Endothelial markers in high altitude induced systemic hypertension (HASH) at moderate high altitude.

BACKGROUND: Chronic intermittent hypoxia is known to induce systemic arterial hypertension whereas chronic hypoxia causes pulmonary arterial hypertension. High altitude (HA) induced systemic hypertension (HASH) in previously normotensive lowlanders following acclimatisation and prolonged stay at moderate HA is a commonly encountered medical problem. HASH has been attributed to increased sympathetic discharge. Endothelial dysfunction (ED) is implicated in hypertension in the plains hence this study was conducted in HA. This is relevant especially because of the established role of ED in the aetiopathogenesis of HA illnesses. Since hypoxia may induce ED, we aimed at studying the association of endothelial dysfunction with HASH in temporary residents at HA. METHODS: In this case-control single-centre study, we evaluated ED, by measuring endothelial molecular markers, soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF) and endothelial selectin (E-Selectin) in 24 cases with HASH and 25 age, sex matched normotensive controls at moderate high altitude (11,500 ft). RESULTS: The levels of sICAM-1 (patients: 214.3 ± 34.2 µg/L, controls: 196.2 ± 28.5 µg/L; p = 0.049) and VCAM-1 (patients 766.1 ± 123.4 ng/mL, controls: 668.6 + 117.6 ng/mL; p = 0.007) were statistically higher in the patient group. However, VEGF and E-Selectin were not significantly different between the groups. sICAM-1 significantly correlated with levels of systolic and diastolic blood pressure (r = 0.401, p = 0.003 and 0.486, p = 0.000) respectively. CONCLUSION: HASH is associated with endothelial dysfunction in form of raised levels of sICAM-1 and VCAM-1.

Interleukin-1 Gene Polymorphisms and their Relation with NFκB Expression and Histopathological Features in Psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory disease driven by exaggerated production of pro-inflammatory cytokines and interleukins. Various genetic polymorphisms including IL-1 are implicated in pathogenesis of psoriasis. The exact role of IL-1 gene polymorphisms and their interaction with NFκB is not yet determined. We aimed to study various genetic polymorphisms of IL-1 in psoriasis and their influence on NFκB and histopathological features. MATERIALS AND METHODS: 112 newly diagnosed cases of psoriasis vulgaris were included in this prospective study. Histology was done on sections and genotyping was done for the IL-1ß and IL-1 receptor antagonist (IL-1RA) genetic polymorphisms. In addition, NFκB immunostaining was performed on 89 sections and the intensity of staining was evaluated in the epidermis, basal cells, and the lymphocytes. RESULTS: A strong association of IL-1ß 511 C/T polymorphism was found with both genotypes and alleles in psoriasis. A strong correlation was also detected between the IL-1ß genotype and the grade of NFκB immunostaining in the epidermis (P = 0.012). The grade of NFκB lymphocyte staining showed a strong correlation with the IL-1RA genotype (P = 0.025) but not with the IL-1ß genotype (P = 0.226). The genetic polymorphisms did not show any correlation with the histological features. CONCLUSIONS: IL-1 genetic polymorphisms may not play a very direct role in pathogenesis of psoriasis. However, their interaction with NFκB appears to be a significant factor in this direction as NFκB is activated by pro-inflammatory genetic polymorphisms and therefore may influence the severity of psoriasis.

Pattern of chilblains in a high altitude region of Ladakh, India.

