Addison's disease presenting with muscle spasm.

Primary hypoadrenalism has various causes and protean manifestation. We report a young female patient who presented with severe muscle spasm as her primary complaint. On evaluation she was found to be a case of Addison's disease secondary to adrenal tuberculosis. Her muscle spasm disappeared rapidly with replacement dose of glucocorticoid.

A novel Gymnema sylvestre extract stimulates insulin secretion from human islets in vivo and in vitro.

Many plant-based products have been suggested as potential antidiabetic agents, but few have been shown to be effective in treating the symptoms of Type 2 diabetes mellitus (T2DM) in human studies, and little is known of their mechanisms of action. Extracts of Gymnema sylvestre (GS) have been used for the treatment of T2DM in India for centuries. The effects of a novel high molecular weight GS extract, Om Santal Adivasi, (OSA(R)) on plasma insulin, C-peptide and glucose in a small cohort of patients with T2DM are reported here. Oral administration of OSA(R) (1 g/day, 60 days) induced significant increases in circulating insulin and C-peptide, which were associated with significant reductions in fasting and post-prandial blood glucose. In vitro measurements using isolated human islets of Langerhans demonstrated direct stimulatory effects of OSA(R) on insulin secretion from human ß-cells, consistent with an in vivo mode of action through enhancing insulin secretion. These in vivo and in vitro observations suggest that OSA(R) may provide a potential alternative therapy for the hyperglycemia associated with T2DM.

Combination of CTL-associated antigen-4 blockade and depletion of CD25 regulatory T cells enhance tumour immunity of dendritic cell-based vaccine in a mouse model of colon cancer.

Immune regulation has been shown to be involved in the progressive growth of some murine tumours. Interruption of immune regulatory pathways via CTL-associated antigen-4 (CTLA-4) blockade or removal of CD4(+) CD25(+) regulatory T (Treg) cells appears to be a promising strategy for cancer immunotherapy. In this study, we tested the hypothesis that the combination of CTLA-4 blockade and depletion of Treg cells would improve the potency of dendritic cell (DC)-based vaccine in a clinically relevant mouse model, which is transgenic for both carcinoembryonic antigen (CEA) and HLA-A2 for the treatment of colon carcinoma in a therapeutic setting. We found that administration of anti-CD25 antibody prior to vaccination or systemic administration of anti-CTLA-4 antibody with the vaccine improved tumour-free survival against CEA-expressing tumours compared with mice immunized with DC-based vaccine alone. However, the efficacy of the vaccine proved to be most effective when anti-CTLA-4 antibody was combined with Treg inhibition. This vaccination strategy dramatically improved the tumour-free survival and allowed the development of long-lasting immune responses. The combined vaccination strategy resulted in increased secretion of IFN-gamma and enhanced HLA-A2-restricted CEA-specific CTL responses. Furthermore, coadministration of anti-CD25 and anti-CTLA-4 antibodies along with the vaccine was effective against more advanced tumours. These results provide evidence that simultaneous blockade of T-cell regulatory pathways is a promising approach for the induction of therapeutic antitumour immunity against CEA(+) colon carcinoma.

A histopathological study of liver and biliary remnants with clinical outcome in cases of extrahepatic biliary atresia.

CONTEXT: The indicators of poor prognosis in cases of extrahepatic biliary atresia (EHBA) continue to remain controversial. AIMS: To correlate the histopathological findings of wedge biopsy from liver and tissue obtained from the shaving at the porta hepatis, during hepatic portoenterostomy, with the clinical outcome. MATERIALS AND METHODS: All cases of EHBA surgically treated in our hospital from 1995 to 2006 have been reviewed. Wedge biopsies of the liver and biopsies from the porta hepatis were analyzed with hemotoxylin-eosin stains and immunohistochemistry. The parameters correlated with clinical outcomes were--presence of large bile ducts ( > 150microm diameter) in the portal tissue plaque, degree of fibrosis (semi-quantitative; graded as mild, moderate and severe), presence of ductal plate malformation (DPM) and age at operation. RESULTS: The proportions of patients with small or large ductal diameter who remained clinically controlled (serum bilirubin < 1.5mg/dl with no evidence of end stage liver failure) were 39% and 66.6% respectively (P=0.44). There was a highly significant correlation between the extent of fibrosis and clinical outcome. Mild, moderate and severe fibrosis resulted in clinical control rates of 78.5%, 34.4% and 24% respectively (P=0.001). Ductal plate malformation was seen in 15% of our cases and was uniformly associated with poor outcome. A non-significant trend towards poorer outcome was seen with increasing age at surgery. CONCLUSIONS: Histopathological correl ations with clinical outcome in EHBA have been rarely reported from the Indian subcontinent. A greater degree of fibrosis at the time of hepatic portoenterostomy and presence of ductal plate malformation is associated with a significantly poorer clinical outcome.

