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Biomedical subjects

H Ashrafian

Publications and source records attributed to H Ashrafian.

11 recordsLinked to original sources
PubMed2004

Sensitizing the insensitive.

Lithium is still the treatment of choice in bipolar affective disorder. The patient presented here represents an example of the possible severity of metabolic defects resulting from lithium use. In this case, it caused severe intractable nephrogenic diabetes insipidus (NDI). Our case report draws attention to 2 important messages. The first is the complexity in treating psychiatric patients that is often not borne out in the medical literature. The second is the role and power of pharmacological augmentation. While the role of these agents has been appreciated for some time, the use of carbamazepine and of drug combinations is not as well recognized. We emphasize the clinical features of NDI, lithium's metabolic sequelae and furthermore collate the most up-to-date account of the signalling effects conferred by these agents in a summary diagram.

Aged↗
PubMed2001

Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis.

Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a genetic model of cardiac hypertrophy and sudden cardiac death. HCM has been defined as a disease of the cardiac sarcomere, but mutations in the known contractile protein disease genes are not found in up to one-third of cases. Further, no consistent changes in contractile properties are shared by these mutant proteins, implying that an abnormality of force generation may not be the underlying mechanism of disease. Instead, all of the sarcomeric mutations appear to result in inefficient use of ATP, suggesting that an inability to maintain normal ATP levels may be the central abnormality. To test this hypothesis we have examined candidate genes involved in energy homeostasis in the heart. We now describe mutations in PRKAG2, encoding the gamma(2) subunit of AMP-activated protein kinase (AMPK), in two families with severe HCM and aberrant conduction from atria to ventricles in some affected individuals (pre-excitation or Wolff-Parkinson-White syndrome). The mutations, one missense and one in-frame single codon insertion, occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, we propose that these data substantiate energy compromise as a unifying pathogenic mechanism in all forms of HCM. This conclusion should radically redirect thinking about this disorder and also, by establishing energy depletion as a cause of myocardial dysfunction, should be relevant to the acquired forms of heart muscle disease that HCM models.

Amino Acid Sequence↗
PubMed2001

A review of the causes of central pontine myelinosis: yet another apoptotic illness?

One of the well recognized stimuli for central pontine myelinosis (CPM) is the rapid correction of chronic hyponatraemia. Conventionally this has been perceived to lead to pontine glial cell swelling through osmosis and eventually to cell death. However, although a purely osmotic argument has been central to any patho-physiological understanding of CPM, there are deficiencies in this approach that do not account for why certain individuals develop CPM with relatively mild osmotic insults. Here we review the varying aetiologies of CPM and propose a novel hypothesis for CPM causation by suggesting that individuals predisposed to CPM have inadequate energy provision as well as other factors that result in a pro-apoptotic drive, which renders them susceptible to brain injury from diverse causes. In CPM, the precipitant of brain injury appears to be osmotic stress. Furthermore, this model suggests a number of therapeutic interventions that may prevent or at least mitigate the consequences of CPM.

Alcoholism↗
PubMed2001

Is amiodarone an underrecognized cause of acute respiratory failure in the ICU?

Amiodarone is a commonly used anti-arrhythmic agent, with well-recognized chronic toxicity. Less well known is amiodarone's potential to cause acute lung damage, which can be severe or, occasionally, life-threatening. Lungs that have already been exposed to physical insults, such as the lungs of patients undergoing cardiac surgery, are particularly susceptible to acute pulmonary toxicity (APT). Unfortunately, cardiac surgery is one of the clinical scenarios in which amiodarone is most commonly used. After reviewing the data, and even in the context of difficulties and discrepancies in the existing literature, we contend that there is sufficient evidence of amiodarone's potentially serious side-effect profile in surgical ICU patients to advise continued caution in its use with this severely ill patient group. We suggest that amiodarone has a potentially important, though underrecognized, role in inducing an APT/ARDS in some patients, such as those undergoing cardiac surgery. We also provide a hypothesis to explain the mechanism by which amiodarone causes lung damage.

Acute Disease↗
PubMed2000

New therapies for heart failure: is thalidomide the answer?

The syndrome of advanced heart failure is associated with considerable morbidity and mortality. Ideas about the reasons for the progressive nature of the heart failure syndrome have changed over the years, with the initial view that progression was principally due to pump failure (the 'haemodynamic' hypothesis), giving way to more modern views, which implicate neuro-endocrine activation (including catecholamine excess, renin-angiotensin system activation, etc.). More recently, an excess of inflammatory cytokines has been found in advanced heart failure and implicated in the progression of the disease. Amongst the cytokines found, TNF-alpha seems to be particularly important. The principle therapeutic action of thalidomide appears to be reduction of TNF-alpha levels. We therefore suggest that there may be a role for thalidomide, or its derivatives, in the management of advanced heart failure.

Heart Failure↗
PubMed1999

Molecular characterization of U937-dependent T-cell co-stimulation.

U937 cells provide a co-stimulatory signal for CD3-mediated T-cell activation which is independent of the CD28/CD80/CD86 interaction. This study set out to identify which molecules contribute to this co-stimulatory activity. Monoclonal antibodies (mAb) to the known accessory molecules CD11a, CD18, CD54 and CD45, all inhibited T-cell proliferation. Although CD11a/18 mAb inhibited U937/T-cell cluster formation as well as proliferation, CD45 enhanced the size of the clusters formed, suggesting that this was not the only mechanism of inhibition. The alternative co-stimulatory pathway provided by U937 cells preferentially stimulated a response in the CD18+ T-cell population, and this reflected the reduced sensitivity of CD8+ T cells to CD28-mediated activation. Monoclonal antibodies to three molecules, CD53, CD98 and CD147, also inhibited U937-dependent T-cell proliferation. The mAb to CD98 and CD147 were inhibitory when prepulsed on to the U937 cells, suggesting an effect mediated by these molecules on the antigen-presenting cell.

Antibodies, Monoclonal↗
PubMed1998

Expression of human papillomavirus type 16 L1 protein in Escherichia coli: denaturation, renaturation, and self-assembly of virus-like particles in vitro.

Major capsid protein L1 of HPV16 was produced in a fused form in Escherichia coli using an inducible expression system. The protein formed insoluble aggregations (inclusion bodies) and the yield was more than 10% of total cell proteins. The inclusion bodies were isolated and solubilised with 8 M urea and the L1 proteins were purified by chromatographic separation. Following removal of the urea by gradual dialysis, the denatured L1 proteins spontaneously renatured and subsequently assembled into polymorphologic aggregations in vitro. Electron microscopy showed that the assembled material included structures resembling native empty capsids as well as incompletely formed capsids. After separation from the pool of polymorphologic structures by sucrose gradient sedimentation, the correctly formed virus-like particles (VLE. coliPs) were recognised by a HPV16 type-specific, conformational-dependent monoclonal antibody in an ELISA. This system offers not only a model for investigation of the intrinsic interactions that occur during L1 assembly, but also a potential route for convenient manufacture of highly purified VLP vaccines.

Capsid Proteins↗