolution/

Larry H Bernstein, MD, FCAP

 

2.4     La vida en la Tierra tiene su origen en la fijación del oxígeno

http://pharmaceuticalintelligence.com/2015/01/19/life-on-earth-is-traced-to-oxygen-binding/

Larry H Bernstein, MD, FCAP

 

2.5     La función de los colores de la vida

http://pharmaceuticalintelligence.com/2015/01/20/the-colors-of-life-function/

Larry H Bernstein, MD, FCAP

 

2.6     Los colores de la respiración y el transporte de electrones

http://pharmaceuticalintelligence.com/2015/01/20/the-colors-of-respiration-and-electron-transport/

Larry H Bernstein, MD, FCAP

 

2.7     Aspectos destacados de una evolución verde

http://pharmaceuticalintelligence.com/2015/01/21/highlights-of-a-green-evolution/

Larry H Bernstein, MD, FCAP

 

Resumen

 

 

Capítulo 3:        Evolución de las nuevas relaciones en los estados neuroendocrinos

 

Introducción

 

3.1     Eje neuroendocrino hipofisario

http://pharmaceuticalintelligence.com/2015/02/04/pituitary-neuroendocrine-axis/

Larry H Bernstein, MD, FCAP

 

3.2     Función tiroidea

http://pharmaceuticalintelligence.com/2015/02/05/thyroid-function-and-disorders/

Larry H Bernstein, MD, FCAP

 

3.3     Hormonas sexuales

http://pharmaceuticalintelligence.com/2015/02/07/sex-hormones/

Larry H Bernstein, MD, FCAP

 

3.4     Corteza suprarrenal

http://pharmaceuticalintelligence.com/2015/02/07/adrenal-cortex/

Larry H Bernstein, MD, FCAP

 

3.5     Islotes pancreáticos

http://pharmaceuticalintelligence.com/2015/02/08/pancreatic-islets/

Larry H Bernstein, MD, FCAP

 

3.6     Las paratiroides y el metabolismo óseo

http://pharmaceuticalintelligence.com/2015/02/10/parathyroids-and-bone-metabolism/

Larry H Bernstein, MD, FCAP

 

3.7     Hormonas gastrointestinales

http://pharmaceuticalintelligence.com/2015/02/10/gastrointestinal-endocrinology/

Larry H Bernstein, MD, FCAP

 

3.8     Acción endocrina en el mesencéfalo

http://pharmaceuticalintelligence.com/2015/02/12/endocrine-action-on-midbrain/

Larry H Bernstein, MD, FCAP

 

3.9     Actividad neuronal que regula la respuesta endocrina

http://pharmaceuticalintelligence.com/2015/02/13/neural-activity-regulating-endocrine-response/

Larry H Bernstein, MD, FCAP

 

3.10   Promesa genómica para las enfermedades neurodegenerativas, las demencias, el espectro autista, la esquizofrenia y la depresión grave

http://pharmaceuticalintelligence.com/2013/02/19/genomic-promise-for-neurodegenerative-diseases-dementias-autism-spectrum-schizophrenia-and-serious-depression/

Larry H Bernstein, MD, FCAP

 

Resumen

 

Capítulo 4:        Problemas de la circulación, la altitud y la inmunidad

 

Introducción

 

4.1     Inervación del corazón y frecuencia cardíaca

http://pharmaceuticalintelligence.com/2015/02/15/innervation-of-heart-and-heart-rate/

Larry H Bernstein, MD, FCAP

 

4.2     Acción de las hormonas sobre la circulación

http://pharmaceuticalintelligence.com/2015/02/17/action-of-hormones-on-the-circulation/

Larry H Bernstein, MD, FCAP

 

4.3     Reacciones a las transfusiones alogénicas

http://pharmaceuticalintelligence.com/2015/02/18/allogeneic-transfusion-reactions/

Larry H Bernstein, MD, FCAP

 

4.4     La reacción de “injerto contra el hospedador”

http://pharmaceuticalintelligence.com/2015/02/19/graft-versus-host-disease/

Larry H Bernstein, MD, FCAP

 

4.5     Problemas únicos del periodo perinatal

http://pharmaceuticalintelligence.com/2015/02/22/neonatal-pathophysiology/

Larry H Bernstein, MD, FCAP

 

4.6     Mal de altura

http://pharmaceuticalintelligence.com/2015/02/24/altitude-adaptation/

Larry H Bernstein, MD, FCAP

 

4.7     Adaptación a las aguas profundas

http://pharmaceuticalintelligence.com/2015/02/24/depth-underwater-and-underground/

Larry H Bernstein, MD, FCAP

 

4.8     Corazón-pulmón-riñón

http://pharmaceuticalintelligence.com/2015/02/27/heart-lung-kidney-essential-ties/

Larry H Bernstein, MD, FCAP

 

4.9     Lesión pulmonar aguda

http://pharmaceuticalintelligence.com/2015/02/26/acute-lung-injury/

Larry H Bernstein, MD, FCAP

 

4.10   La reconstrucción de los procesos vitales requiere tanto la genómica como la metabolómica para explicar los fenotipos y la filogenética

http://pharmaceuticalintelligence.com/2015/02/25/the-reconstruction-of-life-processes-requires-both-genomics-and-metabolomics-to-explain-phenotypes-and-phylogenetics/

Larry H Bernstein, MD, FCAP

 

Capítulo 5:        Problemas de las dietas y los cambios del estilo de vida

 

Introducción

 

5.1     Anorexia nerviosa

http://pharmaceuticalintelligence.com/2015/02/28/anorexia-nervosa-and-related-eating-disorders/

Larry H Bernstein, MD, FCAP

 

5.2     Insuficiencia de S voluntaria e involuntaria

http://pharmaceuticalintelligence.com/2015/03/07/transthyretin-and-the-stressful-condition/

Larry H Bernstein, MD, FCAP

 

5.3     Diarreas bacterianas y no bacterianas

http://pharmaceuticalintelligence.com/2015/03/01/diarrheas-bacterial-and-nonbacterial/

Larry H Bernstein, MD, FCAP

 

5.4     Dietas sin gluten

http://pharmaceuticalintelligence.com/2015/03/01/gluten-free-diets/

Larry H Bernstein, MD, FCAP

 

5.5     La dieta y el colesterol

http://pharmaceuticalintelligence.com/2015/03/02/diet-and-cholesterol/

Larry H Bernstein, MD, FCAP

 

5.6     La dieta y la diabetes mellitus de tipo 2

http://pharmaceuticalintelligence.com/2015/03/02/diet-and-diabetes/

Larry H Bernstein, MD, FCAP

 

5.7     La dieta y el ejercicio

http://pharmaceuticalintelligence.com/2015/03/04/diet-and-exercise/

Larry H Bernstein, MD, FCAP

 

5.8     La ansiedad y la calidad de vida

http://pharmaceuticalintelligence.com/2015/03/04/stress-and-anxiety/

Larry H Bernstein, MD, FCAP

 

5.9     Suplementos nutricionales

http://pharmaceuticalintelligence.com/2015/03/04/neutraceuticals/

Larry H Bernstein, MD, FCAP

 

Resumen

 

 

Capítulo 6:        Avances en genómica, terapéutica y farmacogenómica

 

Introducción

 

6.1     Química de los productos naturales

http://pharmaceuticalintelligence.com/2015/01/27/natural-products-chemistry/

Larry H Bernstein, MD, FCAP

 

6.2     El reto de la resistencia a los antimicrobianos

http://pharmaceuticalintelligence.com/2015/01/28/the-challenge-of-antimicrobial-resistance/

Larry H Bernstein, MD, FCAP

 

6.3     Virus, vacunas e inmunoterapia

http://pharmaceuticalintelligence.com/2015/01/30/viruses-vaccines-and-immunotherapy/

Larry H Bernstein, MD, FCAP

 

6.4     Avances de la genómica y la metabolómica en el cáncer

http://pharmaceuticalintelligence.com/2015/01/30/genomics-and-metabolomics-of-cancer/

Larry H Bernstein, MD, FCAP

 

6.5     Proteómica: interacción de las proteínas

http://pharmaceuticalintelligence.com/2015/01/31/proteomics/

Larry H Bernstein, MD, FCAP

 

6.6     Farmacogenómica

http://pharmaceuticalintelligence.com/2015/01/31/pharmacogenomics/

Larry H Bernstein, MD, FCAP

 

6.7     Terapia guiada por biomarcadores

http://pharmaceuticalintelligence.com/2015/02/01/biomarker-guided-therapy/

Larry H Bernstein, MD, FCAP

 

6.8     La aparición de la industria farmacéutica en el siglo XX. La industria de las pruebas diagnósticas y el desarrollo de medicamentos en la era de la genómica: de mediados de los 80 a la actualidad

http://pharmaceuticalintelligence.com/2014/11/21/diagnostics-industry-and-drug-development-in-the-genomics-era-mid-80s-to-present/

Larry H Bernstein, MD, FCAP

 

6.9     La unión de los biomarcadores con el desarrollo de medicamentos

http://pharmaceuticalintelligence.com/2014/12/24/the-union-of-biomarkers-and-drug-development/ 

Larry H Bernstein, MD, FCAP

 

6.10   Proteómica y descubrimiento de biomarcadores

http://pharmaceuticalintelligence.com/2012/08/21/proteomics-and-biomarker-discovery/

Larry H Bernstein, MD, FCAP

 

6.11   Epigenómica y pruebas diagnósticas complementarias

http://pharmaceuticalintelligence.com/2013/12/07/epigenomics-and-companion-diagnostics/

Larry H Bernstein, MD, FCAP

 

Resumen

 

 

Capítulo 7:        Integración de la fisiología, la genómica y la farmacoterapia

 

Introducción

 

7.1     Dr. Richard Lifton, doctorado por la Universidad de Yale y el Instituto Médico Howard Hughes: galardonado en los Premios Breakthrough 2014 en Ciencias de la Vida por el descubrimiento de los genes y mecanismos bioquímicos que causan la hipertensión

http://pharmaceuticalintelligence.com/2014/03/03/richard-lifton-md-phd-of-yale-university-and-howard-hughes-medical-institute-recipient-of-2014-breakthrough-prizes-awarded-in-life-sciences-for-the-discovery-of-genes-and-biochemical-mechanisms-tha/

Aviva Lev-Ari, PhD, RN

 

7.2     El ciclo del calcio (bomba ATPasa) en la terapia génica cardíaca: terapia génica inhalable para la hipertensión arterial pulmonar e infusión intracoronaria percutánea para la insuficiencia cardíaca. Las aportaciones del Dr. Roger J. Hajjar

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

Aviva Lev-Ari, PhD, RN

 

7.3     Diagnóstico y biomarcadores: nuevas tendencias de la industria de la genómica frente a las condiciones actuales del mercado y un nuevo programa informático de soporte clínico por expertos en tiempo real, Historical Scientific Leaders Memoirs

http://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems/

Aviva Lev-Ari, PhD, RN

 

7.4     Biología sintética: sobre la interpretación avanzada del genoma de las variantes y las vías genéticas. ¿Cuál es la base genética de la aterosclerosis y la pérdida de la elasticidad arterial con el envejecimiento?

http://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Aviva Lev-Ari, PhD, RN

 

7.5     Diagnóstico de enfermedades y terapia génica: edición genómica de precisión y elaboración de perfiles rentables de microARN

http://pharmaceuticalintelligence.com/2013/03/28/diagnosing-diseases-gene-therapy-precision-genome-editing-and-cost-effective-microrna-profiling/

Aviva Lev-Ari, PhD, RN

 

7.6     Biomarcadores por imagen de la rigidez arterial: métodos farmacoterapéuticos de control de la hipertensión y la hipercolesterolemia

http://pharmaceuticalintelligence.com/2013/05/24/imaging-biomarker-for-arterial-stiffness-pathways-in-pharmacotherapy-for-hypertension-and-hypercholesterolemia-management/

Aviva Lev-Ari, PhD, RN

 

7.7     Tratamientos neuroprotectores: farmacogenómica frente a psicofármacos e inhibidores de la colinesterasa

http://pharmaceuticalintelligence.com/2012/11/23/neuroprotective-therapies-pharmacogenomics-vs-psychotropic-drugs-and-cholinesterase-inhibitors/

Aviva Lev-Ari, PhD, RN

 

7.8     Identificación de metabolitos combinando información genética y metabólica: la asociación genética vincula los metabolitos desconocidos con genes funcionalmente relacionados

http://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic-information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/

Aviva Lev-Ari, PhD, RN

 

