Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease

Heterozygous missense mutations in the caveolin-3 gene (CAV3) cause different muscle disorders. Most patients with CAV3 alterations present with rippling muscle disease (RMD) characterized by signs of increased muscle irritability without muscle weakness. In some patients, CAV3 mutations underlie the progressive limb-girdle muscular dystrophy type 1C (LGMD1C). Here, we report two unrelated patients with novel homozygous mutations (L86P and A92T) in CAV3. Both presented with a more severe clinical phenotype than usually seen in RMD. Immunohistochemical and immunoblot analyses of muscle biopsies showed a strong reduction of caveolin-3 in both homozygous RMD patients similar to the findings in heterozygous RMD. Electron microscopy studies showed a nearly complete absence of caveolae in the sarcolemma in all RMD patients analyzed. Additional plasma membrane irregularities (small plasmalemmal discontinuities, subsarcolemmal vacuoles, abnormal papillary projections) were more pronounced in homozygous than in heterozygous RMD patients. A stronger activation of nitric oxide synthase was observed in both homozygous patients compared with heterozygous RMD. Like in LGMD1C, dysferlin immunoreactivity is reduced in RMD but more pronounced in homozygous as compared with heterozygous RMD. Thus, we further extend the phenotypic variability of muscle caveolinopathies by identification of a severe form of RMD associated with homozygous CAV3 mutations.     

Sudden sensorineural hearing loss: systemic steroid therapy and the risk of glucocorticoid-induced hyperglycemia

Sudden sensorineural hearing loss is usually treated with systemic glucocorticoids. Intratympanic injections of glucocorticoids offer a possibly equivalent treatment alternative, avoiding adverse systemic effects on blood glucose. We, therefore, investigated the extent to which different doses of systemic glucocorticoid therapy affects blood glucose levels. We conducted a retrospective analysis of treatment courses in 179 patients from the Departments of Otorhinolaryngology, Ophthalmology and Dermatology who underwent short-course systemic glucocorticoid therapy. Patients were subdivided into three groups on the basis of their cumulative prednisolone dose from days 1 to 3 (Group 1: <750 mg; Group 2: 750–1,499 mg; Group 3: >1,499 mg); in addition, a distinction was made between diabetic and non-diabetic patients. Among the non-diabetic patients on days 2–4, diabetic levels of fasting blood glucose were detected significantly more often (P < 0.01) in Group 3 (67 %) than in Group 1 (28 %) and Group 2 (21 %). Furthermore, there was a highly significant mean Pearson correlation (r = 0.329; P < 0.01) between blood glucose levels and glucocorticoid dose. This correlation was even more pronounced in the diabetic patients (r = 0.51; P = 0.02). In this category, hyperglycemia was detected in 40 % of patients in Group 1, 63 % in Group 2 and 100 % in Group 3. The prevalence of glucocorticoid-induced hyperglycemia during systemic therapy is high and rises as the dose increases. This should be kept in mind when choosing the dosage. Besides, it should also be considered that even short-term hyperglycemia presents possible health risks and the risk of inducing diabetes. This is especially of interest as intratympanic therapy offers a possible alternative to the systemic application.     

To spike or not to spike: A probabilistic spiking neuron model

Spiking neural networks (SNN) are promising artificial neural network (ANN) models as they utilise information representation as trains of spikes, that adds new dimensions of time, frequency and phase to the structure and the functionality of ANN. The current SNN models though are deterministic, that restricts their applications for large scale engineering and cognitive modelling of stochastic processes. This paper proposes a novel probabilistic spiking neuron model (pSNM) and suggests ways of building pSNN for a wide range of applications including classification, string pattern recognition and associative memory. It also extends previously published computational neurogenetic models.     

