Impact of angiotensin II receptor antagonism on the sex-selective dysregulation of cardiovascular function induced by in utero dexamethasone exposure.

In utero exposure to glucocorticoids in late gestation programs changes in cardiovascular function. The objective of this study was to determine the degree to which angiotensin II mediates sex-biased changes in autonomic function as well as basal and stress-responsive cardiovascular function following in utero glucocorticoid exposure. Pregnant rats were administered the synthetic glucocorticoid dexamethasone (Dex; 0.4 mg/kg/day sc) or vehicle on gestation days 18-21. Mean arterial pressure, heart rate, and heart rate variability (HRV) were measured via radiotelemetry in freely moving, conscious adult rats. To evaluate the impact of stress, rats were placed in a restraint tube for 20 min. In a separate cohort of rats, restraint stress was performed before and after chronic treatment with the angiotensin type 1 receptor antagonist, losartan (30 mg/kg/day ip). Frequency domain analysis of HRV was evaluated, and data were integrated into low-frequency (LF, 0.20-0.75 Hz) and high-frequency (HF, 0.75-2.00 Hz) bands. Prenatal Dex resulted in an exaggerated pressor and heart rate response to restraint in female offspring that was attenuated by prior losartan treatment. HF power was higher in vehicle-exposed female rats compared with Dex females. Following losartan, HF power was equivalent between female vehicle and Dex-exposed rats. In utero exposure to Dex produced female-biased alterations in stress-responsive cardiovascular function, which may be indicative of a reduction in parasympathetic activity. Moreover, these findings suggest this autonomic dysregulation may be mediated, in part, by long-term changes in renin-angiotensin signaling.NEW & NOTEWORTHY Our findings reveal the involvement of angiotensin II on sex-selective cardiovascular function and autonomic changes in adult offspring exposed to dexamethasone during the last 4 days of gestation. We show that angiotensin II receptor blockade reverses the exaggerated pressor and heart rate response to acute restraint stress and the autonomic dysregulation observed in female, but not male, offspring exposed to dexamethasone in utero.

Sex-dependent associations of maternal androgen levels with offspring BMI and weight trajectory from birth to early childhood.

CONTEXT: In preclinical studies, high androgen levels during pregnancy are associated with low birth weight and rapid postnatal weight gain in the offspring. However, human data linking prenatal androgens with birth weight and early life weight gain in the offspring are scarce. DESIGN: We evaluated 516 mother-child pairs enrolled in the New England birth cohorts of the Collaborative Perinatal Project (1959-1966). We assayed androgen bioactivity in maternal sera during third-trimester using a receptor-mediated luciferase expression bioassay. Age and sex-specific BMI Z-scores (BMIz), defined using established standards, were assessed at birth, 4 months, 1 year, 4 years, and 7 years. We used linear mixed models to evaluate the relation of maternal androgens with childhood BMIz overall and by sex. We examined the association of maternal androgens with fetal growth restriction. The association of weight trajectories with maternal androgens was examined using multinomial logistic regression. RESULTS: Higher maternal androgen levels associated with lower BMIz at birth (ß = - 0.39, 95% CI: - 0.73, - 0.06); this relation was sex-dependent, such that maternal androgens significantly associated with BMIz at birth in girls alone (ß = - 0.72, 95% CI: - 1.40, - 0.04). The relation of maternal androgens with fetal growth restriction revealed dose threshold effects that differed by sex. There was no significant association between maternal androgens and weight trajectory overall. However, we found a significant sex interaction (p = 0.01); higher maternal androgen levels associated with accelerated catch-up growth in boys (aOR = 2.14, 95% CI: 1.14, 4.03). CONCLUSION: Our findings provide evidence that maternal androgens may have differential effects on the programming of intrauterine growth and postnatal weight gain depending on fetal sex.

Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease.

Comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) represents the fourth leading cause of morbidity and mortality worldwide, and women have a two times greater risk than men. Thus understanding the pathophysiology has widespread implications for attenuation and prevention of disease burden. We suggest that sex-dependent MDD-CVD comorbidity may result from alterations in fetal programming consequent to the prenatal maternal environments that produce excess glucocorticoids, which then drive sex-dependent developmental alterations of the fetal hypothalamic-pituitary-adrenal (HPA) axis circuitry impacting mood, stress regulation, autonomic nervous system (ANS), and the vasculature in adulthood. Evidence is consistent with the hypothesis that disruptions of pathways associated with gamma aminobutyric acid (GABA) in neuronal and vascular development and growth factors have critical roles in key developmental periods and adult responses to injury in heart and brain. Understanding the potential fetal origins of these sex differences will contribute to development of novel sex-dependent therapeutics.

