Molecular docking based virtual screening of carbonic anhydrase IX with coumarin (a cinnamon compound) derived ligands.

It is of interest to design carbonic anhydrase IX (CAIX) inhibitors with improved features using molecular docking based virtual high through put screening of ligands. Coumarin (a cinnamon compound with pharmacological activity) is known as a potent phytal compound blocking tumor growth. Hence, a series of 17 coumarin derivatives were designed using the CHEMSKETCH software for docking analysis with CAIX. The catalytic site analysis of CAIX for binding with ligand molecules was completed using the SCHRODINGER package (2009). Thus, 17 ligands with optimal binding features with CAIX were selected following the calculation of ADME/T properties. We report ligands #41, #42, #19 and #15 showed good docking score, glide energy and hydrogen bond interactions without vdW clash. We further show that N-(3,4,5-trimethoxy-phenylcarbamoylmethyl) designated as compound #41 have the highest binding energy (-61.58) with optimal interactions with the catalytic residues (THR 199, PRO 201, HIS 119, HIS 94) of CAIX.

Impact of dietary deviation on disease progression and gut microbiome composition in lupus-prone SNF1 mice.

Environmental factors, including microbes and diet, play a key role in initiating autoimmunity in genetically predisposed individuals. However, the influence of gut microflora in the initiation and progression of systemic lupus erythematosus (SLE) is not well understood. In this study, we have examined the impact of drinking water pH on immune response, disease incidence and gut microbiome in a spontaneous mouse model of SLE. Our results show that (SWR × NZB) F1 (SNF1 ) mice that were given acidic pH water (AW) developed nephritis at a slower pace compared to those on neutral pH water (NW). Immunological analyses revealed that the NW-recipient mice carry relatively higher levels of circulating autoantibodies against nuclear antigen (nAg) as well as plasma cells. Importantly, 16S rRNA gene-targeted sequencing revealed that the composition of gut microbiome is significantly different between NW and AW groups of mice. In addition, analysis of cytokine and transcription factor expression revealed that immune response in the gut mucosa of NW recipient mice is dominated by T helper type 17 (Th17) and Th9-associated factors. Segmented filamentous bacteria (SFB) promote a Th17 response and autoimmunity in mouse models of arthritis and multiple sclerosis. Interestingly, however, not only was SFB colonization unaffected by the pH of drinking water, but also SFB failed to cause a profound increase in Th17 response and had no significant effect on lupus incidence. Overall, these observations show that simple dietary deviations such as the pH of drinking water can influence lupus incidence and affect the composition of gut microbiome.

Gender bias in lupus: does immune response initiated in the gut mucosa have a role?

The risk of developing systemic lupus erythematosus (SLE) is approximately nine times higher among women compared to men. However, very little is understood concerning the underlying mechanisms that contribute to this gender bias. Further, whether there is a link between immune response initiated in the gut mucosa, the progression of SLE and the associated gender bias has never been investigated. In this report, we show a potential link between the immune response of the gut mucosa and SLE and the gender bias of lupus for the first time, to our knowledge. Both plasma cell- and gut-imprinted- α4ß7 T cell frequencies were significantly higher in the spleen and gut mucosa of female (SWR × NZB)F1 (SNF1 ) mice compared to that of their male counterparts. Importantly, female SNF1 mice not only showed profoundly higher CD45(+) immune cell densities, but also carried large numbers of interleukin (IL)-17-, IL-22- and IL-9-producing cells in the lamina propria (LP) compared to their male counterparts. Intestinal mucosa of female SNF1 mice expressed higher levels of a large array of proinflammatory molecules, including type 1 interferons and Toll-like receptors 7 and 8 (TLR-7 and TLR-8), even before puberty. Our work, therefore, indicates that the gut immune system may play a role in the initiation and progression of disease in SLE and the associated gender bias.

A social cognitive model of health for HIV-positive adults receiving care in India.