BACKGROUND: Extreme sub-zero temperature in winters (15 °C to -25 °C), high velocity winds and wind-chill factor pose risk to those who resides at the high altitude environment to develop cold related injuries like chilblains and frostbite. The aim of this study was to study the patterns of chilblains in high altitude region like Ladakh. METHODS: The study was conducted at Dermatology outpatient department of Military Hospital, Leh from 1 Sep 2009 to 31 May 2010. Patients, satisfying clinical criteria for the diagnosis of chilblains were included into the study. Detailed history and thorough clinical examination was conducted. Complete blood count and Urine routine examination was carried out in every patient. Anti Nuclear Factor tests were carried out in only those who had history suggestive of connective tissue disease. RESULTS: Total 108 (5.75%) were diagnosed to have chilblains. Only a single case of chilblain was found in a local resident (p < 0.005). Family history of chilblains was present in 10 (9.2%) patients, there was recurrence in 12 (11.1%) and 21 patients (19.4%) were smokers. Most (63.8%) of the patients, had BMI between 20 and 22 kg/m(2) (mean = 20.03 kg/m(2); 95% CI = 19.68-20.38 and SD 1.82). 42.1% of cases of chilblains also had hyperhidrosis (p < 0.05). CONCLUSION: In a HA area like Ladakh, the non-natives suffer maximum from chilblains. This could be explained by the protective genetic adaptability of natives to extreme cold environment and their protective life style against cold. Low body mass index (BMI) and hyperhidrosis are important associations for development of chilblains.

Is concurrent prophylactic use of acetazolamide and dexamethasone superior to acetazolamide alone in un-acclimatized lowlanders on ascent to high altitude?

This pilot study was undertaken in lowlanders, during their ascent from 2600 m to 3500 m, to evaluate the effects of Acetazolamide and Dexamethasone on Cardio-Respiratory parameters and Exercise Capacity. 40 unacclimatised low-landers were divided into 2 groups. Subjects of Group 'A' were given Acetazolamide and Dexamethasone and those of Group 'B' were given Acetazolamide and placebo. 8 subjects matched for age, physical fitness, height and weight were randomly selected from each study group and were evaluated for their Exercise Capacities. Both study groups showed significant rise in Heart Rate, Respiratory Rate and a significant fall in Systolic Blood Pressure. There was no difference in Exercise capacities achieved by subjects of two groups at 3500 m.

Rate of decline in CD4 count in HIV patients not on antiretroviral therapy.

BACKGROUND: The progressive decline in the CD4 count in HIV patients leads to a more general decline in immune functioning. The study has been carried out to determine the decline in CD4 count in HIV patients. METHODS: The study was conducted in a medical college hospital at Maharashtra. The information on baseline CD4 count was gathered from positive patient records registered in the central disease registry. The baseline CD4 count was the first count of CD4 obtained when the patient is diagnosed as HIV positive and further two subsequent readings. The time from baseline (t1) till the last CD4 count (t2) was divided into the different quartiles and the median decline in CD4 count in each quartile was determined. As the time between the two CD4 count measurements was not uniform the rate of change in CD4 was measured with respect to time as [X (t2) - X (t1)/(t2 - t1)]. Correlation was assessed using correlation coefficient. RESULTS: As the CD4 counts were following skewed distribution, the normality was achieved by cuberoot transformation. The overall rate of decline in CD4 count was estimated to be 35 cells/µL per year with 95% confidence interval (CI) as (17.01, 85.04). The correlation coefficient between decline in CD4 and the initial CD4 count in the four time quartiles was (r = -0.51; p = 0.001, r = -0.79; p = 0.000, r = -0.48; p = 0.015 and r = -0.80; p = 0.000) respectively. The median decline in the CD4 count in 0-6 months was 3 cells/µL, in (6-11) months was approximately 26 cells/µL, in (11-21.5) months was 30 cells/µL and in more than 21.5 months the median decline was 52 cells/µL. CONCLUSIONS: There was a progressive decline in the CD4 count following HIV infection. An understanding of the influence of decline in CD4 count in HIV patients not on ART is important for clinical management of HIV disease.

A comparative study of efficacy of cultured versus non cultured melanocyte transfer in the management of stable vitiligo.

BACKGROUND: Replenishing melanocytes by autologous melanocytes selectively in vitiliginous macules is a novel and promising treatment. With expertise in culturing autologous melanocytes, it has now become possible to treat larger recipient areas with smaller skin samples. To determine the relative efficacy of cultured versus non cultured melanocyte transfer in the management of stable vitiligo. METHODS: The melanocytes were harvested as an autologous melanocyte rich cell suspension from a donor split thickness graft. Cultured or non cultured melanocytes were then transplanted to the recipient area that had been superficially dermabraded. 100 patches of vitiligo in patients reporting to this hospital were randomly allocated into 2 groups to receive either of the interventions. RESULTS: An excellent response was seen in 62.17% cases with the autologous melanocyte rich cell suspension technique and in 52% with the melanocyte culture technique. CONCLUSION: Autologous melanocyte transplantation can be an effective form of surgical treatment in stable but recalcitrant lesions of vitiligo. Large areas of skin can be covered with a smaller donor skin using melanocyte culture technique; however culture method is more time consuming, and a labour intensive process, requiring state of the art equipments with a sterile lab setup.