Sex-dependent pathophysiology as predictors of comorbidity of major depressive disorder and cardiovascular disease.

There is a strong and growing literature showing that key aspects of brain development may be critical antecedents of adult physiology and behavior or may lead to physiological and psychiatric disorders in adulthood. Many are significantly influenced by sex-dependent factors. Neurons of the paraventricular nucleus (PVN) of the hypothalamus occupy a key position in regulating homeostatic, neuroendocrine, and behavioral functions. This brain area is a critical link for our understanding of the etiology of a number of disorders with components ranging from mood to feeding and energy balance and to autonomic nervous system regulation. Thus, based on common brain circuitry, the PVN may be a critical anatomical intersection for understanding comorbidities among depression, obesity, and cardiovascular risk. Historically, the majority of approaches to brain development examine neuronal, glial, and vascular factors independently, with notably less emphasis on vascular contributions. The realization that the PVN undergoes a unique vascular developmental process places added value on discerning the cellular and molecular mechanisms that drive its late-onset angiogenesis and further implications for neuronal differentiation and function. This has ramifications in humans for understanding chronic, and sometimes fatal, comorbidities that share sex-dependent biological bases in development through functional and anatomical intersections with the hypothalamus.

Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones.

The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design.

A study to evaluate the impact of examination stress on recurrent aphthous ulceration in professional college students in Jaipur district.

AIM: Recurrent aphthous ulcers (RAU) are one of the most common and poorly understood mucosal disorders. Most of the literature suggests that stress has a causal role in RAU and it is estimated that at least 1 in 5 individuals is afflicted with RAU. Review of literature reveals that nutritional and stress factors may be of paramount importance in the occurrence and severity of RAU. To test this hypothesis we have derived a study to explore definitive relationship between nutrition, stress and RAU in professional undergraduate students. METHODS: A total of 80 undergraduate students were selected randomly for the study from professional colleges. On evaluation 50 subjects were identified to be RAU positive and the rest 30 never had ulcers. All the subjects were evaluated during their university examinations and the 50 RAU positive subjects were later evaluated for the stress levels after the examinations. The major variables that were compared were simplified oral hygiene index, body mass index, hemoglobin percentage, mid upper arm circumference and malnutrition universal screening tool, Hamilton anxiety rating scale and general health questionnaire. RESULTS: The stress level was measured using Hamilton anxiety scale (HAS) and a highly significant difference was determined between during exams and post exam period in the students who tested positive for RAU. The General Health Questionnaire (GHQ) also appeared to be a sensitive instrument to determine the stress levels and statistically significant differences were recorded in the RAU positive students during exams and post exam period. General health is also poor during exams as compared after exams. The hematological factor as denoted by HB measurement showed significant statistical difference between patients who had RAU (present and history) and those who did not. Nutritional indicator (Malnutrition Universal Screening Tool) MUST also showed that it was a sensitive measure for detecting nutritional compromise and the statistically significant difference was shown between RAU positive and negative. The BMI, OHI-S and MUAC had no statistical differences shown in our analysis. CONCLUSION: A number of conditions and diseases have been shown to lead to the onset of RAU. However, RAU can occur in the absence of any diagnosable disease or physical condition. According to our evaluation, stress emerged as having a causal role on RAU, along with hematinic deficiencies and poor nutritional status in professional undergraduate college students.

Detection of the membrane attack complex as a diagnostic tool in dermatomyositis.

BACKGROUND: Currently there is no reliable diagnostic marker to distinguish between the subgroups of idiopathic inflammatory myopathies (IIMs), i.e. dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). Membrane attack complex (MAC) has been shown to be involved in the pathogenesis of dermatomyositis but its role as a diagnostic marker has not been evaluated. AIM: To assess the diagnostic utility of MAC deposition in distinguishing dermatomyositis from other neuromuscular disorders. MATERIAL AND METHODS: Immunohistochemical detection of MAC deposition on endomysial microvessels was carried out on 127 muscle biopsies comprising of 21 cases of dermatomyositis, 42 other IIMs and 64 non-IIM neuromuscular diseases. RESULTS: MAC deposition showed a high sensitivity (80.9%) and specificity (85%) to differentiate DM from other IIMs. Its specificity was higher (98.4%) in discriminating DM from non-IIM muscular diseases and IIM from non-IIMs. CONCLUSION: MAC deposition can serve as a reliable marker to distinguish DM from other IIMs (i.e. PM and IBM) as well as from non-IIM diseases. It can also serve as a useful adjunct in diagnosis of IIMs when there is diagnostic dilemma with their morphologic similarities. These results provide further credence to the long-standing view that MAC-mediated capillary destruction is involved in the immunopathogenesis of DM.

