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Cell Research News – What’s to Follow?

Larry H. Bernstein, MD, FCAP, Reporter

Leaders in Pharmaceutical Intelligence

https://pharmaceuticalintelligence.com/2014/08/26/larryhbern/Cell_Research_News_-_What’s_to_Follow?

 

Stem Cell Research ‘Holy Grail’ Uncovered, Thanks to Zebrafish

By Estel Grace Masangkay

With help from the zebrafish, a team of Australian researchers has uncovered how
hematopoietic stem cells (HSC) renew themselves.

HSCs refers to stem cells present in the blood and bone marrow that are used 
for  the replenishment of the body’s supply of blood and immune cells – 

  • in transplants for leukemia and myeloma.
  • Stem cells have the potential to transform into vital cells

    including muscle, bone, and blood vessels.

Understanding how HSCs form and renew themselves has potential application in the
treatment of

  • spinal cord injuries
  • degenerative disorders
  • diabetes.

Professor Peter Currie, of the Australian Regen Med Institute at Victoria’s Monash
University, led a research team to discover a crucial part of HSC’s development. Using 
a high-resolution microscopy, Prof. Curie’s team 

  • caught zebrafish embyonic SCs on film as they formed. 
  • the researchers were studying muscle mutations in the aquatic animal.

“Zebrafish make ESCs in exactly the same way as humans do, but their embryos and
larvae develop free living, but the larvae are both free swimming and transparent, so one could see every cell in the body forming, including ESCs,” explained Prof. Currie.

The researchers noticed in films that a

  •  ‘buddy cell’ came along to help the ESCs form.

Called endotome cells, 

  • they aided pre-ESCs to turn into ESCs.  

Prof. Currie said that endotome cells act as helper cells for pre-ESCs , 

  • helping them progress to become fully fledged stem cells.

The team not only

  • identified some of the cells and signals 
  • required for ESC formation, but also 
  • pinpointed the genes required 
  • for endotome formation in the first place.

The next step for the researchers is to 

  • locate the signals present in the endotome cells 
  • that trigger ESC formation in the embryo. 

This may provide clues for developing

  • specific blood cells on demand for blood-related disorders. 

Professor Currie also pointed out the discovery’s potential for 

  • correcting genetic defects in the cell and 
  • transplanting them back in the body to treat disorders.

The team’s work was published in the international journal Nature.

 

Jell-O Like Biomaterial Could Hold Key to Cancer Cell Destruction

by Estel Grace Masangkay

Scientists from Penn State University reported that a biomaterial made of tiny 
molecules was able to attract and destroy cancer cells.

Professor Yong Wang and bioengineering faculty at Penn State, built the 
tissue-like biomaterial to accomplish what chemotherapy could not –

  • kill every cancer cell without leaving
  • the possibility of a recurrence.

Prof. Wang and team built polymers 

  • from tiny molecules called monomers. They
  • then wove the polymers into 3D networks 

called hydrogels. Hydrogel is soft and flexible, 
like Jell-O, and it contains a lot of water, and

  • can be safely put into the body, unlike 

other implants that the body often tries 

  • to get rid of through the immune response.

“We want to make sure the materials we are using are compatible in the body.”

The researchers 

  • attached aptamers to the hydrogels, 
  • which release bio-chemical signal-only molecules 
  • that draw in cancer cells. 

Once attracted, the cancer cells are entrapped in the Jell-O-like substance. 

What happens next is 

  • an oligonucleotide binds to the protein-binding site of the aptamer 
  • and triggers the release of anticancer drugs at the proper time.

“Once we trap the cancer cells, we can deliver anticancer drugs 

  • to that specific location to kill them. 

This technique would help avoid the need for systemic medications that kill not only cancer cells, but normal cells as well. Systemic chemotherapy drugs

  • make patients devastatingly sick and possibly 
  • leave behind cancer cells to wreak havoc another day

If our new technique has any side effects at all, it would be only local side 
effects and not whole-body systemic side effects,” explained Prof. Wang.

The initial results of the research were published by Prof. Wang in the 
Journal of the American Chemical Society in 2012. Prof. Wang also shared 
the latest results of his work at the Society for Biomaterials Meeting &
 Exposition in April this year.

 

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Guidelines for the Diagnosis and Treatment of Endocarditis

from

British Society of Antimicrobial Chemotherapy (BSAC)

Clinicians who care for patients diagnosed with infective endocarditis (IE) are (un)fortunate to be able to refer to several guidelines about its diagnosis and treatment. The guidelines vary considerably, especially with regards to antibiotic prescribing recommendations, which generally reflect local practice and expert opinion in light of largely observational data. All guidelines recommend a multidisciplinary approach to the management of IE.

Infective endocarditis

Infective endocarditis (Photo credit: Wikipedia)

Echocardiography remains a cornerstone of IE diagnosis but is neither 100% sensitive nor specific and multiple scans may be needed to identify vegetations. Echocardiography should also be used in all patients with Staphylococcus aureus bacteraemia. The prevalence of IE among patients with S aureus bacteraemia is variable but was reported as 13% in one large prospective US study and 22% in a recent European study. Clinical assessment is unreliable in diagnosing IE in patients with S aureus bacteraemia and without echocardiography the diagnosis may be missed. Transoesophageal echocardiography is now recommended in most cases of suspected or confirmed IE but may be unnecessary in patients with right-sided valve involvement.

