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Phosphatidyl-5-Inositol Signaling by Pin1

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Genome Biology, Metabolomics, Molecular Genetics & Pharmaceutical, Nutrigenomics, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Systemic Inflammatory Response Related Disorders, tagged , , , , , , , , , , on March 5, 2013| Leave a Comment »

Phosphatidyl-5-Inositol Signaling by Pin1

 

Reporter: Larry H Bernstein, MD, FCAP

 

Regulation of Phosphatidylinositol-5-Phosphate Signaling by Pin1 Determines Sensitivity to Oxidative Stress

Willem-Jan Keune et al.
Increasing the abundance of the phospholipid PtdIns5P protects cells from oxidative stress.
Science Signaling   27 nov 2012; 5:252.
  1. T cell receptor (TCR) and costimulatory molecule mediated signaling
  2. culminate in maximal cytokine mRNA production and stability.
The transcriptional responses to co-stimulatory T cell signaling involve calcineurin and NF-AT, which
    • can be antagonized by interference with the cis-trans peptidyl-prolyl isomerases (PPIase), cyclophilin A and FKBP.
Signaling molecules downstream of CD28
    • which are essential for the stabilization of cytokine mRNAs are largely unknown.

Pin1, a third member of the PPIase family

    • mediates the post-transcriptional regulation of Th1 cytokines by activated T cells.

Blockade of Pin1 by pharmacologic or genetic means

  • greatly attenuated IFN-γ, IL-2 and CXCL-10 mRNA
    • stability,
    • accumulation and
    • protein expression after cell activation.

In vivo, Pin1 blockade prevented

  • both the acute and chronic rejection of MHC mismatched, orthotopic rat lung transplants by
  • reducing the expression of IFN-γ and CXCL-10.

Combined transcriptional and post-transcriptional blockade with

    • cyclosporine A and the Pin1 inhibitor, juglone, was synergistic.

These data suggest Pin1 inhibitors should be explored for use as immunosuppressants and employed with available calcineurin inhibitors to reduce toxicity and enhance effectiveness.
Esnault S, Braun RK, Shen Z-J, Xiang Z, Heninger E, et al. (2007)
Pin1 Modulates the Type 1 Immune Response. PLoS ONE 2(2): e226.  http://dx. doi.org/10.1371/journal.pone.0000226

Mixed-lineage kinase 3 phosphorylates prolyl-isomerase Pin1 to regulate its nuclear translocation and cellular function
Velusamy Rangasamya,1, Rajakishore Mishraa,1, Gautam Sondarvaa, Subhasis Dasa, et al.
Loyola University Chicago, Maywood, IL 60153;  Beth Israel Deaconess Medical Center, Boston, MA 02115; University of Mississippi Medical Center, Jackson, MS 39216;
University of Wisconsin, Madison, WI 53705; Hines Veterans Affairs Medical Center, Hines, IL 60141; and College of Veterinary Medicine, Iowa State University, Ames, IA 50011
Edited* by Michael Karin, University of California, San Diego School of Medicine, La Jolla, CA, and approved April 11, 2012
Nuclear protein peptidyl-prolyl isomerase Pin1-mediated prolyl isomerization is

  • an essential and novel regulatory mechanism for protein phosphorylation.

Therefore, tight regulation of Pin1 localization and catalytic activity is

  • crucial for its normal nuclear functions.

Pin1 is commonly dysregulated during oncogenesis and likely contributes to these pathologies; The mechanism by which Pin1 catalytic activity and nuclear localization are increased is unknown.
Here we demonstrate that

  1. mixed-lineage kinase 3 (MLK3), a MAP3K family member,
  2. phosphorylates Pin1 on a Ser138 site
  3. to increase its catalytic activity and nuclear translocation.
This phosphorylation event

  1. drives the cell cycle and
  2. promotes cyclin D1 stability and centrosome amplification.

Pin1 pSer138 is significantly

  • up-regulated in breast tumors and
  • is localized in the nucleus.