7.9     Fracción de expulsión conservada comparada con la reducida: tratamientos disponibles y necesarios

http://pharmaceuticalintelligence.com/2014/02/03/preserved-vs-reduced-ejection-fraction-available-and-needed-therapies/

Aviva Lev-Ari, PhD, RN

 

7.10   Biosimilares: creación y protección de la propiedad intelectual por parte del descubridor y de los fabricantes de biosimilares

http://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

Aviva Lev-Ari, PhD, RN

 

7.11   Demostrar la biosimilitud: nuevas directrices sobre biosimilares de la FDA

http://pharmaceuticalintelligence.com/2012/12/13/demonstrate-biosimilarity-new-fda-biosimilar-guidelines/

Aviva Lev-Ari, PhD, RN

 

Resumen

 

 

Capítulo 8:        La industria biofarmacéutica actual

 

Introducción

 

8.1     Una gran universidad dedicada al descubrimiento de fármacos: la Universidad de Pittsburgh

http://pharmaceuticalintelligence.com/2014/07/15/a-great-university-engaged-in-drug-discovery/

Larry H Bernstein, MD, FCAP

 

8.2     Introducción. La evolución del tratamiento del cáncer y de la investigación del cáncer: ¿cómo hemos llegado hasta aquí?

http://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research-how-we-got-here/

Larry H Bernstein, MD, FCAP

 

8.3     Predicción de la respuesta tumoral, la progresión y el tiempo hasta la recidiva

http://pharmaceuticalintelligence.com/2012/12/20/predicting-tumor-response-progression-and-time-to-recurrence/

Larry H Bernstein, MD, FCAP

 

8.4     Uso como diana de protooncogenes no utilizables como diana terapéutica

http://pharmaceuticalintelligence.com/2013/11/01/targeting-untargetable-proto-oncogenes/

Larry H Bernstein, MD, FCAP

 

8.5     Innovación: descubrimiento de fármacos, dispositivos médicos y salud digital

http://pharmaceuticalintelligence.com/2013/10/15/innovation/

Larry H Bernstein, MD, FCAP

 

8.6     Cardiotoxicidad y miocardiopatía por efectos adversos de medicamentos

http://pharmaceuticalintelligence.com/2013/04/11/cardiotoxicity-and-cardiomyopathy-related-to-drugs-adverse-effects/

Larry H Bernstein, MD, FCAP

 

8.7     Nanotecnología y administración ocular de fármacos: Parte I

http://pharmaceuticalintelligence.com/2013/02/23/nanotechnology-and-ocular-drug-delivery-part-i/

Tilda Barliya, PhD

 

8.8     Sistema de administración transdérmica de fármacos (TDD) y nanotecnología: Parte II

http://pharmaceuticalintelligence.com/2013/02/04/transdermal-drug-delivery-tdd-system-and-nanotechnology-part-ii/

Tilda Barliya, PhD

 

8.9     La delicada conexión entre la IDO (indolamina 2,3-deshidrogenasa) y la inmunooncología

http://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-immunology/

Demet Sag, PhD

 

8.10   Descubrimiento de dianas farmacológicas naturales y medicina aplicable en el microbioma humano

http://pharmaceuticalintelligence.com/2014/03/23/natural-drug-target-discovery-and-translational-medicine-in-human-microbiome/

Demet Sag, PhD

 

8.11   De la genómica de los microorganismos a la medicina aplicable

http://pharmaceuticalintelligence.com/2014/03/20/without-the-past-no-future-but-learn-and-move-genomics-of-microorganisms-to-translational-medicine/

Demet Sag, PhD

 

8.12   La indolamina 2,3-dioxigenasa (IDO) confinada controla la hemostasia de las respuestas inmunitarias, para bien y para mal

http://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis-of-immune-responses-for-good-and-bad/

Demet Sag, PhD

 

Resumen

 

 

Capítulo 9:        Tendencias futuras de la industria biofarmacéutica

 

Introducción

 

9.1     La inteligencia artificial frente al científico: ¿quién ganará?

http://pharmaceuticalintelligence.com/2015/03/02/artificial-intelligence-versus-the-scientisitwho-will-win/

Stephen J Williams, PhD

 

9.2     La vibrante escena biotecnológica de Filadelfia: poniendo el foco sobre KannaLife Sciences y la disciplina y el potencial de la farmacognosia

http://pharmaceuticalintelligence.com/2015/02/19/the-vibrant-philly-biotech-scene-focus-on-kannalife-sciences-and-the-discipline-and-potential-of-pharmacognosy/

Stephen J Williams, PhD

 

9.3     La vibrante escena biotecnológica de Filadelfia: poniendo el foco sobre el diseño de fármacos asistido por ordenador y Gfree Bio, LLC

http://pharmaceuticalintelligence.com/2015/02/10/the-vibrant-philly-biotech-scene-focus-on-computer-aided-drug-design-and-gfree-bio-llc/

Stephen J Williams, PhD

 

9.4     Héroes de la investigación médica: el becario postdoctoral

http://pharmaceuticalintelligence.com/2014/10/30/heroes-in-medical-research-the-postdoctoral-fellow/

Stephen J Williams, PhD

 

9.5     Los NIH estudian las directrices de tratamiento con CAR-T: informe del Comité Consultivo sobre el ADN recombinante

http://pharmaceuticalintelligence.com/2014/09/23/nih-considers-guidelines-for-car-t-therapy-report-from-recombinant-dna-advisory-committee/

Stephen J Williams, PhD

 

9.6     1st Pitch Life Science- Philadelphia. Esto es lo que los inversores piensan sobre su presentación

http://pharmaceuticalintelligence.com/2014/09/17/1st-pitch-life-science-philadelphia-what-vcs-really-think-of-your-pitch/

Stephen J Williams, PhD

 

9.7     Múltiples proyectos genómicos sobre el cáncer de pulmón sugieren nuevas dianas; orientación de la investigación para el cáncer de pulmón no microcítico

http://pharmaceuticalintelligence.com/2014/09/05/multiple-lung-cancer-genomic-projects-suggest-new-targets-research-directions-for-non-small-cell-lung-cancer/

Stephen J Williams, PhD

 

9.8     Héroes de la investigación médica: la proteína verde fluorescente y el duro camino de la ciencia

http://pharmaceuticalintelligence.com/2014/07/27/heroes-in-medical-research-green-fluorescent-protein-and-the-rough-road-in-science/

Stephen J Williams, PhD

 

9.9     Aspectos de la medicina personalizada en el cáncer: heterogeneidad intratumoral y evolución ramificada revelada por la secuenciación multirregional

http://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

Stephen J Williams, PhD

 

9.10   El cerdo SCID II: los investigadores desarrollan otro cerdo SCID y otro gran modelo para la investigación del cáncer

http://pharmaceuticalintelligence.com/2014/06/11/the-scid-pig-ii-researchers-develop-another-scid-pig-and-another-great-model-for-cancer-research/

Stephen J Williams, PhD

 

Resumen

 

Epílogo

Larry H Bernstein, MD, FCAP

 

TERCER VOLUMEN

Hitos de la fisiología
Descubrimientos en medicina, genómica y terapéutica: Perspectiva centrada en el paciente

 

2015

Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective 

Disponible en Amazon.com desde el 27/12/2015

http://www.amazon.com/dp/B019VH97LU

 

PART B:

The eTOCs in Bi-lingual format: Spanish and English in Text format

 

Serie E: Medicina centrada en el paciente

 

TERCER VOLUMEN

Hitos de la fisiología
Descubrimientos en medicina, genómica y terapéutica: Perspectiva centrada en el paciente

 

2015

Traducción a español

Montero Language Services

Disponible en Amazon.com desde el 27/12/2015

http://www.amazon.com/dp/B019VH97LU

 

Autor, redactor y editor

Larry H Bernstein, MD, FCAP

Director científico

Leaders in Pharmaceutical Business Intelligence

Larry.bernstein@gmail.com

 

Fuente de la imagen: Adaptado de Google Images

 

Aviva Lev-Ari, PhD, RN

Redactora jefe de la serie de libros electrónicos BioMed

Leaders in Pharmaceutical Business Intelligence, Boston

avivalev-ari@alum.berkeley.edu

 

Series E: Patient-centered Medicine

 

VOLUME THREE

Milestones in Physiology Discoveries in Medicine, Genomics and Therapeutics: Patient-centric Perspective

 

2015

 

Available on Amazon.com since 12/27/2015

http://www.amazon.com/dp/B019VH97LU

 

Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Chief Scientific Officer

Leaders in Pharmaceutical Business Intelligence

Larry.bernstein@gmail.com

 

 

Image Source: Adapted from Google Images

 

Aviva Lev-Ari, PhD, RN

Editor-in-Chief BioMed e-Series of e-Books

Leaders in Pharmaceutical Business Intelligence, Boston

avivalev-ari@alum.berkeley.edu

 

 

 

Lista de colaboradores y sus biografías

List of Contributors & Contributors’ Biographies

 

Autor del volumen, redactor y editor

Volume Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Autores invitados:

Guest Authors:

Stephen J Williams, PhD: 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 9.10

Aviva Lev-Ari, PhD, RN: 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 7.9, 7.10, 7.11

Tilda Barliya, PhD: 8.7, 8.8

Demet Sag, PhD: 8.9, 8.10, 8.11, 8.12

 

 

Los enlaces indicados llevan al contenido original en inglés

MD	Licenciado/a en medicina y cirugía (Estados Unidos)
PhD	Doctorado/a
RN	Enfermero/a titulado/a (National Board of Nursing Registration)
FCAP	Miembro distinguido (Fellow) del Colegio de Anatomopatólogos de los Estados Unidos
FDA	Food and Drug Administration (Administración de Alimentos y Medicamentos de los Estados Unidos)
IDO	Indolamina 2,3-dioxigenasa
TDD	Sistema de administración transdérmica de fármacos
LLC	Compañía de responsabilidad limitada (Limited Liability Company)
RNA	ARN

 

Indice de contenidos electrónico (IDCe)

electronic Table of Contents

 

Prefacio sobre fisiología, medicina, genómica y terapéutica

Preface on Physiology, Medicine, Genomics and Therapeutics

Larry H Bernstein, MD, FCAP

 

Capítulo 1:        Evolución de los fundamentos de las industrias de pruebas diagnósticas y productos farmacéuticos

Chapter 1:         Evolution of the Foundation for Diagnostics and Pharmaceuticals Industries

Introducción

Introduction

 

1.1     Resumen de los descubrimientos médicos realizados entre 1880 y 1980

1.1     Outline of Medical Discoveries between 1880 and 1980

https://pharmaceuticalintelligence.com/2014/12/03/outline-of-medical-discoveries-between-1880-and-1980/

Larry H Bernstein, MD, FCAP

 

1.2     La historia de las enfermedades infecciosas y la epidemiología a finales del siglo XIX y en el siglo XX

1.2     The History of Infectious Diseases and Epidemiology in the Late 19th and 20th Century

http://pharmaceuticalintelligence.com/2014/12/09/the-history-of-infectious-diseases-and-epidemiology-in-the-late-19th-and-20th-century/

Larry H Bernstein, MD, FCAP

 

1.3     La clasificación de la microbiota

1.3     The Classification of Microbiota

http://pharmaceuticalintelligence.com/2015/01/17/an-overview-of-clinical-microbiology-classification-and-antimicrobial-resistance/

Larry H Bernstein, MD, FCAP

 

1.4     Principales aportaciones a la química entre 1880 y 1980

1.4     Selected Contributions to Chemistry from 1880 to 1980

http://pharmaceuticalintelligence.com/2014/12/03/selected-contributions-to-chemistry-from-1880-to-1980/

Larry H Bernstein, MD, FCAP

 

1.5     La evolución de la química clínica en el siglo XX

1.5     The Evolution of Clinical Chemistry in the 20th Century

http://pharmaceuticalintelligence.com/2014/12/13/the-evolution-of-clinical-chemistry-in-the-20th-century/

Larry H Bernstein, MD, FCAP

 

1.6     Hitos en la evolución de las pruebas diagnósticas en el sistema sanitario estadounidense: desde los años 20 hasta la pregenómica

1.6     Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics

http://pharmaceuticalintelligence.com/2014/11/16/milestones-in-the-evolution-of-diagnostics-in-the-us-healthcare-system-1920s-to-pre-genomics/

Larry H Bernstein, MD, FCAP

 

Resumen

Summary

 

Capítulo 2:        La búsqueda de la evolución de la función de las proteínas, las enzimas y los catalizadores metálicos en los procesos vitales

Chapter 2:         The Search for the Evolution of Function of Proteins, Enzymes and Metal Catalysts in Life Processes

 

