Protective effects of novel diazepinone derivatives in snake venom induced sterile inflammation in experimental animals.

Snake envenomation leads to the formation of damage-associated molecular patterns (DAMPs), which are mediated by endogenous intracellular molecules. These are recognized by pattern-recognition receptors (PRRs) and can induce sterile inflammation. AIMS: In the present study, we aim at understanding the mechanisms involved in DAMPs induced sterile inflammation to unravel the novel therapeutic strategies for treating snake bites. The potential of benzodiazepinone derivatives to act against snake venom induced inflammation has been explored in the present investigation. MAIN METHODS: Three compounds VA 17, VA 43 and PA 03 were taken from our library of synthetic compounds. Oxidative stress markers such as lipid peroxidation, superoxide and nitric oxide were measured along with the analysis of DAMPs (IL6, HMGB1, vWF, S100b and HSP70). These compounds have been docked using molecular docking against the snake venom PLA2 structure (PDB code: 1OXL). KEY FINDINGS: The compounds have been found to effectively neutralize viper and cobra venoms induced lethal activity both ex vivo and in vivo. The compounds have also neutralized the viper venom induced hemorrhagic, coagulant, anticoagulant reactions as well as inflammation. The fold of protection have always been found to be higher in case of ex vivo than in in vivo. These compounds have neutralized the venom induced DAMPs as exhibited by IL6, HMGB1, vWF, S100b and HSP70. The fold of neutralization is found to be higher in VA 43. SIGNIFICANCE: The identified compounds could be used as potential candidates for developing treatment of snakebites in areas where antiserums are not yet available.

An Anatomical Variation of Median Artery of Forearm and Palm: Cadaveric Study into its Origin and Course.

Background The median artery (transitory artery) represents the forearm's embryonic arterial axis. At 8th week of gestation retreats into a little canal that supplies the median nerve. Later, ulnar and radial arteries take its place. Adults may still have it in either a palmar or an antebrachial pattern. The persistent median arteries are a long, angular arterial that extends to the hand's palmar surface. The median artery only partially recedes in the antebrachial type. Objective To identify the median artery distribution in the adult Nepalese population. Method Twenty-five adult human cadavers' left and right upper limbs undergone to descriptive research. The persistent median artery was exposed according to the Cunningham's Manual of Practical Anatomy. Result The forearm and hand arteries in each of the fifty upper limbs from the twentyfive formalin-embalmed human cadavers were studied. Among fifty upper limbs, persistent median arteries were found in six (twelve percent) of them. One percent of a cadaver's right and left limbs had bilateral persisting median arteries (ante brachial). Persistent median artery of the ante brachial type that arises from the anterior interosseous artery in a right upper limb. Persistent median artery emerging from the posterior interosseous arteries were visible in one right upper limb. Conclusion The study showed persistent median artery of ante brachial type. The posterior interosseus artery is the source of the majority of antebrachial type. A median artery piercing the median nerve was discovered.

Therapeutic efficacy of G207 in a novel peripheral nerve sheath tumor model.

Nerve involvement poses a significant obstacle for the management of peripheral nervous system tumors, and nerve injury provides a frequent source of postoperative morbidity. The lack of suitable animal models for peripheral nerve tumors has impeded the development of alternative nerve-sparing therapies. To evaluate the effect of a multimutated replication-competent herpes simplex virus (G207) on the growth of peripheral nerve tumors and on nerve function, we developed a novel peripheral nerve sheath tumor model. Human neuroblastoma-derived cells injected into murine sciatic nerve consistently caused tumor development within the nerve sheath after 2 weeks followed by increasingly severe impairment of nerve function. Tumor treatment by a single intratumoral injection of G207 resulted in significant reduction of functional impairment, inhibition of tumor growth and prolonged survival. Direct injection of G207 viral particles into the healthy nerve sheath caused no obvious neurologic sequelae, whereas injections of wild-type virus resulted in uniform lethality. The results indicate that viral therapy might be considered as a safe alternative to surgical removal of tumors with peripheral nerve involvement.

The angiogenic factor midkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen for neurofibroma-derived cells.