In-depth interviews were conducted with 50 HIV-positive adults (23 women, 27 men) with access to care at a non-governmental organization in Chennai, India to gain a broad understanding of how they managed their HIV infection. Using a Social Cognitive Model of Health, we identified factors within the model's three domains--Personal, Environmental, and Behavioral--that are applicable to this socio-cultural context. The Personal domain's factors were a positive self-concept, family-focused goals, and treatment optimism; the Environmental domain comprised family-based support, treatment availability, access and quality, and HIV stigma and discrimination; and the Behavior domain's factors were medication adherence and health habits, sexual behavior, and social relationships and emotional well-being. Significant differences for many of the factors within the three domains were observed across married men and women, widowed women, unmarried men, and female sex workers. Implications for an enhanced intervention for HIV-infected individuals in similar treatment settings are discussed.

A dancer with an unusual cause of neck pain.

A girl presented with a dull ache in the neck and mild difficulty in neck movements. She had limited clinical signs and her initial work up failed to reveal the cause. With the help of imaging modalities and CT guided needle biopsy, she was diagnosed to have an eosinophilic granuloma of the fifth cervical vertebra. There were no neurological symptoms. She was successfully managed with immobilization of spine, local irradiation and systemic vinblastine. The literature is briefly reviewed for clinical features, diagnosis and management.

Unilateral internal jugular phlebectasia.

Jugular phlebectasia is a rare cause of cervical swelling in children. It is a fusiform dilatation of any part of the jugular venous system and can involve the external, internal or anterior jugular veins. Previous reports suggest that the entity is often ignored or misdiagnosed. Unilateral internal jugular phlebactasia presenting as an intermittent neck swelling in a ten-year-old girl is reported. The clinical features are analyzed and the appropriate use of noninvasive imaging modalities is highlighted. The literature is also briefly reviewed.

The humoral immune response in melioidosis patients during therapy.

BACKGROUND: This study was undertaken to identify and quantify the class and subclass antibody responses to the culture filtrate antigen (CFA) of Burkholderia pseudomallei in melioidosis patients under long-term maintenance or eradication therapy. MATERIALS AND METHODS: Sequential sera samples from seven melioidosis patients collected between January 1992 and April 1998 were analyzed for immunoglobulin (Ig) types and IgG isotypes by ELISA using B. pseudomallei CFA. RESULTS: Melioidosis patients generated a strong IgG, IgA and IgM response to the CFA of B. pseudomallei throughout the infection and IgG1 and IgG2 were the predominant IgG istotypes produced. Although high levels of these antibodies were detected in all the seven patients, the IgG, IgG1 and IgG2 antibodies showed a consistent response and good correlation with the clinical history in all cases. CONCLUSION: This study suggests that monitoring IgG antibody or IgG1 or IgG2 isotype antibody levels to CFA in patients under maintenance or eradication antibiotic therapy may be useful as a tool to detect the status of infection and as a guideline to determine the duration of maintenance antimicrobial therapy.

Targeted delivery of anti-CTLA-4 antibody downregulates T cell function in vitro and in vivo.

CTLA-4 is a T cell surface molecule that binds to the costimulatory molecules CD80 and CD86 on antigen-presenting cells and downregulates T cell function. Therefore, we wanted to test whether antigen-specific activated T cells could be inhibited through directed CTLA-4 signaling using a bispecific antibody (BiAb) capable of simultaneously binding to CTLA-4 and a tissue-specific antigen. The BiAb was prepared by linking two separate monoclonal antibodies against CTLA-4 and the thyroid-stimulating hormone receptor (TSHR). The mouse B cell lymphoma line M12 (H2(d)) was used to induce alloreactive T cells in CBA/J mice (H2(k)); M12 cells stably transfected with the cDNA encoding murine TSHR (mM12) were used to restimulate the alloresponse in vitro. Results of assays for in vitro T cell proliferation, IL-2 production, and cytotoxicity in the presence of BiAb demonstrated that the BiAb could inhibit the T cell alloresponse when stimulated with mM12 cells but not with M12 cells. This effect was dependent on binding of TSHR-bound BiAb to CTLA-4, since the addition of soluble CTLA-4-Ig blocked the inhibitory effect. Injection of mM12 cells, along with the BiAb, not with antibodies against TSHR or CTLA-4 either separately or together, into CBA/J mice (H2(k)) downregulated alloreactive T cell responses. Our study demonstrated that the presence of CTLA-4 signaling molecules on the surface of target cells can protect those cells from immune attack by antigen-specific T cells and suggested that a similar approach could have potential therapeutic value in transplant rejection and tissue-specific autoimmune diseases.