Biosorption of heavy metals from industrial waste water by Geobacillus thermodenitrificans.

The metal binding capacity of the thermophilic bacteria Geobacillus thermodenitrificans isolated from Damodar river, India was assessed using synthetic metal solutions and industrial waste water. Biosorption preference of dead biomass of G. thermodenitrificans for the synthetic metal solutions was in the following order Fe(+3)>Cr(+3)>Co(+2)>Cu(+2)>Zn(+2)>Cd(+2)>Ag(+)>Pb(+2). It reduced the concentration of Fe(+3) (91.31%), Cr(+3) (80.80%), Co(+2) (79.71%), Cu(+2) (57.14%), Zn(+2) (55.14%), Cd(+2) (49.02%), Ag(+) (43.25%) and Pb(+2) (36.86%) at different optimum pH within 720 min. When this strain was applied in the industrial waste water biosorption preference was in the following order Fe(+3)>Cr(+3)>Cd(+2)>Pb(+2)>Cu(+2)>Co(+2)>Zn(+2)>Ag(+) and concentrations reduced up to 43.94% for Fe(+3), 39.2% for Cr(+3), 35.88% for Cd(+2), 18.22% for Pb(+2), 13.03% for Cu(+2), 11.43% for Co(+2), 9.02% for Zn(+2) and 7.65% for Ag(+) within 120 min.

Vertigo and dizziness--a clinical approach.

Dizziness is a term which is used to describe a variety of sensations. It is possible to group these complaints into four types: a rotational sensation (Type I dizziness), impending faint (Type II dizziness), dysequilibrium (Type III dizziness) and vague lightheadness (Type IV dizziness). Type I dizziness or vertigo is due to disease of the vestibular system--peripheral or central, and is characterized by a feeling of movement relative to one's surrounding. The majority of dizzy patients, however, belong to Types II, III and IV, collectively called the non-vestibular system disorders. The distinction is usually possible by a detailed history and clinical examination, but some special bedside tests--the dizziness simulation battery--are often required for properly distinguishing the various types of dizziness. Important causes of vertigo and the non-vestibular system disorders have been discussed with focus on benign positional vertigo, acute peripheral vestibulopathy, Menieres' disease, toxic damage to labyrinths, perilymph fistula, cerebrovascular disease, multiple sclerosis, cerebellopontine angle tumors, basilar migraine, vestibular epilepsy, cervical vertigo and phobic postural vertigo.

New modified single chained glycolipids. Part 1: synthesis of deoxy and partially O-methylated glycolipids with or without a sulfur containing spacer.

A way to synthesize neoglycolipids with high yields and anomeric purity is described. Starting point of the synthesis strategy is the glycosylation of allyl alcohol with definite steric orientation. Introduction of the hydrophobic moiety was achieved by photoaddition of n-hexadecanethiol and 3-mercaptopropionic acid followed by amidation with n-hexadecylamine, respectively. In order to investigate the influence of different carbohydrate headgroups in the physicochemical behavior of the general glycolipid, especially the orientation of the alkyl chain, a range of neoglycolipids was synthesized. Beside the differences in the configuration between unfunctionalized glycopyranoses like D-glucose, D-galactose and D-mannose, a number of deoxy and partially O-methylated sugar derivatives was prepared. The divergences concerning the different carbohydrate headgroups and the hydrophobic moiety, respectively, can be compared to relatively simple structured glycolipids with hexadecyl residue and without spacer function.

Squatting, blood pressure and stroke.