Immune reconstitution inflammatory syndrome in leprosy.

Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical deterioration in the clinical status of a patient infected with human immunodeficiency virus (HIV) on highly active antiretroviral treatment (HAART). The immune suppression caused by the virus can initially suppress the clinical manifestations of leprosy which can then be unmasked after treatment with HAART or an inflammatory reaction can occur in the initial months of therapy, resulting from dysregulated recovery of immunity to specific antigens. Both these conditions are identified as IRIS in leprosy. Though this syndrome is a widely recognized entity presently, there is still a lack of universally acceptable diagnostic criteria for the condition. The first case published case of leprosy- associated immune reconstitution disease was reported in 2003 and about 47 confirmed cases of IRIS in leprosy have been reported since then, mostly from Brazil and India. Anti-inflammatory drugs and steroids are the drugs of choice in inflammatory episodes with continuation of antiretroviral therapy. With increasing affordability of antiretroviral therapy, clinicians will put more and more number of human immunodeficiency virus infected patients on therapy and hence an increase in the incidence of IRIS is expected. Therefore, it is important to understand all facets of this syndrome which is becoming more prevalent with each passing day.

Osler-Weber-Rendu syndrome: a case report with familial clustering.

Osler-Weber-Rendu syndrome, also known as hereditary hemorrhagic telangiectasia, is a rare autosomal dominant disorder manifested by telangiectases of the skin and mucous membranes and arteriovenous malformations of various organ systems. We present a case of Osler-Weber-Rendu syndrome with 11 affected members in her family.

The second messenger cAMP elicits eating by an anatomically specific action in the perifornical hypothalamus.

We have previously shown that a membrane-permeant analog of cAMP, 8-bromo-cAMP (8-br-cAMP), elicits a vigorous eating response when microinjected into the perifornical hypothalamus (PFH) or lateral hypothalamus (LH) of satiated rats, suggesting that increases in cAMP in these areas may be important in the neural control of eating. To determine the locus of this effect, we compared the ability of 8-br-cAMP (1-100 nmol/0.3 microl) to elicit eating after microinjection into the PFH, LH, or the following bracketing areas: the anterior and posterior LH, paraventricular nucleus of the hypothalamus, thalamus, and amygdala. 8-br-cAMP at 50 nmol elicited eating (>/=3.4 gm in 2 hr) exclusively in the PFH and LH. At 100 nmol, 8-br-cAMP elicited a larger response in these areas and elicited a smaller, more variable response in the thalamus. We similarly mapped the feeding-stimulatory effects of compounds that increase endogenous cellular cAMP in naive rats. Combined microinjection of matched doses (300 nmol) of 3-isobutyl-1-methylxanthine and 7-deacetyl-7-O-(N-methylpiperazino)-gamma-butyryl-forskolin was effective exclusively in the PFH, eliciting an average 2 hr food intake of 8.4 +/- 2.0 gm. Collectively, these results suggest that increases in cellular cAMP within a specific brain site, the PFH, may play a role in the neural stimulation of eating.

NMDA receptor coagonist glycine site: evidence for a role in lateral hypothalamic stimulation of feeding.

To investigate the role of the glycine coagonist binding site on the N-methyl-D-aspartate (NMDA) receptor in feeding control, we injected the glycine site antagonist 7-chlorokynurenic acid (7-CK) into the lateral hypothalamus (LH) of satiated rats before LH injection of NMDA, 7-CK (10-44 nmol) blocked the 6- to 10-g eating response elicited by NMDA. This block was reversed by LH pretreatment with glycine, arguing for a specific action at the glycine site. In contrast to the suppression produced by high doses, 7-CK at 0.1 nmol enhanced NMDA-elicited eating. For examination of behavioral specificity, 7-CK was injected into the LH before kainic acid (KA) or DL-alpha-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA). 7-CK at a dose of 0.1 nmol suppressed feeding elicited by KA or AMPA, but at 10 nmol it suppressed eating elicited by AMPA while enhancing eating elicited by KA. Finally, bilateral LH injection of 7-CK effectively suppressed eating produced by fasting. These findings support a role for the NMDA receptor coagonist glycine site in LH regulation of eating behavior.