These findings collectively suggest that the MLK3-Pin1 signaling cascade plays a critical role

  1. in regulating the cell cycle,
  2. centrosome numbers, and
  3. oncogenesis. breast cancer

JNK Peptidyl-prolyl isomerase Pin1 plays a critical role in

  • regulating cellular homeostasis by
  • isomerizing the prolyl bond preceded by
  • a phosphorylated Ser or Thr residue (pSer/Thr-Pro) (1).

This isomerization by Pin1 regulates the biological function of several target proteins, including

  • cell-cycle regulators,
  • protooncogenes,
  • tumor suppressors, and
  • transcription factors (2).
Due to its role in controlling the cell cycle, apoptosis, growth, and stress responses, Pin1 has been linked to the pathogenesis of human diseases, including
  • cancer (3, 4),
  • asthma (5),
  • Alzheimer’s disease (AD) (6), and
  • Parkinson disease (PD) (7).

It is thus quite likely that tight regulation of Pin1 catalytic activity or expression is important for normal physiology. It is reported that Pin1 is

  • overexpressed in most types of cancer (8), whereas
  • its expression is diminished in AD brains (2).

Accumulating evidence suggests that Pin1 isomerase activity

  • and thus function are regulated by posttranslational modifications (2).

Pin1 function is also dependent on its

  • predominant nuclear localization (2),
    • consistent with its substrates being involved in transcription and cell-cycle progression.

It was recently reported that Pin1 nuclear import is regulated by a novel nuclear localization sequence in the PPIase domain, composed of basic amino acids (9). Nonetheless, the detailed mechanism that regulates Pin1 nuclear translocation is still not known. It also remains unknown whether any posttranslational modification of Pin1 can regulate its nuclear translocation or catalytic activity, and therefore directly affect its function.

Stereospecific gating of functional motions in Pin1
Andrew T. Namanjaa, Xiaodong J. Wangb, Bailing Xub, et al.
University of Notre Dame, Notre Dame, IN 46556; Virginia Tech, Blacksburg, VA 24061
Edited by Peter E. Wright, The Scripps Research Institute, La Jolla, CA, and approved June 2, 2011
Pin1 is a modular enzyme that

  • accelerates the cis-trans isomerization of phosphorylated-Ser/Thr-Pro (pS/T-P) motifs
  • found in numerous signaling proteins regulating cell growth and neuronal survival.

We have used NMR to investigate the interaction of Pin1 with three related ligands that include

  1. a pS-P substrate peptide, and
  2. two pS-P substrate analogue inhibitors
    • locked in the cis and trans conformations.

We compared the

  • ligand binding modes and
  • binding-induced changes
    • in Pin1 side-chain flexibility.

The cis and trans binding modes differ, and

  • produce different mobility in Pin1.

The cis-locked inhibitor and substrate produced a

  • loss of side-chain flexibility
    • along an internal conduit of conserved hydrophobic residues,
    • connecting the domain interface with the isomerase active site.

The trans-locked inhibitor

  • produces a weaker conduit response.

Thus, the conduit response is stereoselective. We further show

  • interactions between the peptidyl-prolyl isomerase and
  • Trp-Trp (WW) domains
    • amplify the conduit response, and
    • alter binding properties at the remote peptidyl-prolyl isomerase active site.

These results suggest that

  • specific input conformations can gate dynamic changes that support intraprotein communication.

Such gating may help control the propagation of chemical signals by Pin1, and other modular signaling proteins.

allostery ∣ protein dynamics ∣ ligand dynamics ∣ protein evolution
Phospho-serine/threonine-proline (pS/T-P) motifs are
signaling motifs within
intrinsically disordered loops of cell cycle proteins (1).
The imide bond between the pS/T and P residues can adopt

  • either the cis or trans conformation.

These conformations differ

  • in their susceptibility to kinases and phosphatases

that propagate the chemical signals governing the cell cycle.
Accordingly, the cell must regulate the cis/trans populations of these pS/T-P motifs

  • to ensure proper signal routing.