Most Indians still adopt squatting posture in toilets. In a group of 67 healthy volunteers, squatting produced a small (8.09 +/- 7.04 mm Hg) but significant rise in systolic blood pressure (SBP) but not in diastolic (DBP). However, in a group of randomly selected treated hypertensives (N=104) squatting produced a much greater and significant rise in both SBP (14.46 +/- 11.63 mm Hg) and DBP (9.10 +/- 9.19 mm Hg). The possible clinical significance of this rise of BP in squatting has been evaluated in 100 consecutive CT proved patients with stroke by analysing their stroke onset data in relation to time, place, posture and activity. Most strokes (52%) occurred in the morning hours (5 am-9 am) and at home (86%) and over a third (36%) while in toilets. Thirty six percent of strokes occurred when the subjects squatted, mostly during defecation. More than half of hemorrhagic strokes occurred in the squatting position. The relationship of these clinical observations with the BP changes noted above on squatting appears to be more than fortuitous. We would suggest that hypertensive subjects and those at risk of stroke should avoid squatting and urge physicians to check squatting BP while monitoring anti-hypertensive therapy.

Is squatting a triggering factor for stroke in Indians?

BACKGROUND: Undocumented observations of ours suggested increased occurrence of strokes in the early hours of the morning and in the toilets where most Indians still squat. The present study has been designed to assess the validity of this observation and to identify the likely triggering factor in stroke onset in such situations. MATERIAL AND METHODS: Part A of the study looked into stroke onset data of 100 consecutive CT-confirmed stroke patients specially in relation to time of day, place, posture and activity of the individual. Part B of the study included 67 healthy volunteers (age 24-49 years) whose supine and squatting blood pressure (BP) were measured and the differences noted. Part C of the study consisted of repeating the same procedure in 104 known hypertensives on treatment (age 28-60 years). RESULTS: Part A of the study revealed that most strokes (52%) occurred in the morning and at home (86%) and over a third (36%) while in toilets. Thirty-six per cent of the strokes occurred while the subjects squatted, mostly during the act of defecation. More than half of the haemorrhagic strokes occurred while the subjects were in squatting position. In normal healthy volunteers squatting produced a small (8.09 +/- 7.04 mmHg) but significant rise in systolic blood pressure (SBP) but not in diastolic blood pressure (DBP) (0.9 +/- 7.38 mmHg). In contrast, in treated hypertensives squatting produced a significantly higher rise in both SBP (14.49 +/- 11.63 mmHg) and DBP(9.10 +/- 9.19 mmHg). CONCLUSION: The relationship of the clinical observations regarding stroke onset with the BP changes noted on squatting in healthy as well as hypertensive subjects appears to be more than fortuitous. Squatting induced rise in BP appears to be an important triggering factor for stroke onset in subjects at risk in India.

Gene therapy for head and neck cancer using vaccinia virus expressing IL-2 in a murine model, with evidence of immune suppression.

We evaluated the efficiency of recombinant vaccinia virus expressing interleukin-2 (rvv-IL-2) as a tumor vaccine in an immunocompetent mouse model of head and neck squamous cell carcinoma (SCC VII/SF). Mice with five-day-old tumors in the floor of the mouth were treated with rvv-IL-2 by intratumoral injections. These treated mice survived longer (P <.03) than mice treated with control vaccines. Splenocytes, bone marrow, and lymph node cells from tumor-bearing mice responded poorly to concanavalin A stimulation, suggesting induction of immunosuppression. The rvv-IL-2 virus grew for 7 days in the tumor following intratumoral injection. We did not detect any virus particles in several normal organs following rvv-IL-2 injection. Comparison of expression levels of several potential immune inhibitory mediators between the tumors growing in mice and cultured tumor cells demonstrated higher expression of IL-10, GM-CSF, TGF-beta, and NO synthetase in tumors. These results suggested possible roles for these molecules in immunosuppression. We conclude that rvv-IL-2 has potential as a therapeutic vaccine for head and neck cancer and that it can be more effective provided the immunosuppression is reversed.

Rectourinary fistula with a narrow urethra.

A rectourinary fistula is a common accompaniment of anorectal malformations (ARM) in boys. Most boys pass urine normally after reconstruction and closure of the fistula, but a few have serious problems because of a narrow urethra. In our series, a narrow urethra was encountered in three types of male ARM: 3 rectourethral fistulae, 4 rectovesical fistulae, and 6 H-fistulae. We have studied the diagnostic and therapeutic problems that a narrow urethra produces in patients afflicted with each of these malformations.