Introducción

Introduction

 

2.1     La vida y obra de Allan Wilson

2.1     The Life and Work of Allan Wilson

http://pharmaceuticalintelligence.com/2015/01/20/the-life-and-work-of-allan-wilson/

Larry H Bernstein, MD, FCAP

 

2.2     La evolución de la mioglobina y la hemoglobina

2.2     The Evolution of Myoglobin and Hemoglobin

http://pharmaceuticalintelligence.com/2015/01/19/life-on-earth-is-traced-to-oxygen-binding/

Larry H Bernstein, MD, FCAP

 

2.3     Más complejidad en la evolución de las proteínas

2.3     More Complexity in Proteins Evolution

http://pharmaceuticalintelligence.com/2015/01/18/more-complexity-in-protein-evolution/

Larry H Bernstein, MD, FCAP

 

2.4     La vida en la Tierra tiene su origen en la fijación del oxígeno

2.4     Life on Earth is Traced to Oxygen Binding

http://pharmaceuticalintelligence.com/2015/01/19/life-on-earth-is-traced-to-oxygen-binding/

Larry H Bernstein, MD, FCAP

 

2.5     La función de los colores de la vida

2.5     The Colors of Life Function

http://pharmaceuticalintelligence.com/2015/01/20/the-colors-of-life-function/

Larry H Bernstein, MD, FCAP

 

2.6     Los colores de la respiración y el transporte de electrones

2.6     The Colors of Respiration and Electron Transport

http://pharmaceuticalintelligence.com/2015/01/20/the-colors-of-respiration-and-electron-transport/

Larry H Bernstein, MD, FCAP

 

2.7     Aspectos destacados de una evolución verde

2.7     Highlights of a Green Evolution

http://pharmaceuticalintelligence.com/2015/01/21/highlights-of-a-green-evolution/

Larry H Bernstein, MD, FCAP

 

Resumen

Summary

 

Capítulo 3:        Evolución de las nuevas relaciones en los estados neuroendocrinos

Chapter 3:         Evolution of New Relationships in Neuroendocrine States

 

Introducción

Introduction

 

3.1     Eje neuroendocrino hipofisario

3.1     Pituitary endocrine axis

http://pharmaceuticalintelligence.com/2015/02/04/pituitary-neuroendocrine-axis/

Larry H Bernstein, MD, FCAP

 

3.2     Función tiroidea

3.2     Thyroid Function

http://pharmaceuticalintelligence.com/2015/02/05/thyroid-function-and-disorders/

Larry H Bernstein, MD, FCAP

 

3.3     Hormonas sexuales

3.3     Sex Hormones

http://pharmaceuticalintelligence.com/2015/02/07/sex-hormones/

Larry H Bernstein, MD, FCAP

 

3.4     Corteza suprarrenal

3.4     Adrenal Cortex

http://pharmaceuticalintelligence.com/2015/02/07/adrenal-cortex/

Larry H Bernstein, MD, FCAP

 

3.5     Islotes pancreáticos

3.5     Pancreatic Islets

http://pharmaceuticalintelligence.com/2015/02/08/pancreatic-islets/

Larry H Bernstein, MD, FCAP

 

3.6     Las paratiroides y el metabolismo óseo

3.6     Parathyroids and Bone Metabolism

http://pharmaceuticalintelligence.com/2015/02/10/parathyroids-and-bone-metabolism/

Larry H Bernstein, MD, FCAP

 

3.7     Hormonas gastrointestinales

3.7     Gastointestinal Hormones

http://pharmaceuticalintelligence.com/2015/02/10/gastrointestinal-endocrinology/

Larry H Bernstein, MD, FCAP

 

3.8     Acción endocrina en el mesencéfalo

3.8     Endocrine Action on Midbrain

http://pharmaceuticalintelligence.com/2015/02/12/endocrine-action-on-midbrain/

Larry H Bernstein, MD, FCAP

 

3.9     Actividad neuronal que regula la respuesta endocrina

3.9     Neural Activity regulating Endocrine Response

http://pharmaceuticalintelligence.com/2015/02/13/neural-activity-regulating-endocrine-response/

Larry H Bernstein, MD, FCAP

 

3.10   Promesa genómica para las enfermedades neurodegenerativas, las demencias, el espectro autista, la esquizofrenia y la depresión grave

3.10   Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

http://pharmaceuticalintelligence.com/2013/02/19/genomic-promise-for-neurodegenerative-diseases-dementias-autism-spectrum-schizophrenia-and-serious-depression/

Larry H Bernstein, MD, FCAP

 

Resumen

Summary

 

Capítulo 4:        Problemas de la circulación, la altitud y la inmunidad

Chapter 4:         Problems of the Circulation, Altitude, and Immunity

 

Introducción

Introduction

 

4.1     Inervación del corazón y frecuencia cardíaca

4.1     Innervation of Heart and Heart Rate

http://pharmaceuticalintelligence.com/2015/02/15/innervation-of-heart-and-heart-rate/

Larry H Bernstein, MD, FCAP

 

4.2     Acción de las hormonas sobre la circulación

4.2     Action of Hormones on the Circulation

http://pharmaceuticalintelligence.com/2015/02/17/action-of-hormones-on-the-circulation/

Larry H Bernstein, MD, FCAP

 

4.3     Reacciones a las transfusiones alogénicas

4.3     Allogeneic Transfusion Reactions

http://pharmaceuticalintelligence.com/2015/02/18/allogeneic-transfusion-reactions/

Larry H Bernstein, MD, FCAP

 

4.4     La reacción de “injerto contra el hospedador”

4.4     Graft-versus Host reaction

http://pharmaceuticalintelligence.com/2015/02/19/graft-versus-host-disease/

Larry H Bernstein, MD, FCAP

 

4.5     Problemas únicos del periodo perinatal

4.5     Unique Problems of Perinatal Period

http://pharmaceuticalintelligence.com/2015/02/22/neonatal-pathophysiology/

Larry H Bernstein, MD, FCAP

 

4.6     Mal de altura

4.6     High Altitude Sickness

http://pharmaceuticalintelligence.com/2015/02/24/altitude-adaptation/

Larry H Bernstein, MD, FCAP

 

4.7     Adaptación a las aguas profundas

4.7     Deep Water Adaptation

http://pharmaceuticalintelligence.com/2015/02/24/depth-underwater-and-underground/

Larry H Bernstein, MD, FCAP

 

4.8     Corazón-pulmón-riñón

4.8     Heart-Lung-and Kidney

http://pharmaceuticalintelligence.com/2015/02/27/heart-lung-kidney-essential-ties/

Larry H Bernstein, MD, FCAP

 

4.9     Lesión pulmonar aguda

4.9     Acute Lung Injury

http://pharmaceuticalintelligence.com/2015/02/26/acute-lung-injury/

Larry H Bernstein, MD, FCAP

 

4.10   La reconstrucción de los procesos vitales requiere tanto la genómica como la metabolómica para explicar los fenotipos y la filogenética

4.10   Reconstruction of Life Processes requires both Genomics and Metabolomics to explain Phenotypes and Phylogenetics

http://pharmaceuticalintelligence.com/2015/02/25/the-reconstruction-of-life-processes-requires-both-genomics-and-metabolomics-to-explain-phenotypes-and-phylogenetics/

Larry H Bernstein, MD, FCAP

 

Capítulo 5:        Problemas de las dietas y los cambios del estilo de vida

Chapter 5:         Problems of Diets and Lifestyle Changes

 

Introducción

Introduction

 

5.1     Anorexia nerviosa

5.1     Anorexia nervosa

http://pharmaceuticalintelligence.com/2015/02/28/anorexia-nervosa-and-related-eating-disorders/

Larry H Bernstein, MD, FCAP

 

5.2     Insuficiencia de S voluntaria e involuntaria

5.2     Voluntary and Involuntary S-insufficiency

http://pharmaceuticalintelligence.com/2015/03/07/transthyretin-and-the-stressful-condition/

Larry H Bernstein, MD, FCAP

 

5.3     Diarreas bacterianas y no bacterianas

5.3     Diarrheas – bacterial and nonbacterial

http://pharmaceuticalintelligence.com/2015/03/01/diarrheas-bacterial-and-nonbacterial/

Larry H Bernstein, MD, FCAP

 

5.4     Dietas sin gluten

5.4     Gluten-free Diets

http://pharmaceuticalintelligence.com/2015/03/01/gluten-free-diets/

Larry H Bernstein, MD, FCAP

 

5.5     La dieta y el colesterol

5.5     Diet and Cholesterol

http://pharmaceuticalintelligence.com/2015/03/02/diet-and-cholesterol/

Larry H Bernstein, MD, FCAP

 

5.6     La dieta y la diabetes mellitus de tipo 2

5.6     Diet and Type 2 Diabetes Mellitus

http://pharmaceuticalintelligence.com/2015/03/02/diet-and-diabetes/

Larry H Bernstein, MD, FCAP

 

5.7     La dieta y el ejercicio

5.7     Diet and Exercise

http://pharmaceuticalintelligence.com/2015/03/04/diet-and-exercise/

Larry H Bernstein, MD, FCAP

 

5.8     La ansiedad y la calidad de vida

5.8     Anxiety and Quality of Life

http://pharmaceuticalintelligence.com/2015/03/04/stress-and-anxiety/

Larry H Bernstein, MD, FCAP

 

5.9     Suplementos nutricionales

5.9     Nutritional Supplements

http://pharmaceuticalintelligence.com/2015/03/04/neutraceuticals/

Larry H Bernstein, MD, FCAP

 

Resumen

Summary

 

Capítulo 6:        Avances en genómica, terapéutica y farmacogenómica

Chapter 6:         Advances in Genomics, Therapeutics and Pharmacogenomics

 

Introducción

Introduction

 

6.1     Química de los productos naturales

6.1     Natural Products Chemistry

http://pharmaceuticalintelligence.com/2015/01/27/natural-products-chemistry/

Larry H Bernstein, MD, FCAP

 

6.2     El reto de la resistencia a los antimicrobianos

6.2     The Challenge of Antimicrobial Resistance

http://pharmaceuticalintelligence.com/2015/01/28/the-challenge-of-antimicrobial-resistance/

Larry H Bernstein, MD, FCAP

 

6.3     Virus, vacunas e inmunoterapia

6.3     Viruses, Vaccines and Immunotherapy

http://pharmaceuticalintelligence.com/2015/01/30/viruses-vaccines-and-immunotherapy/

Larry H Bernstein, MD, FCAP

 

6.4     Avances de la genómica y la metabolómica en el cáncer

6.4     Genomics and Metabolomics Advances in Cancer

http://pharmaceuticalintelligence.com/2015/01/30/genomics-and-metabolomics-of-cancer/

Larry H Bernstein, MD, FCAP

 

6.5     Proteómica: interacción de las proteínas

6.5     Proteomics – Protein Interaction

http://pharmaceuticalintelligence.com/2015/01/31/proteomics/

Larry H Bernstein, MD, FCAP

 

6.6     Farmacogenómica

6.6     Pharmacogenomics

http://pharmaceuticalintelligence.com/2015/01/31/pharmacogenomics/

Larry H Bernstein, MD, FCAP

 

6.7     Terapia guiada por biomarcadores

6.7     Biomarker Guided Therapy

http://pharmaceuticalintelligence.com/2015/02/01/biomarker-guided-therapy/

Larry H Bernstein, MD, FCAP

 

6.8     La aparición de la industria farmacéutica en el siglo XX. La industria de las pruebas diagnósticas y el desarrollo de medicamentos en la era de la genómica: de mediados de los 80 a la actualidad

6.8     The Emergence of a Pharmaceutical Industry in the 20th Century: Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present

http://pharmaceuticalintelligence.com/2014/11/21/diagnostics-industry-and-drug-development-in-the-genomics-era-mid-80s-to-present/

Larry H Bernstein, MD, FCAP

 

6.9     La unión de los biomarcadores con el desarrollo de medicamentos

6.9     The Union of Biomarkers and Drug Development

http://pharmaceuticalintelligence.com/2014/12/24/the-union-of-biomarkers-and-drug-development/ 

Larry H Bernstein, MD, FCAP

 

6.10   Proteómica y descubrimiento de biomarcadores

6.10   Proteomics and Biomarker Discovery

http://pharmaceuticalintelligence.com/2012/08/21/proteomics-and-biomarker-discovery/

Larry H Bernstein, MD, FCAP

 

6.11   Epigenómica y pruebas diagnósticas complementarias

6.11   Epigenomics and Companion Diagnostics

http://pharmaceuticalintelligence.com/2013/12/07/epigenomics-and-companion-diagnostics/