Cardiovascular co-morbidity in Asians with lupus: theoretical concern or clinical reality?

Immuno-inflammatory diseases like lupus are associated with premature atherosclerosis. With improved survival, atherosclerotic cardiovascular disease has emerged as an important late complication of systemic lupus erythematosus. The burden of this co-morbidity in Asian patients is not fully known but is likely to be high. We review the literature available and draw attention to this oft overlooked problem.

Non-genomic actions of androgens.

Previous work in the endocrine and neuroendocrine fields has viewed the androgen receptor (AR) as a transcription factor activated by testosterone or one of its many metabolites. The bound AR acts as transcription regulatory element by binding to specific DNA response elements in target gene promoters, causing activation or repression of transcription and subsequently protein synthesis. Over the past two decades evidence at the cellular and organismal level has accumulated to implicate rapid responses to androgens, dependent or independent of the AR. Androgen's rapid time course of action; its effects in the absence or inhibition of the cellular machinery necessary for transcription/translation; and in the absence of translocation to the nucleus suggest a method of androgen action not initially dependent on genomic mechanisms (i.e. non-genomic in nature). In the present paper, the non-genomic effects of androgens are reviewed, along with a discussion of the possible role non-genomic androgen actions have on animal physiology and behavior.

Estrogen impairs glucocorticoid dependent negative feedback on the hypothalamic-pituitary-adrenal axis via estrogen receptor alpha within the hypothalamus.

Numerous studies have established a link between individuals with affective disorders and a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, most notably characterized by a reduced sensitivity to glucocorticoid negative (-) feedback. Furthermore there is a sex difference in the etiology of mood disorders with incidence in females being two to three times that of males, an association that may be a result of the influence of estradiol (E2) on HPA axis function. In these studies, we have examined the effect of E2 on glucocorticoid-mediated HPA axis (-) feedback during both the diurnal peak and the stress-induced rise in corticosterone (CORT). Young adult female Sprague-Dawley (SD) rats were ovariectomized (OVX) and 1 week later treated subcutaneous (s.c.) with oil or estradiol benzoate (EB) for 4 days. On the 4th day of treatment, animals were injected with a single dose of dexamethasone (DEX), or vehicle. EB treatment significantly increased the evening elevation in CORT and the stress-induced rise in CORT. In contrast, DEX treatment reduced the diurnal and stress induced rise in CORT and adrenocorticotropic hormone (ACTH), and this reduction was not apparent following co-treatment with EB. To determine a potential site of E2's action, female SD rats were OVX and 1 week later, wax pellets containing E2, the estrogen receptor beta (ERbeta) agonist diarylpropionitrile (DPN), or the estrogen receptor alpha (ERalpha) agonist propylpyrazoletriol (PPT), was implanted bilaterally and dorsal to the paraventricular nucleus of the hypothalamus (PVN). Seven days later, animals were injected s.c. with a single dose of DEX, or vehicle to test for glucocorticoid-dependent (-) feedback. Results show that E2 and PPT increased, while DPN decreased the diurnal peak and stress-induced CORT and ACTH levels as compared to controls. Furthermore, E2 and PPT impaired the ability of DEX to inhibit both the diurnal and the stress-induced rise in CORT and ACTH, whereas DPN had no effect. Neuronal activation was measured by c-fos mRNA expression within the PVN following restraint. E2 and PPT increased c-fos mRNA, and impaired the normal DEX suppression of neuronal activation in the PVN. Taken together, these data indicate that estradiol causes a dysregulation of HPA axis (-) feedback as evidenced by the inability of DEX to suppress diurnal and stress-induced CORT and ACTH secretion. Additionally, the ability of E2 to inhibit glucocorticoid (-) feedback occurs specifically via ERalpha acting at the level of the PVN.

Assessment of atherosclerosis by carotid intimomedial thickness in patients with rheumatoid arthritis.