Stimulation of eating by the second messenger cAMP in the perifornical and lateral hypothalamus.

Despite intense study of neurotransmitters mediating hypothalamic controls of food intake, little is known about which second messengers are critical for these mechanisms. To determine whether adenosine 3',5'-cyclic monophosphate (cAMP) might participate in these mechanisms, we injected the membrane-permeant cAMP analog 8-bromo-cAMP (8-BrcAMP) hypothalamically in satiated rats. Injection of 8-BrcAMP (10-100 nmol) into the perifornical (PFH) and lateral hypothalamus (LH) dose dependently stimulated food intake of up to 15.7 g in 2 h. Significantly smaller responses were obtained with thalamic injections. In contrast to the strong stimulatory effects of PFH and LH 8-BrcAMP, cAMP and 8-bromo-guanosine 3',5'-cyclic monophosphate (100 nmol) were ineffective, suggesting a chemically specific, intracellular action. Consistent with this, combined PFH injection of 7-deacetyl-7-O-(N-methylpiperazino)-tau-butyryl-forskolin dihydrochloride and 3-isobutyl-1-methylxanthine, agents that increase endogeneous cAMP, stimulated eating of up to 9.9 g in 2 h. These results demonstrate that increases in PFH/LH cAMP can elicit complex, goal-oriented behavior, suggesting an important role for cAMP in hypothalamic mechanisms stimulating food intake.

Synthesis of novel phosphoramidite reagents for the attachment of antisense oligonucleotides to various regions of the benzophenanthridine ring system.

Four benzophenanthridine phosphoramidite reagents have been prepared in which the linker chain between the benzophenanthridine and the phosphoramidite moiety is attached to C-2, C-6, C-9, and C-12 of the benzophenanthridine ring system. These benzophenanthridine phosphoramidites should prove to be useful in the syntheses of antisense oligonucleotide-intercalator conjugates in which the linker chain is attached to various regions of the benzophenanthridine intercalator. One of the new benzophenanthridine phosphoramidite reagents was used to prepare an antisense oligonucleotide-intercalator conjugate in which the oligonucleotide TCAGTGGTp was connected at its 5'-hydroxyl group through a linker chain to the C-2 hydroxyl group of a benzophenanthridine.

Immunomodulators in clinical practice.

Immunomodulators have opened new vistas in the management of the immunocompromised patient. They have been shown to enhance the efficacy of vaccines in infections, head and neck malignancy, the immunosuppressed and recently in AIDS. The mechanism of their action is discussed. They hold promise of further advances in immunotherapy.

Scrofuloderma with inguinal and genital syndrome--a case report.

A case of scrofuloderma presented as lymphogranuloma venereum closely mimicking its inguinal and genital syndrome. A lymph node biopsy confirmed the diagnosis.

Pharmacological profile of 1-methylsulphonyl-3-(1-methyl-5-nitro-2-imidazolyl)-2-imidazolidinone (Go-10213), a new antiprotozoal agent, in comparison with metronidazole.

A new antiprotozoal agent, 1-methylsulphonyl-3-(1-methyl-5-nitro-2-imidazolyl)-2-imidazolidinone (Go-10213) has a distinct advantage over metronidazole when their respective neuropharmacological effects on central and peripheral nervous functions are compared in different animal species. The results show that at equivalent dosage schedules with repeated high dosages, Go-10213 is devoid of adverse central and peripheral neural effects in monkeys; cats and dogs, whereas unequivocal evidence of metronidazole neurotoxicity was obtained in all the three species. Go-10213 compares favourably with metronidazole in animal tests for cardiovascular tolerability.