Low frequency of factor V Leiden and prothrombin G20210A mutations in patients with hepatic venous outflow tract obstruction in northern India: a case-control study.

BACKGROUND: Factor V Leiden (FVL) and prothrombin gene (G20210A) mutations are known to be associated with venous thromboembolism. Several studies have shown an association of these mutations with hepatic venous outflow tract obstruction (HVOTO). We studied the prevalence of these mutations among patients with HVOTO in northern India in comparison with healthy population. METHODS: Genomic DNA from patients with HVOTO and healthy controls was analyzed for the presence of FVL and prothrombin gene G20210A mutations, using PCR and restriction-fragment length polymorphism. RESULTS: Fifty-nine patients with HVOTO (age 5-69 years, median 27; 39 male) and 49 unrelated healthy controls from the same geographic region were studied. Of the 59 patients, 19 had a block in the hepatic vein, 7 in inferior vena cava, and 33 had mixed block. Presentation was with acute thrombosis in 9 patients and with long-standing obstruction in 50 patients. Among 49 controls, heterozygous and homozygous FVL mutations were observed in 2 and 0 subjects, respectively, with an allele frequency of 2% (2 of 98). In comparison, among 59 patients with HVOTO, four had heterozygous and none had homozygous FVL mutation, with an allele frequency of 3.4% (p=ns versus controls). The G20210A prothrombin gene mutation was not found in any of the patients or controls. CONCLUSION: FVL and prothrombin G20210A mutations appear to have no role in the pathogenesis of HVOTO in our patients with Budd-Chiari syndrome, consisting largely of those with long-standing obstruction of the inferior vena cava.     

Natural History of Epileptic Seizures

Since 1963 a continuous registration of patients with epileptic seizures has been carried out in Greater Aarhus, Denmark. This registration has been attempted by means of medical records dating back to 1940. On the basis of the established prevalence and the calculated cumulated incidence, we have tried to describe the natural history of the different types of epilepsy. The prevalence of all types of epileptic seizures (including febrile convulsions) has been found to be 2,441/100,000, whereas for patients with the diagnosis of epilepsy the rate is 1,274/100,000. The study describes the natural history of the different types of epilepsy. In addition, the risk-increasing effect of a febrile convulsive seizure on the development of epilepsy is analyzed.     

Effects of a one-year administration of phosphate and intermittent calcitonin on bone-forming and bone-resorbing cells in involutional osteoporosis: A histomorphometric study

Summary The bone histomorphometric effects of intermittent phosphate and calcitonin therapy during 1 year were analyzed in 15 involutional osteoporotic patients. Phosphate was administered continuously (1.5 g/day) and calcitonin was injected during 5 days every third week (50 IU/day). The bone cell response was analyzed in two separate groups, according to the amount of trabecular bone present in the iliac bone biopsy: patients with trabecular bone volume (TBV) beyond the histomorphometric spontaneous fracture threshold (0.16 mm3/mm3) (group 1; 11 patients) and patients with TBV above this threshold (group 2; 4 patients). In group 1, the treatment significantly increased TBV from 0.113±0.025 to 0.156±0.046 mm3/mm3 by thickening the existing trabeculae rather than by creating new trabeculae; stimulation of bone formation rate (+50%) and significant reduction in active trabecular resorption surfaces (from 0.021±0.013 to 0.010±0.006 mm2/mm2;P<.05) may have led to positive bone balance. In group 2, TBV was not changed because of the treatment's relative inefficiency for reducing the bone-resorbing cell activity, leading to likely persistent negative bone balance. Cortical thickness did not change in either group. This study confirms the positive effectiveness of continuous treatment with phosphate and intermittent calcitonin during 1 year on bone balance in involutional osteoporosis with low amount of bone. The lack of response in patients with normal amount of bone must be verified before raising the hypothesis of different bone cell activity and before anticipating the therapeutic response according to local bone mass besides bone remodeling status in osteoporosis.     

Oral candidiasis and human immunodeficiency virus infection

The association of oral candidiasis with the human immunodeficiency virus (HIV) infection has been known since the advent of the acquired immunodeficiency syndrome (AIDS) pandemic. Oral candidiasis is one of the earliest premonitory signs of HIV infection and its diagnosis may have grave prognostic implications for the eventual development of full blown AIDS. There is now an expanding body of data on novel clinical variants of this 'old' disease, its epidemiology in HIV seropositive individuals and, advances in its management, particularly with respect to the recently introduced bis-triazole antifungals. Current concepts pertaining to the epidemiology, clinical features, pathogenesis, laboratory diagnosis and management of oral candidiasis in HIV infection are reviewed.     