In this context, the peptidyl-prolyl isomerase Pin1 has emerged as a critical regulator (2, 3). Pin1 is a reversible enzyme that

  • catalyzes the cis-trans isomerization of the pS/T-P imide linkages (2, 3) of other signaling proteins, such as
  1. CDC25C,
  2. p53,
  3. c-Myc,
  4. NF-kB,
  5. cyclin D1, and
  6. tau (3).

Pin1 engages when external events, such as

  • S/T (de)-phosphorylation, change the cis-trans equilibrium.

Pin1 then

  1. catalyzes the cis-trans isomerization, thereby
  2. accelerating the approach to the new equilibrium (1).

Pin1 is a modular protein of 163 residues consisting of a

  • WW domain (1–39) and a larger
  • peptidyl-prolyl isomerase (PPIase) domain (50–163) (Fig. 1).

A flexible linker connects the two domains.

  1. Both domains are specific for pS/T-P motifs (1).
  2. The WW domain serves as a docking module, whereas
  3. catalysis is the sole province of the PPIase domain.

Earlier structural studies of Pin1 revealed

  1. conformational changes upon substrate interaction, thus
  2. motivating flexibility-function studies of Pin1 (4–6).
Peptidyl-prolyl Isomerase Pin1 Controls Down-regulation of Conventional Protein Kinase C Isozymes
JBC Papers in Press, Feb 8, 2012.       http://dx.doi.org/10.1074/jbc.M112.349753

H Abrahamsen, AK O’Neill, N Kannan, N Kruse¶, et al.
From the University of California, San Diego, La Jolla, California 92093
Background: Conventional PKC isozymes have a putative Pin1

  • isomerization sequence at their turn motif phosphorylation site.
Results: Pin1 binds conventional PKCs and

    • promotes their activation-induced down-regulation.
Conclusion: Pin1 isomerizes the phosphorylated turn motif of conventional PKC isozymes,

    • priming them for subsequent down-regulation.
Significance: Pin1 provides a switch regulating the lifetime of conventional PKCs. The down-regulation or cellular depletion of protein kinase C (PKC)
  • attendant to prolonged activation by phorbol esters is a
  • widely described property of this key family of signaling enzymes.

However, neither the mechanism of down-regulation nor whether this mechanism occurs following stimulation by physiological agonists is known.
**the peptidylprolyl isomerase Pin1 provides a timer for the lifetime of conventional PKC isozymes,

  • converting the enzymes into a species that can be dephosphorylated and ubiquitinated
  • following activation induced by either phorbol esters or natural agonists.

The regulation by Pin1 requires both the catalytic activity of the isomerase and the presence of a Pro immediately following the phosphorylated Thr of
the turn motif phosphorylation site,

  • one of two C-terminal sites that is phosphorylated during the maturation of PKC isozymes.
  • the second C-terminal phosphorylation site, the hydrophobic motif, docks
    • Pin1 to PKC.

Our data are consistent with a model in which Pin1

  • binds the hydrophobic motif of conventional PKC isozymes to catalyze the isomerization of the phospho-Thr-Pro peptide bond at the turn motif, thus
  • converting these PKC  isozymes into species that can be efficiently down-regulated following activation.

The peptidyl-prolyl cis-trans isomerase Pin1 is emerging as an important regulator of signal transduction pathways (1).

Pin1-catalyzed isomerization plays a key role in the control of normal cellular functions, most notably proliferation where

    • Pin1 is essential for cell cycle progression (2).

Pin1 belongs to the Parvulin family of peptidyl-prolyl cis-trans isomerases and is the only member that

  • specifically isomerizes phospho-(Ser/Thr)-Pro ((Ser(P)/Thr(P))-Pro) motifs (3):
  1. the enzyme displays an 1000-fold selectivity for peptides phosphorylated on the
  2. Ser/Thr preceding the Pro compared with unphosphorylated peptides (3).
Pin1–induced conformational changes in target proteins

  • affect a variety of protein properties from
    • folding to
    • regulation of activity and stability.

As a consequence, deregulation of phosphorylation steps and their attendant conformational changes often lead to disease (4). For example, Pin1 is
downregulated in degenerating neurons from Alzheimer disease patients, correlating with age-dependent neurodegeneration (5).
Pin1 has also been implicated in cancer progression:
levels of this protein are increased in many cancers, including those of the

    • breast,
    • prostate,
    • brain,
    • lung, and
    • colon (6–9).