Larry H Bernstein, MD, FCAP

 

Resumen

Summary

 

Capítulo 7:        Integración de la fisiología, la genómica y la farmacoterapia

Chapter 7:         Integration of Physiology, Genomics and Pharmacotherapy

 

Introducción

Introduction

 

7.1     Dr. Richard Lifton, doctorado por la Universidad de Yale y el Instituto Médico Howard Hughes: galardonado en los Premios Breakthrough 2014 en Ciencias de la Vida por el descubrimiento de los genes y mecanismos bioquímicos que causan la hipertensión

7.1     Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

http://pharmaceuticalintelligence.com/2014/03/03/richard-lifton-md-phd-of-yale-university-and-howard-hughes-medical-institute-recipient-of-2014-breakthrough-prizes-awarded-in-life-sciences-for-the-discovery-of-genes-and-biochemical-mechanisms-tha/

Aviva Lev-Ari, PhD, RN

 

7.2     El ciclo del calcio (bomba ATPasa) en la terapia génica cardíaca: terapia génica inhalable para la hipertensión arterial pulmonar e infusión intracoronaria percutánea para la insuficiencia cardíaca. Las aportaciones del Dr. Roger J. Hajjar

7.2     Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

Aviva Lev-Ari, PhD, RN

 

7.3     Diagnóstico y biomarcadores: nuevas tendencias de la industria de la genómica frente a las condiciones actuales del mercado y un nuevo programa informático de soporte clínico por expertos en tiempo real, Historical Scientific Leaders Memoirs

7.3     Diagnostics and Biomarkers: Novel Genomics Industry Trends vs Present Market Conditions and Historical Scientific Leaders Memoirs

http://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems/

Aviva Lev-Ari, PhD, RN

 

7.4     Biología sintética: sobre la interpretación avanzada del genoma de las variantes y las vías genéticas. ¿Cuál es la base genética de la aterosclerosis y la pérdida de la elasticidad arterial con el envejecimiento?

7.4     Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

http://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Aviva Lev-Ari, PhD, RN

 

7.5     Diagnóstico de enfermedades y terapia génica: edición genómica de precisión y elaboración de perfiles rentables de microARN

7.5     Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

http://pharmaceuticalintelligence.com/2013/03/28/diagnosing-diseases-gene-therapy-precision-genome-editing-and-cost-effective-microrna-profiling/

Aviva Lev-Ari, PhD, RN

 

7.6     Biomarcadores por imagen de la rigidez arterial: métodos farmacoterapéuticos de control de la hipertensión y la hipercolesterolemia

7.6     Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

http://pharmaceuticalintelligence.com/2013/05/24/imaging-biomarker-for-arterial-stiffness-pathways-in-pharmacotherapy-for-hypertension-and-hypercholesterolemia-management/

Aviva Lev-Ari, PhD, RN

 

7.7     Tratamientos neuroprotectores: farmacogenómica frente a psicofármacos e inhibidores de la colinesterasa

7.7     Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors

http://pharmaceuticalintelligence.com/2012/11/23/neuroprotective-therapies-pharmacogenomics-vs-psychotropic-drugs-and-cholinesterase-inhibitors/

Aviva Lev-Ari, PhD, RN

 

7.8     Identificación de metabolitos combinando información genética y metabólica: la asociación genética vincula los metabolitos desconocidos con genes funcionalmente relacionados

7.8     Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown Metabolites to functionally related Genes

http://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic-information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/

Aviva Lev-Ari, PhD, RN

 

7.9     Fracción de expulsión conservada comparada con la reducida: tratamientos disponibles y necesarios

7.9     Preserved vs Reduced Ejection Fraction: Available and Needed Therapies

http://pharmaceuticalintelligence.com/2014/02/03/preserved-vs-reduced-ejection-fraction-available-and-needed-therapies/

Aviva Lev-Ari, PhD, RN

 

7.10   Biosimilares: creación y protección de la propiedad intelectual por parte del descubridor y de los fabricantes de biosimilares

7.10   Biosimilars: Intellectual Property Creation and Protection by Pioneers and by Biosimilar Manufacturers

http://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

Aviva Lev-Ari, PhD, RN

 

7.11   Demostrar la biosimilitud: nuevas directrices sobre biosimilares de la FDA

7.11   Demonstrate Biosimilarity: New FDA Biosimilar Guidelines

http://pharmaceuticalintelligence.com/2012/12/13/demonstrate-biosimilarity-new-fda-biosimilar-guidelines/

Aviva Lev-Ari, PhD, RN

 

Resumen

Summary

 

Capítulo 8:        La industria biofarmacéutica actual

Chapter 8:         Biopharma Today

 

Introducción

Introduction

 

8.1     Una gran universidad dedicada al descubrimiento de fármacos: la Universidad de Pittsburgh

8.1     A Great University engaged in Drug Discovery: University of Pittsburgh

http://pharmaceuticalintelligence.com/2014/07/15/a-great-university-engaged-in-drug-discovery/

Larry H Bernstein, MD, FCAP

 

8.2     Introducción. La evolución del tratamiento del cáncer y de la investigación del cáncer: ¿cómo hemos llegado hasta aquí?

8.2     Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

http://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research-how-we-got-here/

Larry H Bernstein, MD, FCAP

 

8.3     Predicción de la respuesta tumoral, la progresión y el tiempo hasta la recidiva

8.3     Predicting Tumor Response, Progression, and Time to Recurrence

http://pharmaceuticalintelligence.com/2012/12/20/predicting-tumor-response-progression-and-time-to-recurrence/

Larry H Bernstein, MD, FCAP

 

8.4     Uso como diana de protooncogenes no utilizables como diana terapéutica

8.4     Targeting Untargetable Proto-Oncogenes

http://pharmaceuticalintelligence.com/2013/11/01/targeting-untargetable-proto-oncogenes/

Larry H Bernstein, MD, FCAP

 

8.5     Innovación: descubrimiento de fármacos, dispositivos médicos y salud digital

8.5 Innovation: Drug Discovery, Medical Devices and Digital Health

http://pharmaceuticalintelligence.com/2013/10/15/innovation/

Larry H Bernstein, MD, FCAP

 

8.6     Cardiotoxicidad y miocardiopatía por efectos adversos de medicamentos

8.6     Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

http://pharmaceuticalintelligence.com/2013/04/11/cardiotoxicity-and-cardiomyopathy-related-to-drugs-adverse-effects/

Larry H Bernstein, MD, FCAP

 

8.7     Nanotecnología y administración ocular de fármacos: Parte I

8.7     Nanotechnology and Ocular Drug Delivery: Part I

http://pharmaceuticalintelligence.com/2013/02/23/nanotechnology-and-ocular-drug-delivery-part-i/

Tilda Barliya, PhD

 

8.8     Sistema de administración transdérmica de fármacos (TDD) y nanotecnología: Parte II

8.8     Transdermal drug delivery (TDD) system and nanotechnology: Part II

http://pharmaceuticalintelligence.com/2013/02/04/transdermal-drug-delivery-tdd-system-and-nanotechnology-part-ii/

Tilda Barliya, PhD

 

8.9     La delicada conexión entre la IDO (indolamina 2,3-deshidrogenasa) y la inmunooncología

8.9     The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

http://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-immunology/

Demet Sag, PhD

 

8.10   Descubrimiento de dianas farmacológicas naturales y medicina aplicable en el microbioma humano

8.10   Natural Drug Target Discovery and Translational Medicine in Human Microbiome

http://pharmaceuticalintelligence.com/2014/03/23/natural-drug-target-discovery-and-translational-medicine-in-human-microbiome/

Demet Sag, PhD

 

8.11   De la genómica de los microorganismos a la medicina aplicable

8.11   From Genomics of Microorganisms to Translational Medicine

http://pharmaceuticalintelligence.com/2014/03/20/without-the-past-no-future-but-learn-and-move-genomics-of-microorganisms-to-translational-medicine/

Demet Sag, PhD

 

8.12   La indolamina 2,3-dioxigenasa (IDO) confinada controla la hemostasia de las respuestas inmunitarias, para bien y para mal

8.12   Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

http://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis-of-immune-responses-for-good-and-bad/

Demet Sag, PhD

 

Resumen

Summary

 

Capítulo 9:        Tendencias futuras de la industria biofarmacéutica

Chapter 9:         BioPharma – Future Trends

 

Introducción

Introduction

 

9.1     La inteligencia artificial frente al científico: ¿quién ganará?

9.1     Artificial Intelligence Versus the Scientist: Who Will Win?

http://pharmaceuticalintelligence.com/2015/03/02/artificial-intelligence-versus-the-scientisitwho-will-win/

Stephen J Williams, PhD

 

9.2     La vibrante escena biotecnológica de Filadelfia: poniendo el foco sobre KannaLife Sciences y la disciplina y el potencial de la farmacognosia

9.2     The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy

http://pharmaceuticalintelligence.com/2015/02/19/the-vibrant-philly-biotech-scene-focus-on-kannalife-sciences-and-the-discipline-and-potential-of-pharmacognosy/

Stephen J Williams, PhD

 

9.3     La vibrante escena biotecnológica de Filadelfia: poniendo el foco sobre el diseño de fármacos asistido por ordenador y Gfree Bio, LLC

9.3     The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC

http://pharmaceuticalintelligence.com/2015/02/10/the-vibrant-philly-biotech-scene-focus-on-computer-aided-drug-design-and-gfree-bio-llc/

Stephen J Williams, PhD

 

9.4     Héroes de la investigación médica: el becario postdoctoral

9.4     Heroes in Medical Research: The Postdoctoral Fellow

http://pharmaceuticalintelligence.com/2014/10/30/heroes-in-medical-research-the-postdoctoral-fellow/

Stephen J Williams, PhD

 

9.5     Los NIH estudian las directrices de tratamiento con CAR-T: informe del Comité Consultivo sobre el ADN recombinante

9.5     NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

http://pharmaceuticalintelligence.com/2014/09/23/nih-considers-guidelines-for-car-t-therapy-report-from-recombinant-dna-advisory-committee/

Stephen J Williams, PhD

 

9.6     1st Pitch Life Science- Philadelphia. Esto es lo que los inversores piensan sobre su presentación

9.6     1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

http://pharmaceuticalintelligence.com/2014/09/17/1st-pitch-life-science-philadelphia-what-vcs-really-think-of-your-pitch/

Stephen J Williams, PhD

 

9.7     Múltiples proyectos genómicos sobre el cáncer de pulmón sugieren nuevas dianas; orientación de la investigación para el cáncer de pulmón no microcítico

9.7     Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

http://pharmaceuticalintelligence.com/2014/09/05/multiple-lung-cancer-genomic-projects-suggest-new-targets-research-directions-for-non-small-cell-lung-cancer/

Stephen J Williams, PhD

 

9.8     Héroes de la investigación médica: la proteína verde fluorescente y el duro camino de la ciencia

9.8     Heroes in Medical Research: Green Fluorescent Protein and the Rough Road in Science

http://pharmaceuticalintelligence.com/2014/07/27/heroes-in-medical-research-green-fluorescent-protein-and-the-rough-road-in-science/

Stephen J Williams, PhD

 

9.9     Aspectos de la medicina personalizada en el cáncer: heterogeneidad intratumoral y evolución ramificada revelada por la secuenciación multirregional

9.9     Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

http://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

Stephen J Williams, PhD

 

9.10   El cerdo SCID II: los investigadores desarrollan otro cerdo SCID y otro gran modelo para la investigación del cáncer

9.10   The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

http://pharmaceuticalintelligence.com/2014/06/11/the-scid-pig-ii-researchers-develop-another-scid-pig-and-another-great-model-for-cancer-research/

Stephen J Williams, PhD

 

Resumen

Summary

 

Epílogo

Epilogue

Larry H Bernstein, MD, FCAP

 

 

 

TERCER VOLUMEN

Hitos de la fisiología
Descubrimientos en medicina, genómica y terapéutica: Perspectiva centrada en el paciente

 

2015

Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective 

Disponible en Amazon.com desde el 27/12/2015

http://www.amazon.com/dp/B019VH97LU

 

PART C:

The Editorials of the original e-Books in English in Audio format

 

Series E: Patient-centered Medicine

 

VOLUME THREE

Milestones in Physiology Discoveries in Medicine, Genomics and Therapeutics: Patient-centric Perspective

 

2015

 

Available on Amazon.com since 12/27/2015

http://www.amazon.com/dp/B019VH97LU

 

Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Chief Scientific Officer

Leaders in Pharmaceutical Business Intelligence

Larry.bernstein@gmail.com

 

 

Image Source: Adapted from Google Images

 

Aviva Lev-Ari, PhD, RN

Editor-in-Chief BioMed e-Series of e-Books

Leaders in Pharmaceutical Business Intelligence, Boston

avivalev-ari@alum.berkeley.edu

  

 

List of Contributors & Contributors’ Biographies

 

Volume Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Guest Authors:

Stephen J Williams, PhD: 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 9.10

Aviva Lev-Ari, PhD, RN: 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 7.9, 7.10, 7.11

Tilda Barliya, PhD: 8.7, 8.8

Demet Sag, PhD: 8.9, 8.10, 8.11, 8.12

 

 

The Editorials of the original e-Books in

English in Audio format

 

Preface on Physiology, Medicine, Genomics and Therapeutics

Larry H Bernstein, MD, FCAP

 

Mankind, species of plants and animals live on every continent. The age of living species is millennia. From single cells to multicellular beings there are common requirements for life. There are also predators and prey. This book is mainly about the history of biology, medicine and mankind, but also about how the invention of technology in modern Western society has enabled us to investigate the origins of life, the working of the cell, the classification of species, and the development of medicine and a molecular based emerging pharmaceutical and diagnostics industry which have been separate, and which are merging. It was a great awakening when Charles Darwin and Humboldt each explored continents in their own manner. It was yet another milestone when Gregor Mendel described inheritance from the observations and experiments of his garden. Along the path there were conflicts with religious doctrine, as was the case in challenging planetary motions in astronomy. This was mostly an observational science, but there was also a developing method of formulating and testing hypotheses.