OBJECTIVES: To determine the prevalence of subclinical (asymptomatic) atherosclerosis in patients with rheumatoid arthritis (RA) and to study the variables affecting such an occurrence. METHODS: Case control study which included 100 patients with RA having disease duration more than 5 years and 100 healthy age and sex matched controls. Cases and controls symptomatic for atherosclerosis or having traditional risk factors for atherosclerosis were excluded. Both cases and controls were subjected to carotid ultrasound examination in addition to detailed history and physical examination. RESULTS: The study population (both cases and controls) included 94 females and 6 males. The mean age of cases and controls was similar (44.06 +/- 11.32 years and 44.1 +/- 11.52 years). The mean disease duration was 155.04 +/- 48.8 months. The mean carotid intimo-medial thickness (CIMT) of the RA patients (0.519 +/- 0.18 mm) was significantly greater than the controls (0.387 +/- 0.085). Age and disease duration were the only factors found to significantly affect CCIMT. RA patients had higher prevalence of carotid plaques (21%) compared to controls (1%). Erosions on hand radiographs were the only significant predictor of plaques in patients with RA. CONCLUSION: Patients with RA exhibit premature atherosclerosis by way of increased CIMT and carotid plaques when compared to age and sex matched controls.

Anti-idiotype-mediated epitope spreading and diminished phagocytosis by a human monoclonal antibody recognizing late-stage apoptotic cells.

Apoptotic cells are considered an important auto-antigenic source in diseases such as systemic lupus erythematosus (SLE). A human monoclonal antibody demonstrating exquisite specificity towards late-stage apoptotic cells was generated from an SLE patient. Polyreactive recognition of ribonucleoproteins Ro52 and Ro60 was observed. The antibody significantly diminished the phagocytosis of apoptotic cells and a concomitant decrease in transforming growth factor-beta (TGF-beta) secretion was observed. Light and heavy chain sequencing revealed the antibody to be in essentially germline configuration. Elicited anti-idiotypic antibodies bound distinct self-antigens and showed augmented reactivity towards apoptotic cells as well. Thus, near-germline encoded antibodies recognizing antigens externalized during the process of apoptosis can mediate a variety of potentially pathogenic effects; decreases in the phagocytic uptake of dying cells would constitute a disease-perpetuating event and stimulation of the idiotypic network could lead to intermolecular epitope spreading, increasing the range of molecular targets..

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex.

Neonatal administration of the synthetic glucocorticoid, dexamethasone (DEX) retards brain growth, alters adult behaviors and induces cell death in the rat brain, thereby implicating glucocorticoids as developmentally neuroendangering compounds. Glucocorticoids also increase expression of pro-apoptotic Bcl-2 family members and exacerbate expression of hypoxic responsive genes. Bnip3 is a pro-apoptotic Bcl-2 family member that is upregulated in response to hypoxia. In these studies, we investigated the interactions of glucocorticoid receptor and hypoxia in the regulation of Bnip3 mRNA in cortical neurons. Using quantitative real time reverse transcription-polymerase chain reaction, we found that DEX treatment of postnatal days 4-6 rat pups caused a significant increase in Bnip3 mRNA expression compared with vehicle controls. A significant increase in Bnip3 mRNA was also measured in primary cortical neurons 72 h after treatment with RU28362, a glucocorticoid receptor selective agonist. In primary cortical neurons, hypoxia increased Bnip3 mRNA expression and this was exacerbated with RU28362 treatment. To elucidate the mechanism of glucocorticoid- and hypoxia-mediated regulation of Bnip3 transcription, a Bnip3 promoter-luciferase reporter construct was utilized in primary cortical neurons. Upregulation of the Bnip3 promoter was mediated by a single glucocorticoid response element and a hypoxic response element. Bnip3 overexpression in primary cortical neurons significantly increased cell death, which is dependent on the Bnip3 transmembrane domain. However, despite the increased expression of Bnip3 following glucocorticoid and hypoxia treatment, corresponding decreases in cell survival were minimal. These studies identify a novel pathway in the developing cortex through which glucocorticoids may enhance a metabolic insult, such as hypoxia.

Activation of the androgen receptor alters the intracellular calcium response to glutamate in primary hippocampal neurons and modulates sarco/endoplasmic reticulum calcium ATPase 2 transcription.