Thus, Pin1 has been proposed to function as a catalyst for oncogenic pathways (10). The molecular mechanisms that lead to disease progression

  • most likely involve postphosphorylation conformational changes
    • catalyzed by Pin1
    • that are required for downstream effects.
Related articles
The human immunophilin protein FKBP12 colored ...

The human immunophilin protein FKBP12 colored by hydrophobicity (white = hydrophobic) with bound FK506, an immunosuppressant used in treating organ transplant patients to prevent rejection. FKBP also has unrelated prolyl isomerase activity. (Photo credit: Wikipedia)

The human immunophilin protein FKBP12 colored ...

The human immunophilin protein FKBP12 colored by secondary structure with bound FK506, an immunosuppressant used in treating organ transplant patients to prevent rejection. FKBP also has unrelated prolyl isomerase activity. (Photo credit: Wikipedia)

 

 

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Modern Society, Risk and Mentally Disordered Offender

Posted in Cerebrovascular and Neurodegenerative Diseases, tagged , , , , , , , on January 4, 2013| 7 Comments »

Author: Dr Anayo Unachukwu, MBBS, LLM

 

Modern society is built on the twin pillars of Judaeo-Christian jurisprudence and Graeco-Roman civilisation. The jurisprudence has provided us with the moral[1], ethical and legal system that has sustained the civilisation. The civilisation prides itself with the legacy it bequeathed modern society-science. Revolution in science has often been preceded by revolution in measurement. The scientific endeavours have led to delineating, characterising, validating and reliably predicting and identifying the origin of concepts, phenomena, etc encountered by mankind and seeking remedies for these with some degree of certainty and accuracy. The prodigious advances in science and technology within the ethico-legal framework that stemmed from it have brought with it advantages in medical science and related fields. These pervade our every day environment; and we are all witnesses to the consequences of its innovation and creativity. Given the new found confidence in these fields, there have been attempts by medical and behavioural scientists to stretch its research frontiers further in providing succinct explanation to often complex human behaviour and interaction within social spheres. The science behind these quests usually has aural of purity-value free and bereft of ideology. However as Rose puts it: “It may well be that it is only in the periods of social and intellectual crisis that we can glimpse the interconnections between science and social system.[2]

One of the preoccupations of prehistoric man has been attempts at classification and categorisation; this heuristic pursuit-through generalisation-is a way of navigating the complex environment he finds himself. Attempts at generalisation by extrapolating from medical model to account for mental disorders[3] have not altogether been helpful. This could be due to lack of clarity in understanding the aetiological underpinnings; stigma and labeling intrinsic to the sufferers and skepticisms that surround the practice of psychiatry.

The mentally disordered offender raises questions which have troubled theologians, moral philosophers and lawyers throughout the Christian era.[4] It is not only these professions that grapple with this group of offenders; as Eastman puts it psychopaths[5] are the moral and scientific junctional case between the mad and the bad, both in terms of treatment and of punishment.[6]

Psychopathy[7] as a construct throws up more questions than answers-origin, remedial attempts[8] and heuristic generalisation as regards prognostic inferences. There is larger debate on whether psychopathy and personality disorder[9] are primarily legal or diagnostic categories, or neither.[10] Given that psychopathy straddles interpersonal and social domain in everyday human endeavours which impacts on both clinical and legal settings; one would have thought that a complete delineation and categorisation would have been understood by relevant practitioners[11] involved, but this appears not to be the case. Some researchers both clinical and non clinical strongly disagree on the nosological certainty of psychopathy and its inclusion in the medical classificatory system.

However, all agrees that the disorder generates a lot of controversy; and the emotive[12] issue that it provokes-social, psychological, economic and legal-reverberates further afield way beyond the field of clinical sciences.