A huge invention came with the introduction of the calculous independently by Sir Isaac Newton and by and Gottfried Wilhelm Leibniz in the 17^th century, some elements of which were preceded by Archimedes and others. Further, Newton’s first Law of physics was Galileo’s concept of inertia. Newton’s laws of motion are three physical laws that together laid the foundation for classical mechanics, which stood as a foundation for physics until it could not resolve longstanding controversies at the atomic level by the late 19^th century. Euler’s laws of motion extended Newton’s laws of motion for a point particle to a rigid body motion 50 years after Newton introduced his principles of mechanics.

In the 19^th century, Physics had the emergence of electricity. There were contributions by Coulomb, Ampere, Gauss, Lorenz, and then giant leaps forward by James Clerk Maxwell and by Faraday, who laid a solid foundation in the laws of electromagnetism.

The atomic theory was fathered by Neils Bohr, and this led to the Copenhagen School, which had Heisenberg, Schroedinger, Lise Meitner, Wolfgang Pauli, and others, which was influential during a critical time at Los Alamos and at Berkeley in the late 1930’s.

We see here that while biology was most primitive in that it was a descriptive science, based largely on observation, physics moved chemistry forward to more mechanistic principles, which would have a huge impact in moving organic chemistry to a more mechanistic basis. This would have a great impact on Woodward’s synthesis of chlorophyll, as well as the structural work by Pauling and his group in solving the structure of Sickle Cell hemoglobin. Moreover, the developments in structural analysis were crucial for the development of the model of the genetic code credited to Watson and Crick.

This book outlines the history of medicine and biology that is enriched by the allied sciences early in the 20^th Century, and accelerated by the discoveries of insulin, penicillin, and vitamins. The structure of medical education is changed by the Flexner Report to the Carnegie Commission that required the teaching of anatomy, physiology, and concurrently, required the enrichment of professional education by basic and clinical research. It is proximate to that time that the Rockefeller Institute Was established, and Rockefeller University established a hospital that was founded on the principle of research to improve medicine.

However, the Mayo Clinic developed independently of this event. Mayo Clinic evolved gradually from the frontier practice of Dr. William Worrall Mayo and his two sons, William J. and Charles H. Mayo. The elder Dr. Mayo emigrated from his native England to the United States in 1846. He became a doctor in 1850. In 1863 he was appointed a surgeon for the enrollment board in southern Minnesota, to examine recruits for the Union Army. In 1864, the Mayos moved to Rochester where the enrollment board was headquartered. Dr. Mayo remained in Rochester after the Civil War ended.

Dr. Mayo’s two sons began their medical training early — first by observing and then later by assisting their father on patient visits and with autopsies. Dr. Will said, “We came along in medicine like farm boys do on a farm,” learning by doing. After graduating from medical school — Dr. Will from the University of Michigan Medical School in 1883 and Dr. Charlie from Chicago Medical College of Northwestern University in 1888 — both sons returned to Rochester and joined their father. The Drs. Mayo join with the Sisters to build the first general hospital in southeastern Minnesota after a tornado swept through the region. The 27-bed Saint Marys Hospital opened in 1889.

The Mayo brothers developed a practice that required “to develop medicine as a cooperative science; the clinician, the specialist and the laboratory workers uniting for the good of the patient,” explained Dr. Will. “Individualism in medicine can no longer exist.” Group practice also was a natural expression of the Mayo brothers’ personalities. In 1919, the Mayo brothers dissolved their partnership and turned the clinic’s name and assets, including the bulk of their life savings, to a private, not-for-profit, charitable organization now known as Mayo Foundation.

The organization that is now Kaiser Permanente began at the height of the Great Depression with a single inventive young surgeon and a 12-bed hospital in the middle of the Mojave Desert. When Sidney Garfield, MD, looked at the thousands of men involved in building the Colorado River Aqueduct Project, he saw an opportunity. He borrowed money to build Contractors General Hospital; six miles from a tiny town called Desert Center, and began treating sick and injured workers. But financing was difficult, and Dr. Garfield was having trouble getting the insurance companies to pay his bills in a timely fashion. To compound matters, not all of the men had insurance.

Enter Harold Hatch, an engineer-turned-insurance agent. Hatch suggested that the insurance companies pay Dr. Garfield a fixed amount per day, per covered worker, up front. This would solve the hospital’s immediate money troubles and, at the same time, would enable Dr. Garfield to emphasize maintaining health and safety rather than merely treating illness and injury. Thus, “prepayment” was born. For the princely sum of five cents per day, workers were provided this new form of health coverage. For an additional five cents per day, workers could also receive coverage for non-job related medical problems.

http://share.kaiserpermanente.org/article/history-of-kaiser-permanente/#sthash.M175TCPV.dpuf

 

Chapter 1:         Evolution of the Foundation for Diagnostics and Pharmaceuticals Industries

 

Introduction

 This chapter has the following sequence:

1. Outline of Medical Discoveries between 1880 and 1980
2. The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century
3. The Classification of Microbiota
4. Selected Contributions to Chemistry from 1880 to 1980
5. The Evolution of Clinical Chemistry in the 20th Century
6. Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics

The first article is a quite extensive presentation of the Nobel Prize discoveries made from the late 19^th to the 3^rd quintile of the 20^th century. The period beyond that is an accelerated discovery centered on genomic and proteomic technologic discoveries, accompanied by computational advances that help to propel both the diagnostics and pharmaceutical industries forward. One might conclude that the awarding of the Nobel Prize to Watson and Crick in 1953 is a harbinger of what is to follow, and a milestone in the emergence of molecular biology, after which the departments of biochemistry were redefined as departments of Molecular Biology and Biochemistry.   I don’t see the discovery as less monumental that the series of experiments by Otto Warburg in 1931, which identified malignant cells as having altered respiration, and thereby, producing more lactic acid than benign cells. That work was instrumental in relationship to a body of work on respiration, muscle metabolism, oxidative phosphorylation, and the purification and characterization of purines and pyrimidines, and the discovery of the electron transport chain, also enabled by the elucidation of cellular organelles that are involves in oxidative metabolism, and in cellular repair. This led to the description of the systems we now refer to as catabolic and anabolic, and have a huge importance in our understanding of differentiated organ function. The work described can be attributed to remarkable scientists in France, United States, and Germany, which is systematically uncovered in subparts 1.4 and 1.5, contributions to chemistry, which put down a strong foundation for the emergence of clinical chemistry.

The developments in microbiology also had great impetus from the development of a germ theory by Pasteur and Koch, later leading to both microbiology and the development of antibiotics. This was preceded by plagues and infestations intermittently since the middle ages. However, the history of Western Civilization is pockmarked by divisions in society, landowners and peasants or slaves, a slave trade in the Americas, and successive wars in the 18^th, 19^th, and 20^th centuries. There were serious plagues affecting growing urban populations in Memphis and the South during the Civil War in the 19^th century, and during American reconstruction, and the 20^th century saw the Great Depression, two World Wars, and more. This was closely linked to the great Influenza epidemic, tuberculosis, malaria, small pox, and polio. This is described in 1.2 and 1.3.

The last two parts deal with the emergence of a pharmaceutical industry based on discoveries in antimicrobial therapy, and discoveries in endocrine function that affect millions of lives. The pharmaceutical industry became overvalued as it was essential for treatment, and because of the development of bacterial, virus and fungal resistance, the introduction of increasing powerful drugs. Finally, we introduce a significant change in the relationship of diagnostics to pharmaceuticals. This is because the greatly increased depth of our understanding of cellular metabolic changes in disease, pharmaceuticals will have to target cellular metabolic pathways. The future of pharmaceutical innovation then becomes dependent on basic science discovery.

 

1.1 Outline of Medical Discoveries between 1880 and 1980

 

Introduction by Larry H Bernstein, MD, FCAP

This outline follows the history of physiology and medicine from the work at the end of the 19^th to the late 20^th century. While the Nobel Prizes are guideposts of important achievements, they don’t encompass the full body of the story. The discoveries in synthetic organic chemistry began in the late 19^th century and led to a medicinal chemistry. The development of dyes led to discoveries in histology and opened research into neuroanatomy and cell structure. The studies of respiration was tied to the investigation of oxygen’s role in living organisms, and led to the work of Pasteur in the wine industry in France. The work of Otto Warburg on respiration followed the earlier work of Pasteur and extended the concept to malignant transformation related to loss of respiratory controls at a time that the mitochondrion was not yet known. This also had two directions of further study. The first was the study of muscle contraction by anaerobic glycolysis, and recovery from intense work by respiration. Then there was further extensive investigation that elucidated aerobic metabolism by Hans Krebs and by Albert Szent-Gyorgyi, who had first embarked on the discovery of ascorbic acid, and muscle later, and finally cancer.

There were other developments, such as the discoveries of insulin, and also of penicillin. The discovery of insulin opened a door to endocrine function, and was tied to indirectly, the work by the Cori’s on liver glycogen conversion and release of glucose. The work on endocrine function included the discovery of pituitary, sex hormones, and the adrenals (fight or flight). It was during World War II that the Lawrence Radiation Laboratory led to the use of radioactive tracers, and to the opening of a collaboration between biochemists and physicists. It was a period of explosive development of biochemistry after the war that led to the discovery of coenzyme A, and following the earlier work of Warburg in discovery of pyridine nucleotides, the research in enzymatic reactions and metabolic pathways by Duderoff, Colowick and Kaplan, Arthur Kornberg (DNA polymerase) and Roger Kornberg (RNA polymerase), and Bernard Horecker (pentose phosphate shunt, NADPH), and the work on DNA structure, and much more to follow.
This subchapter attempts to follow the activities and scholars that participated in these events.

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/12/03/outline-of-medical-discoveries-between-1880-and-1980/

 

1.2 The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

 

Introduction by Larry H Bernstein, MD, FCAP

 

This portion of the Chapter 1 contents deals with the evolution of a concept of infectious diseases and a development of public health measures to deal with this. The concept of the contagion had to be upended prior to the period we are concerned with. The ancient concepts of the humors was descriptive, but not based on science. The anatomy depicted by Galen was based on dissection of animals, and was inaccurate. It was passed on to Moses Maimonides by the Moorish Muslim physicians of the 14^th Century. It was shown to be inaccurate by the discovery of the circulation by William Harvey, opening modern day physiology. The Crusades includes centuries of dispute over Jerusalem in the first millennium between the Christians and Muslims. There were pandemics – the Great Plague – that fell on Europe. There was no concept of a source (ticks and mice), or a connection with microorganisms. A challenge came with the Hungarian physician, Semmelweis, who observed that women died in childbirth from an unsterile delivery (though a microbial cause was not known). The next clue came from John Hunter, who pulled soldiers out of the mud to avoid infection (not yet known). His student was Edward Jenner, who observed that milkmaids did not develop cowpox.

This dissertation follows that period, and recounts the many epidemics that occurred in the American South, especially during and after the great civil war. The conditions of the water supply and the conditions of the cities were ripe for the transmission of disease. Of course, the same was true of London, France, and other cities. The story continues to the world wars, and to the role of the United States in developing a system of public health, led by the concerns that soldiers were more likely to die on the battlefield of contagious disease than of battle wounds. The United States also helped Europe to confront the issue, not least because US has been a major location for immigration.