A 43-kDa circulating filarial antigen fraction of Wuchereria bancrofti in immunoprophylaxis against Brugia malayi in jirds.

A 43 kiloDaltan (kDa) antigen fraction (CFA2-6) isolated from microfilaraemic plasma of bancroftian filarial patients showed selective reactivity with sera samples collected from endemic normals. Antibodies raised against this antigen showed a strong reactivity with the surface of Brugia malayi infective larvae as well as microfilariae. Similar antigenic determinants were detected in the parasite extracts, but not in the excretory-secretory products. Further analysis was done on the immunoprophylactic potential of CFA2-6 in inducing immunity against Brugia malayi in Meriones unguiculatus (jird) in vivo. A strong protective response of approximately 84% was observed against the development of the filarial parasite in the jirds immunized with CFA2-6. The immunized jirds also showed a significant clearance (87%) of microfilariae inoculated intravenously. Approximately 65% of infective larvae failed to survive in jirds transferred with anti-CFA2-6 serum compared to the jirds transferred with sera from the control jirds. Passive transfer of anti-CFA2-6 antibody to the jirds followed by intravenous inoculation of microfilariae resulted in the reduction of 77% of circulating microfilariae. This study suggests that the 43-kDa CFA2-6 could stimulate a strong protective immune response against infective larvae and microfilariae in experimental animals.

Nail-patella syndrome with some unusual features.

Nail-patella syndrome is a rare hereditary disease. We report a patient who was the lone member affected in the family. The patient additionally had a bony defect of the skull which has not been reported so far in the literature.

Effect of empiric antiarrhythmic therapy in resuscitated out-of-hospital cardiac arrest victims with coronary artery disease.

The effect of empiric antiarrhythmic therapy with quinidine and procainamide on long-term mortality was examined in 209 patients with coronary artery disease resuscitated after out-of-hospital cardiac arrest. The antiarrhythmic agent used was determined by the patient's private physician without knowledge of the study ambulatory electrocardiogram. Of the 209 patients, procainamide was prescribed in 45 (22%), quinidine in 48 (23%) and no antiarrhythmic therapy in 116 (55%). Digoxin therapy was initiated in 101 patients. The 2-year total survival rate for the quinidine, procainamide and nontreated patients was 61, 57 and 71% (p less than 0.05), and for sudden death was 69, 69 and 89% (p less than 0.01), respectively. These observations suggest that empiric antiarrhythmic therapy in survivors of out-of-hospital cardiac arrest did not affect total mortality and was associated with an increased frequency of sudden death.

Predictive value of ventricular arrhythmias in resuscitated out-of-hospital cardiac arrest victims.

Twenty-four hour ambulatory electrocardiograms recorded in 103 survivors of out-of-hospital cardiac arrest were analyzed to find those characteristics of the ventricular premature complex (VPC) which provide the best combination of sensitivity, specificity, and predictive accuracy for subsequent mortality. VPC characteristics were grouped as: (1) frequent (greater than or equal to 25 h-1), (2)bigeminal, (3) multiform, (4) early coupled, (5) pairing, (6) repetitive greater than or equal to 2, (7) repetitive greater than or equal to 3, (8) repetitive greater than or equal to 6, (9) the combination of frequent and repetitive, or (10) complex defined as any multiform, early, bigeminal or repetitive VPC. In an average follow-up period of 43 months, 42 deaths occurred, 17 of which were classified as sudden. Each characteristic was a significant predictor for all causes of subsequent death except early coupled VPCs and repetitive VPCs greater than 6. None of the characteristics reached significance as predictors for sudden death. The number of repetitive VPCs when stratified to none, greater than or equal to 2 and greater than or equal to 3 successive VPCs correlated with mortality in an incremental fashion. The combination of frequent VPCs and repetitive VPCs provided the best combination of sensitivity, specificity and predictive accuracy for death from all causes within five years.