From social policy perspective, other characteristics of psychopathy notwithstanding, criminal and violent behaviours are the main hallmarks of the disorder.[13] Psychopaths are high risk offenders with many criminogenic needs (i.e., personal characteristics correlated with recidivism).[14] In fact, recent research efforts have shown that there is a relationship between psychopathy and both general and violent crimes.[15] The criminogenic derivative that stem from the disorder had a legal ringing endorsement.[16]

In contrast to the relationship between psychopathy and rate of recidivism; Gibbens et al[17] eight-year comparative follow-up study on criminal psychopaths (diagnosed as ‘severe cases’) and criminal non psychopaths as regards their reconviction rates showed insignificant differences in the reconviction rate for both groups. The conclusion from this study was broadly similar to a two year follow-up study by Walker et al[18] which compared the rates of reconviction amongst psychopaths and non psychopaths who were diagnosed with severe mental illness, schizophrenia and those diagnosed as subnormal (learning disability); the rate of recidivism for both groups were not statistically significant.

Without making an extraordinary reading of the follow-up studies, Cooke et al[19] had argued that criminal behaviour should not play a central role in the diagnosis of psychopathy; instead such behaviour is best viewed as a secondary feature; or sequel of the disorder. This view is consistent with Cleckley’s original classical description of psychopathy where criminal behaviour was not intrinsic to the disorder; the motivation of the behaviour when it is present is usually obscure.[20] Criminality and psychopathy are not the same construct; the core features of the disorder-glib charm, callousness, arrogance, shallow affect, deceitfulness, and lack of empathy do not necessarily involve or imply criminal behaviour.[21] Why then is there such a great emphasis in diagnosis of this disorder? The answer partly lies in the society we live. There appears to be an inverse relationship between the tolerance of risk[22] in a given society and its level of affluence. There is a political imperative driven by popular lay press for a ‘risk free’ society; such an unrealistic expectation has led to the bourgeoning of research in risk instruments for assessment and management of risks. The trend in the wider society, technological advances and rise in consumerism has all further fueled this gusto-risk intolerance. Risk assessment as a concept is not a legal issue per se as competence to stand trial or criminal responsibility; however, it forms important part of different decision making in law. As Fennell puts it, there is a role redefinition whereby risk management has assumed increasing centrality in the role of psychiatrists and other mental health professionals, and philosophies of risk management now permeate decision-making in both the psychiatric system and penal system.[23] It is a given that psychopaths are involved in violent crimes and they recidivate for both violent and non violent crime compared to non psychopath; hence violence risk is an “indirect” legal issue often relevant to ultimate decisions but rarely defining the ultimate issue specifically.[24] Therapeutic jurisprudence[25] partly relies on risk assessment and management in deciding on disposal options available when dealing with mentally disordered offenders. As Leacock and Sparks remarked; Risk…is a fashionable idea—one whose moment would appears to have arrived.[26] Risk is now so integral to every day discourse given the high profile homicides; most notable was the killing of Jonathan Zito (in England) by a stranger, Christopher Clunis, who suffered from schizophrenia. As a result, the risk management/public protection agenda is now prominent-in England and Wales-and since 1992, health authorities have a duty to carry out an independent inquiry in any case of homicide or suicide by a mentally disordered person in their care.[27]

Conclusion

 

Mentally disordered offenders-like the poor-will always be in our midst. Labelling and stigmatising this group as a whole may be unhelpful at best and amounts to discrimination. Managing risk out every day discourse is naivete to the extreme, given that in any society a trade-off has to be made as far as risk goes. Criminality as a construct should not be synonymous with psychopathy, given that not all psychopaths offend and not all criminals are psychopaths.

[1] Psychopathy which under the Mental Health Act 1983 is classified as a mental disorder is seen by some philosophers, lawyers, clinicians and the society at large as essentially a moral disorder. See Maibon, H.L. The Mad, the Bad, and the Psychopath. Neuroethics (2008) 1:167-184. DOI 10.1007/s12152-008-9013-9.