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/12/09/the-history-of-infectious-diseases-and-epidemiology-in-the-late-19th-and-20th-century/

 

1.3 The Classification of Microbiota

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2015/01/17/an-overview-of-clinical-microbiology-classification-and-antimicrobial-resistance/

 

1.4 Selected Contributions to Chemistry from 1880 to 1980

Introduction by Larry H. Bernstein, MD, FCAP

The fourth article in the history of physiology, medicine, and genomics series is concerned with selected contributions to chemistry in the late 19^th and 20^th centuries. The developments in chemistry were vital to the development of medicinal chemistry, medicine, biochemistry and molecular biology in the 20^th century. Perhaps the development of modern biochemistry owes much to the precedent and parallel discoveries in physics, which was elemental for the understanding of molecular orbital theory, covalent bonds, and molecular structure.

This became clear in the post World War I period. In the 1920’s Otto Warburg was establish with a Rockefeller Foundation funded Institute in Berlin. He pioneered in cellular respiration studies of cells cut to a tissue thickness of a single cell. He found in manometric experiments that the oxygen supplied to cells had an impact on cell metabolism and growth. These experiments were based on studies by Pasteur 60 years earlier. He determined that cells provided with insufficient oxygen shifted their metabolism to reliance on glycolysis. This is a metabolic state that was later shown to be more costly in energy than respiration. He determined that malignant transformation to cancer cells involves impairment of respiration. It was from his laboratory that further elucidation of the foundation for biochemistry came from his student Hans Krebs and Albert Szent-Gyorgyi. Krebs established the citric acid cycle, and Szent-Gyorgyi continued the work of Myerhoff and of AV Hill on muscle metabolism, and he also purified ascorbic acid from Hungarian paprika. All of these researchers received the Nobel Prize in Physiology or Medicine. The work done in that early post World War I period led to the elucidation of the pyridine nucleotide coenzymes, and the flavin nucleotide.

It was in the 1930’s that Linus Pauling was carrying out studies in physical chemistry that led to a better understanding of molecular structure. He learned that Tiselius, with support from the Rockefeller Foundation, developed the “Tiselius apparatus” for moving boundary electrophoresis, which was described in 1937 in the well-known paper “A New Apparatus for Electrophoretic Analysis of Colloidal Mixtures”.
He asked his graduate students, including Harvey Itano, to construct the apparatus. From there they isolated sickle cell hemoglobin, and later received the Nobel Prize for establishing the amino acid substitution that is pathognomonic for Sickle Cell Anemia. Pauling later became engaged in the effort to determine the structure of DNA, which was decoded by Watson, Crick, and Franklin.

There were two major events that were defined post World War II. The Lawrence Radiation Laboratory introduced biobhemistry to the use of radioactive tracers. Nathan O Kaplan trained with Duderoff at Berkeley, and also came into contact with Sid Colowick. He was involved in the discovery of coenzyme A in Fritz Lipmann’s laboratory, then went to John’s Hopkins, and with Colowick wpublished the seminal paper on the transhydrogenases. He then established the Graduate School of Biochemistry at Brandeis with Sid Colowick, bringing the young university to the forefront in biochemistry. His work with pyridine nucleotide linked dehydrogenases would establish Kaplan in the top ranks of enzymology.   Kaplan would later go to University of California, San Diego, and Colowick would go to Vanderbilt.

The other major development was in the genetic code. Arthur Kornberg received the Nobel Prize for the discovery of DNA polymerase. The signature discovery that followed was the elucidation of the genetic code by Watson, Crick, and Franklin. Kornberg, and also Watson and Crick received Nobel Prizes. The intensive work on the genetic code was preceded by the birth of Molecular Biology, a transformation of biochemistry that was led by a series of experiments promulgated by Meselson and Stahl, Salvador Luria, and others, with a focus on molecular structure, and on experiments of genetics with phage and bacterial cells, eventually leading to the central dogma – concerned with understanding the interactions between the various systems of a cell, including the interactions between the different types of DNA, RNA and protein biosynthesis as well as learning how these interactions are regulated.

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2014/12/03/selected-contributions-to-chemistry-from-1880-to-1980/

 

Summary to 1920s to Pre-Genomics: Evolution of Diagnostics in the US HealthCare System

 

This chapter was a series of discussions about the history of medicine, physiology, diagnostics, and pharmacology. It is clear from the presentations that the developments over the last 150 years have been significant advances. I was unable to develop some lines of discussion. For example, the Periodic Table was introduced in the 19^th century. It was a landmark achievement that would guide chemistry in the 20^th century, and it has an impact on metallo-organic chemistry today, and had an impact on our understanding of biology. In addition, the foundation for modern electrical theory and the duality of particle and wave property of light was a huge development in physics, leading to quantum physics, at the beginning of the 20^th century, with Planck, Einstein, Bohr, Sommerfeld, Heisenberg, Schrodinger, Pauli, Dirac, Born, were instrumental in changing our view of the atom. This would have an impact on chemistry in changing from a description of model reactions to a molecular orbital construct. Such a construct led Linus Pauling to the structural basis for sickle cell anemia. As physics impacted chemistry, chemistry impacted biology. There were many who stood on the shoulders of giants. There were great advances between the 1930’s and the 1970’s, prior to the emergence of a mature molecular biology, that accelerated after that. There was a foundation to build on. Moreover, this has been helped by the computer revolution.

There were several large controversies in this period.

• The Warburg Hypothesis of carcinogenesis

After extensive research and testing, two Boston College biology professors, Dr. Thomas Seyfried and Dr. Jeffrey Chuang, in conjunction with former BC doctoral student Dr. Michael Kiebish, have found evidence to support Nobel Prize winner Otto Warburg’s theory regarding the origin of cancer. The group worked with a team at Washington University in St. Louis School of Medicine, where much of the actual testing took place. Their findings and results were published in the December 2008 issue of the Journal of Lipid Research. Warburg’s theory of cancer was one of the most controversial theories and lacked support in the scientific community due to the lack of empirical evidence behind his claims. The theory claimed that cancer originated from irreversible damage to mitochondrial respiration. Seyfried said a person’s cells need a certain amount of energy in order to survive and can receive this energy from respiration or glycolysis, the breakdown of sugar. In tumor cells, the majority of the cell’s energy comes from glycolysis, as the cell has abnormal respiration, which creates an imbalance of the energy sources and a dependence on glycolysis. Cancer is a disease of energy metabolism and the cells’ dependence on glycolysis leaves them extremely vulnerable to attack. “In cancer, respiration is damaged slowly over a long period of time,” Seyfried said.

The team determined that it was abnormalities in cardiolipin that lead to the respiration problems and that all cancers originate in the mitochondria, and as a result, have a defective mitochondria.

• The genetic code
• Protein conformation and cooperativity
• Oxidative phosphorylation

 

 

Chapter 2:         The Search for the Evolution of Function of Proteins, Enzymes and Metal Catalysts in Life Processes

 

Introduction

 This chapter is divided as follows:

2.1 The life and work of Allan Wilson
2.2 The Evolution of Myoglobin and Hemoglobin
2.3 More Complexity in Proteins Evolution
2.4 Life on Earth is Traced to Oxygen Binding
2.5 The Colors of Life Function
2.6 The Colors of Respiration and Electron Transport
2.7 Highlights of a Green Evolution

The subchapters depict the evolution of protein structure and function, but the colors are associated with protein metal complexes that have evolved that are essential to plant and animal life, and also exist in microbiota, though, not necessarily in organelles. It is important to note that the colors are related to the type of metal complex involved. Hemoglobin and myoglobin contain iron, and are red. There is also copper in cytochrome, and zinc in metalloproteases. All of this metallo-protein complexing is related to enzymatic activity, multimeric structures, and essential interactions with oxygen.

 

Summary

 

In the previous chapter I asserted that there was a prolonged debate over the elucidation of the electron transport mechanism. There was brilliant work done in the pursuit of an explanation by Britton Chance, but the hypothesis was difficult to comprehend. The solution came with the alternative explanation and elucidation of an electron transport mechanism by which protons are moved across a linear arrangement of proteins on the mitochondrial inner membrane, which was the equivalent of electron transport. The ETC is a multimeric membrane bound complex. The discovery was awarded the Nobel Prize. Another enormous achievement was the synthesis of chlorophyll in the laboratory of Woodward, at Harvard University Department of Chemistry. Zinc metalloproteases have taken on great significance in more recent times, especially with respect to neurological science and brain disorders.

In the previous chapter I also mentioned a debate about the function of proteins related to their structure and the associated concept is called conformational change. This is extremely important and was associated with the Nobel Prize awarded to Jakob and Monod. The change in conformation that occurs in proteins is related to noncovalent interactions that may be attraction or repulsion, determined by the proximity of amino acid residues in the folded protein.   This has relevance to the catalytic behavior of enzymes, which are catalytic proteins. In additions, as seen in the metal binding, the association of a metal with protein subunits is also important for understanding catalysis or transport properties in plasma or across membranes.

It is also important to point out that proteins play a distinctive role in evolution and in adaptation in the functioning organism. The genome carries a genetic message. The genome interacts with a chromatin matrix. The chromatin matrix actually contracts over time increasing the compactness of the nuclear construct. In contracting, the chromatin protein interactions have an effect on structure and expression. Has this anything to do with what we refer to as ‘epigenomics’. I don’t know! What we can be sure of is that mutations occur, but they are not necessarily expressed through translation. Many are silent, and have no consequence. Many are carried over for generations. There is also ‘dark matter’ that has function in regulation, but not in translation. We have to make a comparison between the stability of the genome, changing only over time, with the ultrafast metabolic reactions of proteins and enzymes. The proteins have a reaction to environmental influences that are measured in msec and less. This is what is essential for evolutionary change and adaptation to the environment. This is elaborated in a reference to JEDS Rosalino below.

I pointed out JEDS Rosalino’s observation about the construction of a complex molecule of acetyl coenzyme A, and the amount of genetic coding that had to go into it. Furthermore, he observes – millions of years later, or as soon as, the information of interaction leading to activity and regulation could be found in RNA, proteins like reverse transcriptase move this information to a more stable form (DNA). In this way it is easier to understand the use of CoA to make two carbon molecules more reactive.

JEDS Rosalino has referred to the important conclusion in Erwin Schroedinger’s “What is Life?”, and Schroedinger’s cat. It is impossible to come up with a predictive equation to explain life.

It had to come from a founder of “Quantum Mechanics” because, unlike economics, physics is a science based on experimental validation. In entering biology from Physics to make it more rigorous, as was the case for Max Delbruck, who was preceded by the Cori’s, Beadle and Tatum, Herschey, Luria, Dubecco, Kornberg and Ochoa, Lipmann, Watson and Crick, a discipline called “Molecular Biology and Biochemistry” emerged that would open the secrets of life. Beadle and Tatum gave us “one gene – one enzyme”, a formulation that led in medical teaching from William Osler’s edict to “Inherited Metabolic Disorders” – gene related disruption of the chemical reactions taking place in the body to convert or use energy.

Conversations with Jose Eduardo des Salles Rosalino raised this question? How is it that developments late in the 20th century diverted the attention of biological processes from a dynamic construct involving interacting chemical reactions under rapidly changing external conditions affecting tissues and cell function to a rigid construct that is determined unilaterally by the genome construct, diverting attention from mechanisms essential for seeing the complete cellular construct?

He calls attention to the article titled Neo -Darwinism, The Modern Synthesis and Selfish Genes that bares no relationship with Physiology with Molecular Biology J. Physiol 2011; 589(5): 1007-11 by Denis Noble. Further, he identifies it as the key factor required in order to understand the dislodgement of physiology as the foundation of medical reasoning. This is because of the near unilateral emphasis of genomic activity as a determinant of cellular. The DNA to protein link goes from triplet sequence to amino acid sequence. That is the realm of genetics. However, protein conformation, activity and function require that environmental and micro-environmental factors should be considered (Biochemistry). If that were not the case, we have no way to bridge the gap between the genetic code and the evolution of cells, tissues, organs, and organisms.

He continues with this example. I would like to stress in the cAMP coupled hormonal response, the transfer of conformation from protein to protein is paramount. For instance, if your scheme goes beyond cAMP, it will show an effect over a self-assembly (inhibitor protein and protein kinase). This effect is not in any way determined by the translation of the genetic code. It is an energetic homeostatic response. Most important, sequence alone does not explain conformation, activity and function of regulatory proteins. If this important mechanism was not ignored, the work of S Prusiner would be easily understood. For, self-assembly versus change in covalent modification of proteins (see R. A Kahn and A. G Gilman 1984 J. Biol. Chem. v. 259,n 10 pp6235-6240.) In this case, trimeric or dimeric G does not matter.” Signaling transduction tutorial”.