Clinical characteristics and survival experience of out-of-hospital cardiac arrest victims without coronary heart disease.

Of 270 patients successfully resuscitated from out-of-hospital cardiac arrest, 16% had no evidence of coronary heart disease. In these 43 patients, other forms of heart disease were found in 81% (35/43): cardiomyopathy in 18 patients, valvular disease in six, congenital heart disease in two, and primary arrhythmia in nine. Seven patients had evidence of only pulmonary disease and one had pancreatitis as his precipitating event. Nineteen of the 43 patients (44%) had serum potassium less than 3.6 mEq l-1 in the initial blood sample after cardiac arrest. One- and two-year mortalities were 30% and 43%, respectively, for the group, which is similar to one-year (20%) and two-year (35%) mortalities of the 227 resuscitated patients with coronary heart disease. Patients who survive a sudden death experience and who have no evidence of coronary artery disease are a unique but heterogeneous group who usually have identifiable cardiac or pulmonary disease.

Analysis of cardiac symptoms preceding cardiac arrest.

Prodromal symptoms and cardiac history were examined in 227 patients with coronary artery disease who were successfully resuscitated after out-of-hospital cardiac arrest. Cardiac arrest was sudden--with either no symptoms or symptoms for less than 1 hour--in 71% of the patients. Nonsudden death--death occurring after more than 1 hour of symptoms--occurred in 29% of the patients. A history of cardiovascular disease was present in 85% of patients with sudden cardiac arrest and in 83% with nonsudden arrest. Cardiac arrest occurred without symptoms in 38% of the patients with sudden cardiac arrest and was the first expression of coronary artery disease in 4% of the entire study group. This study indicates that cardiac arrest usually occurs with symptoms and almost always in the setting of a history of cardiovascular disease.

The effect of bystander CPR on survival of out-of-hospital cardiac arrest victims.

The effect of bystander cardiopulmonary resuscitation (CPR) was studied in 2142 emergency medical service (EMS) cardiac arrest runs. When bystander CPR was administered to cardiac arrest victims, 22.9% of the victims survived until they were admitted to the hospital and 11.9% were discharged alive. In comparison, the statistics for cardiac arrest victims who did not receive bystander CPR were 14.6% and 4.7%, respectively (p less than 0.001). A critical factor in patient survival was the amount of time that elapsed before the EMS personnel arrived and administered CPR. Patients who received bystander CPR were more likely to have ventricular fibrillation when the EMS arrived. Other factors relating to patient survival were the location of the victim at the time of the cardiac arrest and the age of the victim. Understanding these factors is important in developing community strategies to treat patients with cardiac arrest out of hospital.

Predictive survival models for resuscitated victims of out-of-hospital cardiac arrest with coronary heart disease.

Resuscitated victims of cardiac arrest with coronary heart disease represent a group of patients with an accelerated mortality rate. Among 227 such patients in our follow-up study, 20% had died at 1 year and 50% were dead in slightly over 3 years. Predictors of death were related to use of digitalis, elevated blood urea nitrogen, cerebral vascular accident, previous myocardial infarction, and age. In a subset of 103 patients in whom ambulatory electrocardiographic recordings were available within 3 months of the arrest event, the presence of complexity and high-frequency ventricular premature beats (VPBs) (greater than or equal to 25/hr) were added to the mortality predictors of digitalis and diuretic therapy and elevated blood urea nitrogen. An almost equal number of patients died suddenly and nonsuddenly. Predictors of sudden death were treatment with quinidine and paired VPBs. Occurrence of arrhythmias was an important addition to the previous mortality predictors related to left ventricular dysfunction.