Establishing a microbiological diagnosis in an era of increasingly complex infections with unpredictable resistance patterns is important. However, traditional recommendations for blood culture sampling have been amended for patients with suspected IE and severe sepsis or septic shock. In this situation, two (rather than three) sets of blood cultures, taken at different times within an hour before the start of empirical treatment, are now advised. This is a pragmatic recommendation to avoid undue delay in starting empirical antimicrobial treatment. In other patients, the usual need for three sets of blood cultures is recommended but with at least 6 h between sampling times; an important aim of multiple sampling is to demonstrate the presence of a sustained or persistent bacteraemia, which is characteristic of IE. Identification of atypical micro-organisms using serology in culture-negative cases should be limited to Coxiella and Bartonella in the first instance—a reflection of the extremely small numbers of reported cases of IE caused by Mycoplasma, Brucella and Legionella.

Fungal causes of IE should be considered in culture-negative IE if serology is non-diagnostic and the patient is immunocompromised, has a prosthetic valve, is an intravenous drug user or is not responding to empirical antibacterial treatment. The application of broad-range (16S ribosomal RNA gene) PCR on surgically resected valves or embolic material should be used when culture has failed. False-negative 16S ribosomal RNA gene PCR reactions can occur in the presence of inhibitors of the DNA polymerase within clinical samples or as a result of the vagaries of sampling (ie, processing a piece of tissue that does not contain any bacteria). Bacterial DNA has been shown to be present within cardiac tissue several years after successful treatment of IE, so results should be interpreted with caution in a patient with a previous diagnosis of IE. Application of 16S ribosomal gene PCR to blood in patients with IE is problematic owing to the low levels of bacteria present (1–10 fu/ml) and subsequent difficulty in DNA extraction; as a result it is not currently available for routine clinical use.

Empirical treatment (that started before obtaining a microbiological diagnosis) is generally discouraged, except in those who are acutely unwell or shocked. There is no clear evidence that speeding up the diagnosis, and instigation of treatment, improves outcomes, although this would seem intuitive. Early treatment (started within days of onset of symptoms rather than weeks) is a laudable aim, but the few days delay in hospital while appropriate echocardiographic and microbiological tests are undertaken on a stable patient are unlikely to have a negative impact on outcome. Conversely, the administration of broad-spectrum antibiotics when the diagnosis of IE has not been considered (and often when inadequate samples have been obtained) may have considerable impact on the ability to establish the diagnosis and subsequently deliver effective treatment.

Outpatient antibiotic treatment (OPAT) for IE is included in the BSAC guidelines in response to increasing efforts to expand these services and manage more patients outside hospital. Patients who might be considered for OPAT include those who are stable and responding well to treatment, are without signs of heart failure and without any indications for surgery or uncontrolled extracardiac foci of infection. Delivery of OPAT requires appropriate funding, support and infrastructure, coupled with the ability to rapidly access inpatient services and obtain urgent expert advice if needed. This has been proved to be feasible and safe in the UK, even in high-risk IE cases.

Although the guidelines include recommendations for most causes of IE, the predominant pathogens remain staphylococci, streptococci and enterococci. Routine addition of gentamicin to flucloxacillin for the treatment of native valve staphylococcal IE is no longer recommended (see Table 1). This recommendation is unchanged from previous BSAC guidelines but the ESC continue to include gentamicin as an optional addition. Further evidence of the toxicity of gentamicin has been published, based on findings from a randomised controlled trial comparing daptomycin with either vancomycin or cloxacillin plus gentamicin for the treatment of S aureus bloodstream infection or IE Recommendations for meticillin-resistant staphylococci also differ from those of the ESC; although vancomycin is the primary agent in both sets of guidelines, rifampicin is recommended by BSAC in place of gentamicin because of concerns about efficacy and toxicity. Daptomycin, a recently licensed lipopeptide, is also recommended as an alternative agent for patients who are intolerant to vancomycin or have infection caused by vancomycin-resistant isolates.

Previous recommendations for treatment of streptococcal IE have been simplified, with greater emphasis placed on benzylpenicillin rather than amoxicillin as the primary agent to reduce risk of Clostridium difficile infection. Enterococcal treatment regimens are largely consistent with the ESC guidelines, though a low threshold for withdrawing gentamicin in patients with deteriorating renal function or other signs of toxicity is advised, based on observational data that shorter gentamicin courses are not associated with worse outcomes.

The timing of cardiac surgery in IE should be evaluated by the multidisciplinary team on a case by case basis. Attempts to advise whether cardiac surgery should be emergent, urgent or elective can seem artificial. The traditional indications for surgery in IE are well established but it is becoming apparent that patients with IE caused by S aureus, or patients with evidence of systemic embolisation, should also be considered for early surgery, which may confer a mortality benefit.

Device-related infections have been deliberately omitted from the current BSAC guidance as the challenges in preventing, diagnosing and treating cases of intracardiac device IE are different from ‘traditional’ native or prosthetic valve IE. Further specific device-related guidance is likely to be published in the future and a joint working party involving the BSAC, BCS and Heart Rhythm UK has been established. IE guidelines are always imperfect owing to the difficulties in studying this relatively uncommon condition and the scarcity of randomised trials. At present, we are uncertain of the incidence, risk factors, causative micro-organisms (and their antimicrobial sensitivities), and patient outcomes in IE affecting the UK population. A recently established national endocarditis database may help to answer some of these questions, but its success will be crucially determined by the degree of support and national participation. See http://www.neemo.leedsth.nhs.uk/ (only via the N3 network) for details.

see source for more

Reported by: Dr. V. S. Karra, Ph.D

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