Inhibitory gating modulation of small conductance Ca2+-activated K+ channels by the synthetic compound (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) reduces afterhyperpolarizing current in hippocampal CA1 neurons

SK channels are small conductance Ca(2+)-activated K(+) channels important for the control of neuronal excitability, the fine tuning of firing patterns, and the regulation of synaptic mechanisms. The classic SK channel pharmacology has largely focused on the peptide apamin, which acts extracellularly by a pore-blocking mechanism. 1-Ethyl-2-benzimidazolinone (1-EBIO) and 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309) have been identified as positive gating modulators that increase the apparent Ca(2+) sensitivity of SK channels. In the present study, we describe inhibitory gating modulation as a novel principle for selective inhibition of SK channels. In whole-cell patch-clamp experiments, the compound (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) reversibly inhibited recombinant SK3-mediated currents (human SK3 and rat SK3) with potencies around 100 nM. However, in contrast to known pore blockers, NS8593 did not inhibit (125)I-apamin binding. Using excised patches, it was demonstrated that NS8593 decreased the Ca(2+) sensitivity by shifting the activation curve for Ca(2+) to the right, only slightly affecting the maximal Ca(2+)-activated SK current. NS8593 inhibited all the SK1-3 subtypes Ca(2+)-dependently (K(d) = 0.42, 0.60, and 0.73 microM, respectively, at 0.5 microM Ca(2+)), whereas the compound did not affect the Ca(2+)-activated K(+) channels of intermediate and large conductance (hIK and hBK channels, respectively). The site of action was accessible from both sides of the membrane, and the NS8593-mediated inhibition was prevented in the presence of a high concentration of the positive modulator NS309. NS8593 was further tested on mouse CA1 neurons in hippocampal slices and shown to inhibit the apaminand tubocurarine-sensitive SK-mediated afterhyperpolarizing current, at a concentration of 3 microM.     

Salivary cortisol and self-reported stress among persons with environmental annoyance

OBJECTIVES: Increased vulnerability to stress has been suggested as a possible mechanism behind medically unexplained conditions such as sensitivity to electricity and common smells. This study examined whether subjective environmental annoyance among the general population is associated with increased physiological reactivity or subjective stress scores. METHODS: Four groups were studied (N=141): an electrically annoyed (N=17), a smell-annoyed (N=29), and a generally annoyed group (N=39) and a reference group matched for age, gender, and socioeconomic status (N=56). Over 5 days, the participants collected saliva for cortisol determination at awakening, 30 minutes after awakening, 8 hours after awakening, and at 9 o'clock in the evening. On the evening preceding the fifth day, the participants ingested a 0.5-mg dexamethasone tablet so that possible differential suppression of the hypothalamic-pituitary-adrenal (HPA) axis could be assessed. Each day, the participants also rated their subjective stress and health complaints. RESULTS: No significant differences were found between the groups regarding cortisol secretion over 5 days. The dexamethasone suppression test showed inhibited cortisol secretion in all four groups. No associations were found between the cortisol concentrations and the self-reported stress scores or subjective health complaints. CONCLUSIONS: Although the environmentally annoyed groups showed no signs of increased HPA-axis activation, being annoyed by both electrical devices and smells seems to be related to increased psychological activation in terms of self-reported stress. Because the participants were otherwise healthy and recruited from the general population, the results imply that subtle psychological stress processes may be important in the early development of environmental annoyance.     

Pharmacological effect on pyeloureteric dynamics with a clinical perspective: a review of the literature

We searched to review experimental and clinical trials concerning the capabilities of impacting on the ureteric and pelvic activity by means of pharmacological stimulation. Ureteropyeloscopy may cause high renal pelvic pressure. The normal pressure is in the range of 5–15 mmHg whereas pressure of 410 mmHg has been measured during endoscopy. The threshold pressure for intrarenal reflux is about 35 mmHg. Studies in animals have revealed that high renal pelvic pressures may cause permanent damage to the renal parenchyma. Furthermore, it has been demonstrated that elevated pressures may entail an increased risk of several complications related to endourological procedures including bleeding, perforation and infection. In other words, means by which intrarenal pressure could be lowered during endourological procedures might be beneficial with respect to clinical outcomes. In vitro experiments support the existence of different receptors in the ureter and renal pelvis. The ureteric and pelvic responses to the corresponding neurotransmitters have been determined. It seems that α-adrenergic and cholinergic agents are stimulating whereas β-adrenergic agents inhibit ureteric activity. The effect may depend on the mode of administration. Drugs exerting advantageous effects in the pyeloureter may cause undesirable systemic side effects when administered intravenously. In animal studies, renal pelvic pressure can be significantly lowered by topical administration of β-adrenergic agonists without systemic side effects. In vivo human studies are necessary to clarify the exact dose–response relationship and the degree of urothelial absorption of a drug before clinical use may be adopted.