[2] Rose, S., Rose, H. (1971). The myth of the neutrality of science. In Watson Fuller (ed). The SOCIAL IMPACT OF MODERN BIOLOGY.Routledge & Keegan Paul. London. p.233

[3] The adoption of this term was recommended in the Report of the Royal Commission on the law relating to Mental Illness and Mental deficiency 1954-1957 (Cmnd 169 (1957)) Pt 3 paras 146-198. The Commission recommended its use as a general term covering all forms of mental ill-health or disability. S (1) of the amended Mental Health Act 2007 gives a broader description of mental disorder-any disorder of the mind; ‘mentally disordered’ shall be construed accordingly.

[4] Walker, N. (1968) Crime and Insanity in England. vol. I. Edinburgh University Press. p. 6

[5] Psychopathy is a personality disorder defined by a cluster of interpersonal, affective, and lifestyle characteristics that results in serious, negative consequences for society.

[6] Eastman, N (2002). The Ethics of Clinical Risk Assessment and Management:Developing Law and the Role of Mental Health Professionals. In Gray, N,  Lain, J,  Noaks, L. (Eds.). Criminal Justice, Mental Health and the Politics of Risk.(pp. 49-66). Cavendish Publishing Limited.

[7] The adverb psychopathic means literally ‘psychically damaged’ and was introduced in the 19th century Germany to cover all forms of psychopathology. From the outset it should be distinguished from psychopathic disorder which is a legal concept. Authors disagree on its definition; sometimes the usage is in vernacular, and this paints a derogatory picture. See Gunn, J. and Robertson G. (1976b) Psychopathic Personality: a conceptual problem. Psychological Medicine, 6, 63-4 (386).

[8] Cleckley, H. (1941). The mask of insanity. St. Louis, MO: Mosby. The present day conceptualisation of psychopathy is credited to the systematic writings and observation of Cleckley. He expressed concerns about the progressive nature of the disorder, social malady it posed to the society and therapeutic nihilism associated with it.

[9] The defining characteristic of personality disorder more than any symptom is the incomprehensibility and inaccessibility that the sufferer provokes in other people. It is classified as a mental disorder by both two international classificatory systems- World Health Organisation. (1992) International Classification of Disease and Related Health Problems: ICD-10. Geneva: WHO; and American Psychiatric Association. (1994) Diagnostic and Statistical Manual of Mental Disorders. DSM-IV. WashingtonDC: Mental Health Service.

[10] Ogloff, J.R.P., & Lyon, D.R. (1998). Legal issues associated with the concept of psychopathy. In D.J. Cooke, A.E. Forth, & R. D. Hare (Eds) Psychopathy: theory, research, and implications for society (pp. 401-422). Dordrecht, The Netherlands: Kluwer.

[11] Unfortunately among various practitioners not just legal practitioners, but most clinicians the conceptual cousins of psychopathy-sociopathy, dissocial personality and antisocial personality have been mistaken for psychopathy. See Gacono, C.B., Nieberding, R., Owen, A., Rubel, J., & Bodholdt, R. (2000). Treating juvenile and adult offenders with conduct disorder, antisocial and psychopathic personalities. In J. Ashford, B. Sales, & W.Reid (Eds.), Treating clients with special needs. WashingtonDC: American Psychological Association.

[12] Hare, R.D. (1996a). Psychopathy: A construct whose time has come. Criminal Justice Behavior. 23, 25-54.

[13] Patrick, C.J. (2006). Handbook of Psychopathy The Guilford Press. p.555

[14] Zinger, I., & Forth, A.E. (1998). Psychopathy and Canadian criminal proceedings: The potential for human right abuses. Canadian Journal of Criminology, 40, 237-276.

[15] Salekin, R.T., Rogers, R., & Sewell, K. W. (1996). A review and meta-analysis of the Psychopathy Checklist and Psychopathy checklist-Revised. Clinical Psychology: Science and Practice, 3, 203-215

[16] Carraher v HM Advocate 1946 JC 108 at 117, per Lord Normand: it is to my mind descriptive rather of a typical criminal than a person…regarded as being possessed of diminished responsibility.

[17] Gibbens, T.C.N., Pond, D.A. and Stafford-Clark, ‘A Follow-up Study of Criminal Psychopaths’ in (1959) 105, Journal of Mental Science, 108 ff.