Synthesis and microtubule binding of fluorescent paclitaxel derivatives.

The preparation of two new fluorescent derivatives of paclitaxel in which the fluorophore is bonded to paclitaxel at the C-10 position is reported. Both analogues, 10-deacetyl-10-(m-aminobenzoyl)paclitaxel (1, BTax) and 10-deacetyl-10-[7-(diethylamino) coumarin-3-carbonyl]paclitaxel (2, CTax) retain good activity as promoters of in vitro tubulin assembly. Microtubule binding enhances the emission intensity of both probes.

Synthesis and biological evaluation of novel macrocyclic paclitaxel analogues.

[reaction: see text] This work describes the synthesis of two novel macrocyclic taxoid constructs by ring-closing olefin metathesis (RCM) and their biological evaluation. Computational studies examine conformational profiles of 1 and 2 for their fit to the beta-tubulin binding site determined by electron crystallography. The results support the hypothesis that paclitaxel binds to microtubules in a "T" conformation.

Baccatin III induces assembly of purified tubulin into long microtubules.

Baccatin III is widely considered to be an inactive derivative of Taxol. We have reexamined its effect on in vitro assembly of tubulin under a variety of conditions. We found baccatin III to be active in all circumstances in which Taxol is active: it assembled GTP-tubulin, GDP-tubulin, and microtubule protein into normal microtubules and stabilized these polymers against cold-induced disassembly. The effect of baccatin III on in vitro microtubule assembly was quantitatively assessed through determination of critical concentrations, which can be used to obtain the apparent equilibrium constants for the addition of tubulin subunits to growing microtubules. The apparent equilibrium constants for the growth reaction for baccatin III-induced GTP-tubulin and GDP-tubulin assembly measured at 37 degrees C were 4.2-4.6-fold less than those measured for Taxol-induced GTP-tubulin and GDP-tubulin assembly. These data indicate that the entire Taxol side chain contributes only about -1 kcal/mol to the apparent standard free energy of microtubule growth at 37 degrees C regardless of the nature of the E site nucleotide. These data also support the idea that the majority of the interactions between Taxol and tubulin that affect this equilibrium occur between the baccatin portion of the molecule and the binding site. We have also observed a structural difference in microtubules formed using baccatin III and Taxol. Baccatin III-induced microtubules were routinely much longer than those assembled by Taxol, even when very high concentrations of baccatin III were employed. One interpretation of these data is that baccatin III and Taxol differ in their abilities to nucleate GTP-tubulin. This difference in activity may have bearing on the large disparity in cytotoxicity of the two molecules.

Posterior urethral valves: the scenario in a developing center.

We have reviewed 233 patients with posterior urethral valves treated in a single center in Calcutta, India, over the last 20 years: 37 were neonates, 75 were between 1 and 12 months, 88 were between 1 and 5 years, and 33 were more than 5 years old when first seen. The clinical presentation and methods employed in diagnosis and assessment are described. Primary endoscopic valve ablation was performed in 140 patients (60%). One or other form of diversion was done in 100 (43%), 93 before and 7 either during or after valve ablation. The short- and long-term results have been studied. Eleven patients died during the initial hospitalization, 3 died subsequently, 15 are in end-stage renal disease, 17 are in poor health, and 18 have been totally lost to follow-up. The remaining 169 have been in good health for periods between 1 and 20 years. While our results of primary valve ablation in low-risk patients with responsible parents are as good as anywhere else in the world, we are concerned at our relatively high diversion rate and relatively poor long-term follow up; the methods being adopted to reduce these problems are discussed.

The anti-idiotype vaccines for immunotherapy.

Certain anti-idiotypic antibodies that bind to the antigen-combining sites of antibodies can effectively mimic the three-dimensional structures and functions of the external antigens and can be used as surrogate antigens for active specific immunotherapy. Extensive studies in animal models have demonstrated the efficacy of these vaccines for triggering the immune system to induce specific and protective immunity against bacterial, viral and parasitic infections as well as tumors. Several monoclonal anti-idiotype antibodies that mimic distinct human tumor-associated antigens have been developed and characterized. Encouraging results have been obtained in recent clinical trials using these anti-idiotype antibodies as vaccines. In this article, we will review the current literature and discuss the potential of this novel therapeutic approach for various human cancers.