Androgens have been shown to have a number of effects on hippocampal function. Although androgen receptors (AR) are found at high levels in hippocampal neurons, the intracellular mechanisms responsible for androgen's actions are unknown. If androgens were capable of altering internal calcium concentration ([Ca(2+)](i)), they could influence a variety of intracellular signaling pathways, maintain neuronal homeostasis and Ca(2+) induced excitotoxicity. In the present study, calcium imaging was used to measure the [Ca(2+)](i) in rat primary hippocampal neurons treated with either the AR agonist dihydrotestosterone (DHT), DHT+flutamide (AR antagonist), flutamide alone, or vehicle for 24 h and subsequently presented with an excitatory glutamate stimulus. In the absence of glutamate stimulation, DHT treatment caused a significant upward shift in baseline [Ca(2+)](i) when compared with neurons from all other groups. Glutamate had a greater effect on [Ca(2+)](i) in DHT-treated neurons and DHT-treated neurons returned to baseline levels significantly faster than all other groups. Cyclopiazonic acid, an inhibitor of sarco/endoplasmic reticulum calcium ATPase (SERCA) had a larger response in DHT-treated neurons compared with controls, suggesting increased Ca(2+) stores in DHT-treated neurons. In all cases the effects of DHT were blocked by treatment with flutamide indicating an AR-mediated mechanism. To determine a possible mechanism by which AR activation could be influencing [Ca(2+)](i), SERCA2 mRNA levels were measured in primary hippocampal neurons. SERCA2 is inserted into the endoplasmic reticulum (ER) membrane and functions to rapidly pump [Ca(2+)](i) into the ER. Following treatment of primary hippocampal neurons with DHT, SERCA2 mRNA was increased, an effect that was blocked in the presence of flutamide. Taken together these results indicate that DHT, working through AR, causes an up-regulation of SERCA2, which increases the sequestering of [Ca(2+)](i) in the endoplasmic reticulum of hippocampal neurons. Such changes may allow the neurons to respond more robustly to a stimulus and recover more quickly following a highly stimulatory challenge.

Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase.

Binding of type I interferons (IFNs) to their receptors induces rapid tyrosine phosphorylation of multiple proteins, including the alpha and beta subunits of the receptor, the polypeptides that form the transcriptional activator ISGF3 alpha (Stat113, Stat84, and Stat91), and the p135tyk2 and Jak-1 tyrosine kinases. In this report, we demonstrate that the alpha subunit of the type I IFN receptor (IFN-R) corresponds to the product of a previously cloned receptor subunit cDNA and, further, that the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit. Glutathione S-transferase (GST) fusion proteins encoding the different regions of the cytoplasmic domain of the alpha subunit can bind the p135tyk2 contained in human cell lysates. The association between the alpha subunit and Tyk2 was demonstrated by immunoblotting with anti-Tyk2 and antiphosphotyrosine antibodies and by using an in vitro kinase assay. Analogous experiments were then performed with recombinant baculoviruses encoding constitutively active Jak family tyrosine kinases. In this case, p135tyk2, but not Jak-1 or Jak-2 protein, binds to the GST-IFN-R proteins, suggesting that the interaction between these two proteins is both direct and specific. We also demonstrate that Tyk2, from extracts of either IFN alpha-treated human cells or insect cells infected with the recombinant baculoviruses, can catalyze in vitro phosphorylation of GST-IFN-R protein in a specific manner. Deletion mutants of the GST-IFN-R protein were used to localize both the binding and tyrosine phosphorylation site(s) to a 46-amino-acid juxtamembrane region of the alpha subunit, which shows sequence homology to functionally similar regions of other cytokine receptor proteins. These data support the hypothesis that the Tyk2 protein functions as part of a receptor complex to initiate intracellular signaling in response to type I IFNs.

Estrogen Receptors Modulation of Anxiety-Like Behavior.

Estrogens exert profound effects on the expression of anxiety in humans and rodents; however, the directionality of these effects varies considerably within both clinical and preclinical literature. It is believed that discrepancies regarding the nature of estrogens' effects on anxiety are attributable to the differential effects of specific estrogen receptor (ER) subtypes. In this chapter we will discuss the relative impact on anxiety and anxiety-like behavior of each of the three main ERs: ERα, which has a generally anxiogenic effect, ERß, which has a generally anxiolytic effect, and the G-protein-coupled ER known as GPR30, which has been found to both increase and decrease anxiety-like behavior. In addition, we will describe the known mechanisms by which these receptor subtypes exert their influence on emotional responses, focusing on the hypothalamic-pituitary-adrenal axis and the oxytocinergic and serotonergic systems. The impact of estrogens on the expression of anxiety is likely the result of their combined effects on all of these neurobiological systems.