 

 

Chapter 3:         Evolution of New Relationships in Neuroendocrine States

 

Introduction

The third chapter of Physiology, Medicine, Genomics and Therapeutics is an intensive review of endocrine metabolism as it has developed to date, in a great complexity, and involved with many systemic interactions with the neural systems, especially but not exclusively, the hypophysis, with the gastrointestinal mucosa and muscularis, with cardiac sympathetic innervation, with the vascular endothelium, with kidney tubular structures, hepatocytes, bone matrix, and to be clear, other endocrine organs. The chapter is divided as follows:

3.1 Pituitary endocrine axis
3.2 Thyroid function
3.3 Sex hormones
3.4 Adrenal Cortex
3.5 Pancreatic Islets
3.6 Parathyroids
3.7 Gastrointestinal hormones
3.8 Endocrine action on midbrain
3.9 Neural activity regulating endocrine response

3.10 Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

 

The central nervous system is undoubtedly vital to animal behavior. But it is also closely tied to in homeostatic balance with the endocrine system. The nervous system has both motor and autonomic components, of which the latter is sympathetic of parasympathetic. It is the latter that is essential in its relationship to ‘involuntary’ bodily activities.

How does this work? The pituitary gland is at the base of the brain, adjacent to the hypophysis and in proximity to the brain stem. There are neural connections that extend to the pituitary gland through the hypophysis. There is also a paracrine secretion in the hypophysis that acts on the pituitary. Our knowledge of paracrine and autocrine effects in this area of research is not in a mature state. However, we do know that endocrine interactions between the pituitary and the thyroid, adrenals, and pancreas quite well, and the action on the pancreas of insulin-like growth factor-1, and the relationship of glucose control to a gluco-static mechanism that keeps a balance between insulin and glucagon. We also have a concept of the hormonal response to stress – the fight or flight response. But there is also a distinction to levels of stress and to the duration. This means that in the short-term glucose is released for energy by glycogenolysis, but as the glycogen is depleted, there is an anti-insulin effect, because insulin is tied to provision of substrate to the cell and to anabolic activity as the catabolic phase of the stress reaction subsides. But the catabolic phase may be prolonged, which results in high levels of adrenocorticotropic hormone (ACTH) and glucocorticoids. In hypertension there is an imbalance the affects the adrenal over-secretion of aldosterone, and we also know that the atrium and the ventricle of the heart are secretors of natriuretic peptides and pro-peptides. So here I bring in the concept of two basic types of hormones – steroidal and peptide. This should be sufficient for an introduction to a complex subject.

Discussion

We have now seen in some incomplete detail the endocrine system, its relationship to energy metabolism, a relationship to stress, and an intermediation between the endocrine secreting glands by a feedback mechanism through the hypothalamus and midbrain, communicating with the pituitary – acting as the master gland – secreting thyrotropic hormone, adrenocorticotropic hormone, gonadotropin, growth hormone, chorionic gonadotropin, melatonin, prolactin, and ghrelin. I have referred to the existence of steroid hormones, of which vitamin D may be included, and of peptide hormones. The existence of the two types could well be related to the fact that peptides may act over a short distance. This touches also on the existence of endocrine, paracrine and autocrine effects.

Summary

 

We have now seen in some incomplete detail the endocrine system, its relationship to energy metabolism, a relationship to stress, and an intermediation between the endocrine secreting glands by a feedback mechanism through the hypothalamus and midbrain, communicating with the pituitary – acting as the master gland – secreting thyrotropic hormone, adrenocorticotropic hormone, gonadotropin, growth hormone, chorionic gonadotropin, melatonin, prolactin, and ghrelin. I have referred to the existence of steroid hormones, of which vitamin D may be included, and of peptide hormones. The existence of the two types could well be related to the fact that peptides may act over a short distance. This touches also on the existence of endocrine, paracrine and autocrine effects. What has been presented is necessarily incomplete.

 

 

Chapter 4:         Problems of the Circulation, Altitude, and Immunity

 

Introduction

 

This chapter is about the importance of animals adaptive ability under a variety of environmental conditions and circumstances, and is so titled: Problems of the Circulation, Altitude, and Immunity. This engages the sympathetic nervous system, motor neurons, the shivering response, fat thermogenesis, the respiratory system, circulation and kidneys, and the immune response. The chapters are as follows:

4.1 Innervation of Heart and Heart Rate

4.2 Action of Hormones on the Circulation

4.3 Allogeneic Transfusion Reactions

4.4 Graft-versus Host Reaction

4.5 Unique Problems of Perinatal Period

4.6. High Altitude Sickness

4.7 Deep Water Adaptation

4.8 Heart-Lung-and Kidney

4.9 Acute Lung Injury

4.10 Reconstruction of Life Processes requires both Genomics and Metabolomics to explain Phenotypes and Phylogenetics

 

Chapter 5:         Problems of Diets and Lifestyle Changes

 

Introduction

 

This chapter is composed of the following sections:

5.1 Anorexia nervosa
5.2 Voluntary and Involuntary S-insufficiency
5.3 Diarrheas – bacterial and nonbacterial
5.4 Gluten-free diets
5.5 Diet and cholesterol
5.6 Diet and Type 2 diabetes mellitus
5.7 Diet and exercise
5.8 Anxiety and quality of Life
5.9 Nutritional Supplements

 

It is clear from the topics that the chapter is primarily concerned with the consequences of human lifestyles. These topics are readily found in many sources, but the scientific accuracy of many sites may be called into question. For the most part they might be grouped into voluntary and involuntary. If a diarrhea is a result of poor water quality, it is involuntary. The same might be said of gluten insensitivity. Anorexia nervosa is also not really a voluntary condition, but has to be considered a psychological condition. Diet and cholesterol and a relationship to diabetes mellitus is not a voluntary condition, as it is a worldwide problem. Is it a public health problem? Is it comparable to cigarette smoking? Perhaps it is best seen as highly related to the types of food that are available, food choices that are customary, and not to be underestimated – stress and the eating drive. That is why I have included a topic on anxiety and quality of life. The last piece covers food supplements.
It is most interesting that natural foods have been selected for thousands of years before there was a scientific discipline. The advances in extraction technologies and in synthetic organic chemistry have given new life to natural products chemistry and new therapeutic avenues.

 

Discussion

In the introduction I mentioned all of the subtopics except deficiency states. I chose not to go into the deficiency states, except for S. There is a worldwide concern over the consequences of obesity as a result of excess sugar, especially related to the widespread availability of fructose sweetened beverages. This is related to the triad of obesity, type 2 diabetes mellitus, and plasma lipidemias.

It is the case that there is a notable widespread deficiency of vitamin D, but there is not a clear agreement on the recommended daily allowance or on the mechanism. In Western countries, children are exposed to less sunlight than might be considered sufficient. We don’t see Rickets, as in the past. We also don’t see gross deficiency of vitamin C deficiency, but there is still much investigation into the benefits of vitamin C, water soluble, and with no known toxicities. Considering the importance of oxidative stress, vitamin C might have much to offer as a reductant.

The most common elements are – C, O, H, N, and then S (sulfur). Just as there has been historic iodine deficiency in the Midwestern United States that was resolved by ionized salt, there are geographic regions where S is deficient. S is found in regions that have had a natural supply from volcanic ash. Veganism has been popular, mainly among women, with concerns about keeping a slim appearance. Perhaps one might argue that it would seem to be a way to avoid coronary heart disease, but that is not the case. Kwashiorkor was described in 1972 by Dr. Yves Ingenbleek, MD, PhD, of Catholic University in Belgium, and later as Prof. at the laboratory of Nutrition in the School of Pharmacy at University Louis Pasteur, in Strasbourg.   He observed African children with Kwashiorkor who have thin limbs and fluid filled bellies. They also are prone to have thyroid goiters. He measured levels of transthyretin (then called proalbumin) that were so low that they could not be measured. He sent the many specimens to Prof. Young at MIT, who was known for his work on amino acids. He obtained the same results. It was known that serum albumin is low, typically less than 28 mg/L (2.8 mg/dl – normal > 4.5). The low serum albumin accounts for generalized edema. The low TTR accounts for severe loss of lean body mass. Years later they found that by comparing two populations separated only by living with availability or unavailability to animal-based protein, the deficient population developed hyper-homocysteinemia. The elevated homocysteine was tied to a higher incidence of coronary artery disease. This is an INVOLUNTARY deficiency of S from methionine. In addition, Drs. Ingenbleek and Young established that the S/N ratio in plant sourced food is less than half that in animal sourced protein. The ratios compared are:
animal, 1:22; plant, 1:34. The role of S in forming disulfide bonds, and the role of methionine in the reaction with acetyl CoA are good indications of the importance of this finding.

 

Summary

 

In the introduction I mentioned all of the subtopics except deficiency states. I chose not to go into the deficiency states, except for S. There is a worldwide concern over the consequences of obesity as a result of excess sugar, especially related to the widespread availability of fructose sweetened beverages. This is related to the triad of obesity, type 2 diabetes mellitus, and plasma lipidemias.

It is the case that there is a notable widespread deficiency of vitamin D, but there is not a clear agreement on the recommended daily allowance or on the mechanism. In Western countries, children are exposed to less sunlight than might be considered sufficient. We don’t see Rickets, as in the past. We also don’t see gross deficiency of vitamin C deficiency, but there is still much investigation into the benefits of vitamin C, water soluble, and with no known toxicities. Considering the importance of oxidative stress, vitamin C might have much to offer as a reductant.

 

 

Chapter 6:         Advances in Genomics, Therapeutics and Pharmacogenomics

 

Introduction

 

This chapter is a broad topic that includes natural products, antivirals, antifungals, antibiotics, and antimicrobial resistance, anticancer agents and immunotherapy, and the advances in genomics and metabolism of cancer, as identified below. The remaining parts are proteomics, pharmacogenomics, and biomarker guided therapy.

In the 20^th century there have been important developments in antibiotics and in vaccines with the near disappearance of some diseases in the Western hemisphere. Unfortunately, there are occasional endemics that occur from travel or from a failure to receive public health preventive vaccination. For example, there has been near elimination of polio, measles, mumps. The population has grown, and lifespan has been extended by a median of 20 years with elimination of many childhood illnesses. On the other hand, the survival has not been the same based on class status. There has been some relief from inflammatory lung disease in segments of the population, once a serious occupational hazard. There has been a reduction in the severity of influenza, except in the elderly. The hazards of smoking have not gone away, and are not limited to cancer. The antibiotic front has seen cycles of resistance, and the war on cancer has not subsided. Microorganisms mutate, and so do cancers.

 

Summary

 

In summary with regard to the Advances in Genomics, Therapeutics and Pharmacogenomics, there has been substantial progress with respect to infectious diseases, chronic inflammatory diseases, endocrine diseases, and to some extent with cancer, but the success in the last case has been mainly with breast cancer, endocrine cancer, and prostate cancer. The success in dealing with the severe mental illnesses, such as schizophrenia and severe depressions has been limited to control of symptoms at best with medications that have serious side effects, and significant impairment of the quality of life and of social engagement. Despite a long time-span for the war on cancer, there has been limited success in early treatment because of limitations in timely diagnosis, particularly for cancer of the internal organs, which have a survival measured in months.

It is not the case that we have not made much progress in many respects. The understanding of genetic associations has been dramatic. The development of instrumental analysis, such as mass spectrometry and of separation methods, and of recent progress in stem cell biology has made a huge difference projected into the near future. The progress involves proteomics as well as genomics, as well as lipidomics. Whereas infectious disease was life limiting in the 19^th and early 20^th century, there has been a shift to chronic diseases, and cardiovascular disease and stroke have been in the number 1 position, followed by cancers. Chapter 7 will carry this a bit further.

 

 

Chapter 7:         Integration of Physiology, Genomics and Pharmacotherapy

 

Introduction

 

The material for the seventh chapter of this volume has been prepared by the Series Editor, Dr. Aviva Lev-Ari. It has the following notable features:

1. It contains valuable information related to the pathophysiology of the heart and vasculature in loss of arterial and arteriolar flexibility, and presumed reflexivity.
2. It deals with cardiac pathophysiology with respect to ejection fraction and heart failure.
3. It covers genomics and genomic biomarker development with respect to cardiac contraction, calcium signaling, and metabolism.
4. It presents a new evolving development of BioSimilars in the therapeutic markets.