Loss of the tumor suppressor gene NF1 in neurofibromatosis type 1 (NF1) contributes to the development of a variety of tumors, including malignant peripheral nerve sheath tumors (MPNST) and benign neurofibromas. Of the different cell types found in neurofibromas, Schwann cells usually provide between 40 and 80%, and are thought to be critical for tumor growth. Here we describe the identification of growth factors that are upregulated in NF1-/- mouse Schwann cells and are potential regulators of angiogenesis and cell growth. Basic fibroblast growth factor (FGF-2), platelet-derived growth factor (PDGF) and midkine (MK) were found to be induced by loss of neurofibromin and MK was further characterized. MK was induced in human neurofibromas, schwannomas, and various nervous system tumors associated with NF1 or NF2; midkine showed an expression pattern overlapping but distinct from its homolog pleiotrophin (PTN). Immunohistochemistry revealed expression of MK in S-100 positive Schwann cells of dermal and plexiform neurofibromas, and in endothelial cells of tumor blood vessels, but not in normal blood vessels. Furthermore, MK demonstrated potent mitogenic activity for human systemic and brain endothelial cells in vitro and stimulated proliferation and soft agar colony formation of human MPNST derived S100 positive cells and fibroblastoid cells derived from an NF1 neurofibroma. The data support a possible central role for MK as a mediator of angiogenesis and neurofibroma growth in NF1. Oncogene (2001) 20, 97 - 105.

Current status of passive tuberculosis detection in a rural district of J & K.

PIP: Tuberculosis affects one-fifth of mankind and kills more people than any other infectious disease; yet misdiagnosis and under-reporting are rampant. The situation in rural areas is especially disappointing. Despite decades of a national-level program for control of tuberculosis, no improvement has occurred in detection and reporting. Analysis and comparison of the records of the District Tuberculosis Centre in a rural district have shown almost no improvement in the dismal performance over the last full decade. The failure of passive detection of cases, especially the bacillary positive cases, has suggested that active detection coupled with epidemiological investigation is needed to boost routine case detection and to find out the bottlenecks in the implementation of the National Tuberculosis Program in rural areas.^ieng

Beta 2-microglobulin amyloidosis presenting as esophageal perforation in a hemodialysis patient.

A 45-year-old male with hypertensive end-stage renal disease and on maintenance hemodialysis for 13 years is reported. He presented with life-threatening hematemesis, secondary to esophageal rupture. Immunohistological staining and electron microscopy examination of the esophageal perforation showed depositions of beta 2-microglobulin (beta 2-M) amyoloid. The unique aspect presented here is the localized esophageal involvement with beta 2-M amyloidosis. This is the first reported patient with esophageal perforation, due to the deposition and infiltration of the lower esophagus with beta 2-M which predisposed to its rupture.

Recognizing Weber-Christian disease.

The eponym Weber-Christian Disease (WCD) defines a chronic disorder characterized by relapsing febrile episodes and panniculitis. Systemic manifestations due to visceral involvement may be present. WCD is associated with no identifiable cause, although chronic panniculitis may be due to definable underlying disorders. A variety of distinctive disease entities, such as systemic lupus erythematosus (SLE), pancreatic disease, alpha-I-antitrypsin disease, lymphoproliferative neoplasia, infections, or trauma are associated with chronic panniculitis. The accurate diagnosis of panniculitis requires an adequate deep skin biopsy showing inflammation of the subcutaneous layers. We describe a white woman with fever and recurrent episodes of painful nodules of the lower extremities, excisional biopsy of which confirmed panniculitis. The febrile episodes and skin lesions responded dramatically with the use of oral corticosteroids.

Recurrence of systemic lupus erythematosus in a hemodialysis patient presenting as a unilateral abducens nerve palsy.

A 45-year-old hemodialysis patient presenting with recurrence of SLE which manifested predominantly as a unilateral left abducens (VIth) nerve palsy is described. The signs and symptoms of the cranial nerve palsy resolved within two weeks of initiating corticosteroid therapy. This is the first reported case of an abducens nerve palsy occurring in a maintenance hemodialysis patient associated with recurrence of SLE.

Fulminating systemic capillary leak syndrome with lymphocytosis and hypogammaglobulinemia.

We report a case of fulminating systemic capillary leak syndrome which temporarily responded to verapamil, a calcium channel blocker. We noted two features of the disease not previously reported: a rise in lymphocyte count 2-3 days prior to an attack, and hypogammaglobulinemia. These findings are discussed in relation to the possible etiology of this disease.

Pulmonary haemorrhage following renal transplantation.