Role of anti cyclic citrullinated peptide antibodies in erosive disease in patients with rheumatoid arthritis.

BACKGROUND & OBJECTIVES: Antibodies to cyclic citrullinated peptide (CCP) are a recently described marker in rheumatoid arthritis (RA), which are said to connote aggressive disease. No data on these antibodies are available from India. We undertook this study to evaluate the role of second generation anti CCP antibodies (anti CCP-2) in predicting erosive disease in Indian patients with rheumatoid arthritis and to define their role in seronegative RA. METHODS: A total of 211 patients with established RA were evaluated in this cross-sectional study for radiographic erosions. A high percentage of seronegative RA patients (40%) were included to assess the role of anti CCP-2 antibodies in this subgroup. Radiographic damage was quantified using modified Sharp score. Apart from anti CCP-2 antibodies, other factors evaluated for their ability to predict erosions included rheumatoid factor (RF) positivity, disease duration, and disease modifying anti rheumatic drugs (DMARD) naïve period. RESULTS: Anti CCP-2 antibodies were seen in 80 per cent patients with RA. Predictors of erosive disease included anti CCP-2 antibody positivity and DMARD naïve period. Patients positive for both RF and anti CCP-2 antibodies had a higher prevalence of erosions as compared to patients positive for only one antibody or negative for both. In seronegative RA (RF absent), anti CCP-2 antibodies were seen in over 50 per cent patients and were associated with a higher incidence of erosive disease. INTERPRETATION & CONCLUSION: Our finding showed that anti CCP-2 antibodies were present in 80 per cent patients with established RA. These have an independent role in predicting erosive disease, especially in the seronegative subgroup.

Comparison of nebulised magnesium sulphate and salbutamol combined with salbutamol alone in the treatment of acute bronchial asthma: a randomised study.

OBJECTIVE: To test the hypothesis that combined administration of multiple doses of nebulised salbutamol and magnesium sulphate provides additional benefit compared with salbutamol alone in adult patients with acute asthma. DESIGN: Randomised, double blind, prospective study. METHODS: A total of 100 patients presenting to an emergency department with an acute attack of bronchial asthma were randomised to two groups: nebulisation with a combination of salbutamol and magnesium sulphate (group A) and nebulisation with salbutamol only (group B). Both groups received nebulisation thrice at intervals of 20 minutes. Salbutamol and magnesium sulphate were administered in doses of 0.5 mg and 500 mg, respectively, and the solutions were made isotonic to plasma osmolality. Pulse rate, blood pressure, and peak expiratory flow rate (PEFR) were measured at baseline and at 15, 60, 75, and 120 minutes. Serum magnesium levels and blood gases were measured at 0 and 120 minutes in both groups. RESULTS: All patients had either acute severe or life threatening asthma. The baseline characteristics were comparable in the two groups. Both groups showed significant rise in PEFR at all time intervals, however, there was no significant difference between the groups in rise in PEFR at any time point. Serum magnesium levels remained within normal limits, and there was no difference in requirement of additional medication during the study or hospital admission rates in both groups. No significant side effects were noted. CONCLUSION: This study suggests that there is no therapeutic benefit of adding magnesium sulphate to salbutamol nebulisation in the treatment of patients with acute severe or life threatening asthma.

Hepato-biliary Scintigraphy in diagnosis of Biliary Atresia.

BACKGROUND: Biliary Atresia and Neonatal Hepatitis are the two major causes of Persistent Neonatal Jaundice. Differentiation is done by biochemical and radiological tests. Radiological investigations use intra-or extra-hepatic biliary dilation for diagnosing biliary atresia but this is not always reliable. METHODS: 14 neonates with persistent conjugated hyperbilirubinemia who had undergone hepato-biliary scintigraphy were retrospectively evaluated and those having Extrahepatic Biliary Atresia were analyzed with reference to operative findings. RESULTS: 11 out of 14 had Extrahepatic Biliary Atresia during operation whereas 3 proved to be false positive. CONCLUSION: Mebrofenin hepato - biliary scintigraphy is a simple, safe, accurate and cost effective investigation for diagnosis of biliary atresia.