Heat shock protein 90 mediates macrophage activation by Taxol and bacterial lipopolysaccharide

Taxol, a plant-derived antitumor agent, stabilizes microtubules. Taxol also elicits cell signals in a manner indistinguishable from bacterial lipopolysaccharide (LPS). LPS-like actions of Taxol are controlled by the lps gene and are independent of binding to the known Taxol target, beta-tubulin. Using biotin-labeled Taxol, avidin-agarose affinity chromatography, and peptide mass fingerprinting, we identified two Taxol targets from mouse macrophages and brain as heat shock proteins (Hsps) of the 70- and 90-kDa families. Geldanamycin, a specific inhibitor of the Hsp 90 family, blocked the nuclear translocation of NF-kappaB and expression of tumor necrosis factor in macrophages treated with Taxol or with LPS. Geldanamycin did not block microtubule bundling by Taxol or macrophage activation by tumor necrosis factor. Thus, Taxol binds Hsps, and Hsp 90 helps mediate the activation of macrophages by Taxol and by LPS.     

Development of a Master of Health Policy and Management programme in the framework of the Tempus project at the Centre School of Public Health,Belgrade

Background  

The most important instrument of EU support for the reforms of higher education in the European countries with the final goal of joining the European Higher Education (HE) Area by the year 2010 is TEMPUS (Trans-European Mobility Programme for University Studies). So far, Tempus is the only EU programme providing support for the reform of HE in the Western Balkans.     

The role of lecithin cholesterol acyltransferase and organic substances from coal in the etiology of Balkan endemic nephropathy: a new hypothesis.

Balkan endemic nephropathy (BEN) occurs in Serbia, Bulgaria, Romania, Bosnia and Herzegovina, and Croatia. BEN has been characterized as a chronic, slowly progressive renal disease of unknown etiology. In this study, we examined the influence of soluble organic compounds in drinking water leached from Pliocene lignite from BEN-endemic areas on plasma lecithin-cholesterol acyltransferase (LCAT) activity. We found that changes for all samples were the most prominent for the dilution category containing 90% plasma and 10% of diluting media. Water samples from BEN villages from Serbia and Romania showed higher LCAT inhibiting activity (p=0.02) and (p=0.003), respectively, compared to deionised water and non-endemic water. A secondary LCAT deficiency could result from this inhibitory effect of the organic compounds found in endemic water supplies and provide an ethiopathogenic basis for the development of BEN in the susceptible population.     

Toll-like receptor 9: a new target of ischemic preconditioning in the brain.

Preconditioning with lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) ligand, provides neuroprotection against subsequent cerebral ischemic brain injury, through a tumor necrosis factor (TNF)alpha-dependent process. Here, we report the first evidence that another TLR, TLR9, can induce neuroprotection. We show that the TLR9 ligand CpG oligodeoxynucleotide (ODN) can serve as a potent preconditioning stimulus and provide protection against ischemic brain injury. Our studies show that systemic administration of CpG ODN 1826 in advance of brain ischemia (middle cerebral artery occlusion (MCAO)) reduces ischemic damage up to 60% in a dose- and time-dependent manner. We also offer evidence that CpG ODN preconditioning can provide direct protection to cells of the central nervous system, as we have found marked neuroprotection in modeled ischemia in vitro. Finally, we show that CpG preconditioning significantly increases serum TNFalpha levels before MCAO and that TNFalpha is required for subsequent reduction in damage, as mice lacking TNFalpha are not protected against ischemic injury by CpG preconditioning. Our studies show that preconditioning with a TLR9 ligand induces neuroprotection against ischemic injury through a mechanism that shares common elements with LPS preconditioning via TLR4.     

Symptom structure and psychiatric comorbidity of combat-related post-traumatic stress disorder

The placement of the diagnostic category of post-traumatic stress disorder (PTSD) among anxiety disorders reflects the recognition that anxiety is a predominant reaction to trauma. Indeed, the symptoms of PTSD overlap considerably with those of other anxiety disorders. The nosological criteria render PTSD as quite a heterogeneous diagnosis. Two individuals with no common symptoms can be diagnosed as having PTSD. In this report we provide information on the phenomenology and psychiatric comorbidity in a sample of 33 patients with combat-related PTSD. The finding of clinical heterogeneity in subjects with combat-related PTSD and the therapy implications are discussed.     

Hepatitis B virus infection among pregnant women in Split region

A seroepidemiologic survey of pregnant women in Split region was performed in order to determine a strategy for prenatal screening for HBsAg. Thirty (7.5%) of 400 women had the markers of past or current HBV infection, while 3/400 (0.75%) were carriers. According to demographic data and risk factors they represent low risk population. General prenatal screening for HBsAg is advisable.