The case history is presented of a 32 year old black man who developed haemoptysis leading to pulmonary haemorrhage and bilateral pulmonary infiltrates. He was found to have Kaposi's sarcoma of the lung with no evidence of skin or endobronchial lesions.

Interpretation of positive edrophonium (Tensilon) test in patients with end-stage renal disease.

Many patients with end-stage renal disease (ESRD) have signs and symptoms of easy fatigability, fluctuating weakness, apathy, dry mouth, and blurring of vision. These symptoms can be confused with disorders of neuromuscular transmission. When present, the physician may want to determine whether the patient has myasthenia gravis--the commonest of all neuromuscular disorders--and administer the edrophonium (Tensilon) test. An unequivocally positive response to the test must be interpreted with caution in ESRD. However, the exact mechanism of a positive response is unclear but may be explained by metabolic abnormalities related to end-stage renal disease, i.e., uremic toxins, disordered calcium metabolism, abnormal neuromuscular mechanism, associated neurological disorders, or myopathic processes in uremia, all of which can affect neuromuscular transmission.

Mechanism of vasoconstriction induced by chronic inhibition of nitric oxide in rats.

Either acute or chronic inhibition of nitric oxide synthesis by L-arginine analogues results in increases in mean arterial pressure and reductions in renal blood flow. The role of endogenous vasoconstrictors in mediating these effects is not entirely clear. In the present study, nitric oxide was inhibited in male Sprague-Dawley rats by oral administration of nitro-L-arginine for 3 weeks. At the end of this time, mean arterial pressure was 30 to 40 mm Hg higher than in normal controls, renal blood flow and glomerular filtration rate were 25% to 30% lower, and renal vascular resistance was markedly increased. Intravenous infusion of receptor antagonists for angiotensin II, thromboxane, epinephrine, and endothelin-1 had no significant effect on the hypertension. Inhibition of prostaglandin synthesis and furosemide-induced diuresis in the presence of angiotensin blockade also had no effect on blood pressure. Renal vascular resistance was also unaffected by these interventions, except that saralasin did reduce renal resistance in both control and nitric oxide-inhibited groups. However, the absolute level of renal vascular resistance remained higher in the latter group. Calcium channel blockade partially corrected blood pressure and renal resistance, but the levels remained significantly higher than in control animals. The findings are consistent with the view that the increase in vascular smooth muscle tone caused by inhibition of nitric oxide synthesis cannot be accounted for by overexpression of common endogenous vasoconstrictors. Rather, the generalized increase in vascular smooth muscle tone appears to be due to a direct effect of reduced nitric oxide availability, which may lead to an increase in intracellular calcium concentration or sensitivity.

An adult patient with hyperimmunoglobulemia E (Job's) syndrome, end-stage renal disease and repeated episodes of peritonitis.

We report the first case of an adult patient with hyperimmunoglobulemia E (Job's) syndrome, end-stage renal disease and repeated episodes of Staphylococcus peritonitis. A 42-year-old black female with end-stage renal disease was treated with hemodialysis, and later switched to peritoneal dialysis because of severe vascular access problems. On CAPD, she had numerous (> 15) episodes of staphylococcal peritonitis. Past history included chronic atopic eczema and repeated sinopulmonary infections since childhood. She was found to have serum IgE levels greater than 10,000 units/ml. This combination of repeated infections, chronic skin condition and phenomenal elevation of IgE levels establish the diagnosis of hyperimmunoglobulemia E (Job's) syndrome. The cause of repeated episodes of Staphylococcal peritonitis are presumed to be related to impaired host defense mechanisms known to be present in patients with this disorder. As nephrologists, we should be aware that patients with impaired host defense mechanisms are highly susceptible to peritonitis in the presence of an indwelling peritoneal catheter.

Pathology of mesenteric lymph nodes of buffaloes and cattle with special reference to salmonellosis.

Enlarged mesenteric lymph nodes were collected from ninety buffaloes and sixty cattle slaughtered at Faisalabad abattoir. Among these, salmonellae were isolated from lymph nodes of 32 (21.33%) animals. Maximum preponderance of salmonellosis was recorded in animals over two years of age. Enlargement, pale to dark red in color, increased consistency and even calcification were the main gross pathological lesions. Histopathological lesions included thickened capsule, typical lymphofollicular reaction, accumulation of oedematous fluid and haemorrhages.