The chapters are outlines as follows:

7.1 Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

7.2 Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

7.3 Diagnostics and Biomarkers: Novel Genomics Industry Trends vs Present Market Conditions and Historical Scientific Leaders Memoirs

7.4 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

7.5 Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

7.6 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

7.7 Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors

7.8 Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

7.9 Preserved vs Reduced Ejection Fraction: Available and Needed Therapies

7.10 Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

7.11 Demonstrate Biosimilarity: New FDA Biosimilar Guidelines

 

Summary

 

Hypertension

It has become clear that cardiovascular disease is a disease of the vascular endothelium, involves the vascular tone in the stiffness of the arteries, which involves the smooth musculature. On the vascular endothelial part of the equation we focus attention on plaque formation, subintimal erosion, and plasma lipids. The injury sustained leads to both damage in the contact between the submucosal/muscularis layers. Whether hypertension occurs leading to endothelial damage or vice versa is just a matter of conjecture. We are dealing with chronic disease of the vasculature. In addition, nothing is expressly noted concerning the interstitium, which is the likely target of catecholamine stimulation, which should be a factor in stress. However, the effect of brain natriuretic peptide (BNP), which is degraded by the endothelium needs explanation in this respect. Moreover, vasopeptides and aldosterone also need to be considered. This is not by any means worked out in detail, but some of the pieces are found below.

1. In this respect, the work of Richard Lifton has identified genetic effects that contribute to the Na+/K+ equilibrium and plasm volume involved in essential hypertension. As noted, Lifton and his colleagues identified patients around the world with exceptionally high or low blood pressure due to single gene mutations. They identified the mutated genes and established their role in salt reabsorption by the kidney and regulation of blood pressure. The work gave scientific rationale to limit dietary salt intake and suggested rational combinations of antihypertensive medications and development of new therapies.
2. With respect to Roger Haggar, he has developed gene transfer methods and techniques in the heart to improve contractility. Dr. Hajjar’s laboratory focuses on targeting signaling pathways in cardiac myocytes to improve contractile function in heart failure and to block signaling pathways in hypertrophy and apoptosis. Dr. Hajjar has significant expertise in gene therapy. His laboratory focuses on molecular mechanisms of heart failure and has validated the cardiac sarcoplasmic reticulum calcium ATPase pump, SERCA2a, as a target in heart failure, developed methodologies for cardiac directed gene transfer that are currently used by investigators throughout the world, and examined the functional consequences of SERCA2a gene transfer in failing hearts. His basic science laboratory remains one of the preeminent laboratories for the investigation of calcium cycling in failing hearts and targeted gene transfer in various animal models.
3. In the Phase III Stability outcomes trial were focused on the drug target, LpPLA2 enzyme activity measured at baseline. GWAS analysis of LpPLA2 activity adjusting for age, gender and top 20 principle component scores identified 58 variants surpassing GWAS-significant threshold (5e-08). 
4. Aortic stiffness, measured through cfPWV, can thus be considered as a novel imaging biomarker for predicting CV events, although its value as a true surrogate end point requires a large intervention trial to demonstrate that the reduction in arterial stiffness translates into a reduction in CV events.

Prediction of Occurrence of Cardiovascular Events Independently of Left Ventricular Mass in Hypertensive Patients: Monitoring of Timing of Korotkoff Sounds as Indicator of Arterial Stiffness

5. Firefly BioWorks Inc., provides technology that allows for rapid miRNA detection in a large number of samples using standard lab equipment. This technology has the potential to increase the body of research on miRNA, which could help lead to better disease diagnosis and screening. The company’s core technology, called Optical Liquid Stamping (OLS) — which was invented at MIT by Firefly co-founder and Chief Technical Officer Daniel C. Pregibon PhD ’08 — works by imprinting (or stamping) microparticle structures onto photosensitive fluids.
6. These investigators identified previously undescribed genotype–metabotype associations for six distinct gene loci (SLC22A2, COMT, CYP3A5, CYP2C18, GBA3, UGT3A1) and one locus not related to any known gene (rs12413935). Overlaying the inferred genetic associations, metabolic networks, and knowledge-based pathway information, we derive testable hypotheses on the biochemical identities of 106 unknown metabolites. As a proof of principle, we experimentally confirm nine concrete predictions. We demonstrate the benefit of our method for the functional interpretation of previous metabolomics biomarker studies on liver detoxification, hypertension, and insulin resistance.
7. A significant proportion of patients with heart failure happen to have a normal ventricular ejection fraction at echocardiography during examination. Previously called diastolic heart failure, it is nowadays referred to as heart failure with normal ejection fraction (HFNEF) or HF with preserved ejection fraction. The significance of these different HF conditions is of therapeutic importance.
8. It is estimated that, within a few years, biologics will be half of the biopharmaceutical market. As a result, there have been mounting calls for a biosimilar pathway for companies obtaining Food and Drug Administration (FDA) approval of generic versions of existing biologics based upon lesser showings of safety and efficacy than is required for a pioneer biologic.

 

Chapter 8:         Biopharma Today

 

Introduction

 

The pharmaceutical industry has advanced with the development of organic chemistry, biochemistry and molecular biology, supported by advances in analytical instrumental that could not have been imagined a half century earlier. The topics of this portion of the discussion are below. We have reached the stage where it is possible to view a cell in three-dimensional imaging, and to illuminate processes within the cell using bioluminescent and fluorescent markers. The challenge has been to unlock or to target critical steps in the processes that are central and limiting to metabolic control through the interactions that are involved in signaling, and through tipping the sensitive balance between autophagy and respiration. The science has progressed step by step in the manner that models are constructed to test hypotheses. However, the step-by-step process is limited by the time constraints of observation. The chemistry is beneath the surface related to molecular reactions at the atomic level that is related to binding affinities and repulsions, and is also translated into the conformation of proteins that are aligned at near distance in a vibrant association. It is these actions at a distance that determines catalytic behavior. Moreover, as life proceeds forward, the molecular configurations of the cells and the tissue are remodeled. The success of pharmaceutical development will always be limited by this understanding in a fundamental and practical formulation.

 

Summary

 

The advances in genomics in the last 30 years have been dramatic and have overturned the classical model of cellular replication, cell turnover, and cell death. We have reviewed here the impact of genomics on diagnostics and treatment. The discovery of and recent finding with respect to dark matter of the cell has constricted the concept of DNA as solely restricted to the sequence: DNA begets RNA begets protein. There is a portion of DNA that is not involved in replication. There is also RNA that is not directly involved in transcription, but rather with the regulation of gene expression. This is a significant part of what is referred to as the murky underworld of EPIGENOMICS. Moreover, the protein is dynamic and has secondary, tertiary and multimeric structure. The chromatin that binds to DNA is also compressing on its special configuration over time. There is also a regulatory interaction between the endoplasmic reticulum and the nuclear RNA, which has relevance to remodeling, assembly, and autophagy. In addition, we view the vital importance of the mitochondrion in respiration via the electron transport chain, but it has become clear that the mitochondrion is also involved in mitophagy. So, what do we have that’s new here – lysosome, ER, and mitochondria participate in autophagy in some balance with apoptosis – leading to death or repair. This is not genetically driven. This has been the challenge of cancer and cell metastasis. Mutations occur, but these are downstream, as the cancer cell takes on a survival strategy of its own, separating from and in conflict with the tissue of origin.

Thus, we have a great challenge to pharmaceutical development. The importance of diagnostics that is improving at a rapid rate becomes critical for discovery at an early stage. However, despite the seeming importance of early screening, it is not necessarily feasible for early detection. Then we have to rely on symptoms and signs, which are less than perfect. Our knowledge of metabolic pathways, forays into signaling, and targeting may make further inroads to success. The understanding of the neuroendocrine balance and diseases of cognition is still in infancy.

 

 

Chapter 9:         BioPharma – Future Trends

 

Introduction

 

The early chapters gave extensive coverage of physiology, biochemistry, the emergence of related molecular biology discipline, and investigational tools.
Chapter 7 was concerned with physiology and therapeutics. This last chapter looks at the future of pharmaceuticals. We have seen that DNA, RNA and proteins have provided biomarkers for disease that have been explosively identified over the last two decades. The first biomarkers were the first generation troponins and the pro B- and B- terminal natriuretic peptides that have now been followed by second and third generation biomarkers of much higher sensitivity, and the atrial natriuretic peptic in cardiac ischemia and heart failure. These are critical for guiding cardiovascular intervention, which has to be done in a timely manner. If anything might be said about this, it follows Burton Sobel’s dictum – ‘Time is muscle’.

In the last decade the genome has been mapped and the methods have been introduced for the detection of circulating DNA and RNA’s. The RNAs are not uniform species, after the knowledge of mRNA, mtRNA, siRNA, and miRNA. The microRNAs have been a focus of biomarker discovery.

Finally, we now have a window into the mechanism of cell regulation, autophagy, respiration, glycolysis, the pentose phosphate shunt, and cell replication. These processes involve interacting pathways called signaling pathways, of which there are a good number. The result of this evolving picture of the cell has redirected pharmaceutical development towards the targeting of enzymes and signaling pathways that are expressed in the dysregulated cell.

 

Summary

 

This concluding chapter is focused on the future of therapeutics. Stents and surgical procedures are not a topic, but it is important to state that stent design now commonly uses pharmacologic agents. The articles selected are significantly represented by Dr. Stephen J. Williams, who is actively representing the Pharmaceutical Development. There are also two important contributions from Tilda Barliya on biopharma immobilized on microparticle delivery beads. Finally, there are unique contributions to the work in cellular immunology by Dr. Demet Sag.

Where is research being directed into the future?

1. The identification of targets specific for pathways of interest.
2. The reduction of toxicities – not merely livable side effects
3. The reduction of side-effect activation of alternative pathways that may well be associated with drug failure.
4. The improvement of quality of life and greater acceptance of preventive measures in public health.
5. Expansion of research and results in understanding neurophysiology and neural cognitive mechanisms.
6. Greater ability to improve the conundrum of the rapid evolution of mild to moderate systemic inflammatory response syndrome to sepsis to multiple organ failure.
7. Greater ability to manage chronic inflammatory diseases through therapeutic resolution of a hyperactive T- cell recognition.
8. Improved design and validation of animal models.
9. Progress in the development of tissue regeneration.

 

Epilogue

Larry H Bernstein, MD, FCAP

 

This book cannot be complete, as there is much work that needs to be done to advance medicine beyond what exists today. In the brief presentations, it is perhaps not surprising that much is left out. What we have achieved in making this journey should have made this a valuable read.

There is a certain unity that the consecutive chapters hold between one another. The following points have been made:

1. The history of medical advances is reviewed and the related basic sciences viewed through the awarding of Nobel Prizes, and the shift from the discoveries in biochemistry – which required extraction, purification, and characterization of molecules – initially catalytic proteins.
2. The important technological advances are identified that enabled discoveries in several periods – largely after the 1920’s.
3. The history of plagues and the emergence of microbiology, parasitology, virology, especially after the Civil War, and public health measures after the Second World War.
4. The increasing utilization of natural products as sources for development of new drugs is pointed out.
5. Molecular biology emerges as a rigorous framework for translating the molecular mechanisms of signaling, protein conformation, DNA transcription and protein synthesis, suppression of metabolic pathways and the opportunities for targeted pharmaceutical development.
6. The impact of environmental factors and behavioral factors on health is dissected from – Diet, exercise, stress, altitude, deep water immersion, underground existence, disordered endocrine activities, mental disabilities.
7. The evolution of both the diagnostics and the pharmaceutical industries is followed, and the need to move forward with early diagnosis using biomarkers, and the need for biomarker guided therapy, and for biomarker based pharmaceutical targeting of critical pathways.
8. A special treatment of protein structure, and of the role of proteins in fast reactions is stressed.
9. A discussion of All-transthyretin, retinol-binding protein, the impact of retinol (vitamin A) on growth and development, and a role in vitamin D synthesis. Protein energy malnutrition may be a S insufficiency brought on either by voluntary or involuntary deficient diet intake, not without consequence.
10. The intricate relationship between the endocrine hormones and the brain, and some insights into cognitive balance are provided.
11. Pharmacogenomics and genomics are included as important factors in treatment decisions.
12. The metabolic response to injury is divided into a catabolic phase with multi-hormone drivers of the response, with limits to tissue loss, and the healing phase is anabolism.
13. The metabolism of the cell appears to be a balancing between autophagy, mitochondrial respiration, and ER and cell matrix health.

 

Volume Three

2015

Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective 

Disponible en Amazon.com desde el 27/12/2015

http://www.amazon.com/dp/B019VH97LU