[18] Walker, N., McCabe, S. (1973) Crime and Insanity in England. Vol. II. p.212. Edinburgh University Press.

[19] Cooke, D. J., Michie, C., Hart, S. D., et al (2004) Reconstructing psychopathy: Clarifying the significance of antisocial and socially deviant behavior in the diagnosis of psychopathic personality disorder. Journal of Personality Disorders, 18, 337-357.

[20] Cleckley,H. (1988) The Mask of Sanity (5th edn). Mosby. p.279

[21] Hare, R.D. (1998). Psychopathy, affect, and behaviour. In D.J. Cooke, A.E.Forth, & R.D. (Eds.), Psychopathy, theory, research, and implication for society (pp104-137). Dordrecht, the Netherlands: Kluwer.

[22] Risk is defined as the uncertainty of outcome whether opportunity or negative threat, of actions and event

[23] P, Fennell (2002) .The Ethics of Clinical Risk Assessment and Management:Developing Law and the Role of Mental Health Professionals. In Gray, N,  Lain, J,  Noaks, L. (Eds.). Criminal Justice, Mental Health and the Politics of Risk.(pp. 49-66). Cavendish Publishing Limited.

[24] Roesch, R., & McLachlan, K. (2007). Clinical Forensic Psychology and Law. Ashgate Publishing Ltd.

[25] Wexler, D., & Winck, B. (Eds.) (1996). Law in a therapeutic key. Durham, NC: Carolina Academic Press. At p. 32 describe it as a concept that addresses the issue of how knowledge, theories and insight of the mental health disciplines can help shape the development of law.

[26] R.D. Mackay (2002). Criminal Justice, Mental Health and the Politics of Risk. Crim. L.R. 2002, Sep, 765-767.

[27] Fennell, P (2010). HISTORY AND CONTEXT OF MENTAL HEALTH LAW AND POLICY. In Gostin, L., Bartlett, P., McHale, J., Mackay, R. (eds). PRINCIPLE OF MENTAL HEALTH POLICY AND LAW. Oxford University Press. p.53.

 

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Why is Dysthymia, a chronic form of Depression, serious, requiring Medical Intervention

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Innovations in Neurophysiology & Neuropsychology, Pain: Etiology, Genetics & Innovations in Treatment, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, tagged , , , , , on October 16, 2012| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Dysthymia: Often Chronic, Always Serious

Johns Hopkins Health Alert

Dysthymia is a chronic form of depression that is characterized by the presence of a depressed mood for most of the day, for more days than not, over a period of at least two years. Dysthymia may be intermittent and interspersed with periods of feeling normal, but these periods of improvement last for no more than two months.

Dysthymia often goes unnoticed. And because of its chronic nature, the person may come to believe, “I’ve always been this way.” In addition to depressed mood, symptoms of dysthymia include two or more of the following:

It is far better to treat dysthymia than to think of it as a minor condition. Bypassing treatment places people at increased risk for subsequently developing major depression. In fact, about 10 percent of people with dysthymia also have recurrent episodes of major depression, a condition known as double depression.

What causes of dysthymia?  Some medical conditions, including neurological disorders (such as multiple sclerosis and stroke), hypothyroidism, fibromyalgia and chronic fatigue syndrome, are associated with dysthymia. Investigators believe that, in these cases, developing dysthymia is not a psychological reaction to being ill but rather is a biological effect of these disorders.

There are many reasons for this connection. It may be that these medical conditions interfere with the action of neurotransmitters, or that medications (such as corticosteroids or beta-blockers) taken for a medical illness may trigger the dysthymia or that both dysthymia and the medical illness are related in some other way, reinforcing each other in a complicated manner.

Dysthymia can also follow severe psychological stress, such as losing a spouse or caring for a chronically ill loved one. Older people who have never had psychiatric disorders are particularly susceptible to developing dysthymia after significant life stresses.

Posted in Depression and Anxiety on October 16, 2012

Medical Disclaimer: This information is not intended to substitute for the advice of a physician. Click here for additional information: Johns Hopkins Health Alerts Disclaimer

 

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