Concurrent Pneumonia in Children under 5 Years of Age Presenting to a Diarrheal Hospital in Dhaka,Bangladesh

Respiratory and gastrointestinal infections are the top killers of children worldwide, and their co-occurrence is reported but not well understood. Our aim was to determine the risk factors for concurrent presentation of diarrhea and pneumonia (DP) in a resource-limited setting in Bangladesh. We used data from the Diarrheal Disease Surveillance System of the icddr,b Dhaka Hospital to identify children < 60 months of age with diarrhea and concurrent pneumonia, defined as a history of cough, an abnormal lung examination, and tachypnea. For the years 1996–2007, out of total 14,628 diarrheal patients surveyed, there were 607 (4%) patients who satisfied criteria for pneumonia. Those with DP had a higher mortality rate (4% versus 0.05%, odds ratio [OR] = 86, 95% confidence interval [CI] = 26–286) and a longer hospital stay (mean 84 versus 26 hours, difference 58 hours, 95% CI = 52–64 hours) than those with diarrhea (D) only. In multivariable logistic regression comparing cases (N = 607) with controls matched for month and year of admission at a ratio of 1:3 (N = 1,808), we found that DP was associated with younger age, male gender, severe acute malnutrition (SAM), less maternal education, lower family income, and lack of current breast-feeding history.     

Plasma Leptin Levels in Children Hospitalized with Cholera in Bangladesh

Vibrio cholerae, the cause of cholera, induces both innate and adaptive immune responses in infected humans. Leptin is a hormone that plays a role in both metabolism and mediating immune responses. We characterized leptin levels in 11 children with cholera in Bangladesh, assessing leptin levels on days 2, 7, 30, and 180 following cholera. We found that patients at the acute stage of cholera had significantly lower plasma leptin levels than matched controls, and compared with levels in late convalescence. We then assessed immune responses to V. cholerae antigens in 74 children with cholera, correlating these responses to plasma leptin levels on day 2 of illness. In multivariate analysis, we found an association between day 2 leptin levels and development of later anti-cholera toxin B subunit (CtxB) responses. This finding appeared to be limited to children with better nutritional status. Interestingly, we found no association between leptin levels and antibody responses to V. cholerae lipopolysaccharide, a T cell–independent antigen. Our results suggest that leptin levels may be associated with cholera, including the development of immune responses to T cell–dependent antigens.     

Correlation between In Vitro Complement Deposition and Passive Mouse Protection of Anti-Pneumococcal Surface Protein A Monoclonal Antibodies

The shortcomings of the licensed polysaccharide-based pneumococcal vaccine are driving efforts toward development of a protein-based vaccine that is serotype independent and effective in all age groups. An opsonophagocytic killing assay (OPKA) is used to evaluate the antibody response against polysaccharide-based pneumococcal vaccines. However, the OPKA is not reliable for noncapsular antigens. Thus, there is a need to develop an in vitro surrogate for protection for protein vaccine candidates like pneumococcal surface antigen A (PspA). PspA is a serologically variable cell surface virulence factor. Based on its sequence, PspA has been classified into families 1 (clade 1 and 2), 2 (clades 3, 4 and 5), and 3 (clade 6). Here, we report the characterization of 18 IgG anti-PspA monoclonal antibodies (anti-PspA^hkR36A MAbs) generated from mice immunized with heat-killed strain R36A (clade 2). An enzyme-linked immunosorbent assay (ELISA)-based analysis of the reactivity of the MAbs with recombinant PspAs from the 6 clades indicated that they were family 1 specific. This was confirmed by flow cytometry using a hyperimmune serum generated against PspA from R36A. Eight MAbs that bind at least one clade 1- and clade 2-expressing strain were evaluated for complement deposition, bactericidal activity, and passive protection. The anti-PspA^hkR36A MAb-dependent deposition of complement on pneumococci showed a positive correlation with passive protection against strain WU2 (r = 0.8783, P = 0.0041). All of our protective MAbs showed bactericidal activity; however, not all MAbs that exhibited bactericidal activity conferred protection in vivo. The protective MAbs described here can be used to identify conserved protection eliciting B cell epitopes for engineering a superior PspA-based vaccine.     

Vi polysaccharide of Salmonella typhi targets the prohibitin family of molecules in intestinal epithelial cells and suppresses early inflammatory responses

Vi capsular polysaccharide (Vi) was first identified as a virulence antigen of Salmonella typhi, the causative agent of typhoid fever in humans; it renders S. typhi resistant to phagocytosis and the action of serum complement. However, the role of Vi during the infection of intestinal epithelium with S. typhi is not completely understood. We show here that Vi can interact with a model human intestinal epithelial cell line, Caco-2, through a cell-surface-associated molecular complex containing two major proteins of 30 and 35 kDa and a minor protein of approximately 68 kDa. The two major proteins were identified as the putative tumor suppressor molecule, prohibitin, and its closely related homolog, B cell receptor-associated protein 37. These two proteins were enriched in lipid rafts, and Vi readily associated with these membrane microdomains. Engagement of Caco-2 cells with Vi inhibited their ability to produce an inflammatory response upon infection with Vi(-) S. typhi. Consistent with this effect, infection of Caco-2 cells with Vi(+) S. typhi produced less IL-8 compared with Vi(-) S. typhi. Cells treated with Vi showed reduced extracellular signal-regulated kinase phosphorylation in response to infection with Vi(-) S. typhi or stimulation with phorbol 12-myristate 13-acetate, suggesting that the mitogen-activated protein kinase pathway might be a target for Vi-mediated inhibition of inflammatory responses. These findings reveal a crucial role for Vi in the modulation of early inflammatory responses during infection with S. typhi. This kind of a modulation could play a significant role in the establishment of infection by S. typhi.     

Coronary artery disease epidemic in Pakistan: more electrocardiographic evidence of ischaemia in women than in men

Indo-Pakistani populations have one of the highest risks of coronary artery disease (CAD) in the world. A population-based, cross-sectional survey was conducted on 3143 adults aged >or=40 years from 12 randomly selected communities in Karachi, Pakistan. Apart from smoking, women had more CAD risk factors (diabetes, hypertension, obesity, dyslipidaemia) than men. Definite CAD (history and Q waves on ECG) was more prevalent in men than in women (6.1% vs 4.0%; p = 0.009). In contrast, ischaemic and major ECG changes were twice as prevalent in women as in men (29.4% vs 15.6%, and 21.0% vs 10.5%; p<0.001 for each, respectively). All measures of CAD were strongly predicted by the metabolic syndrome, but that failed to account for the greater prevalence of ECG abnormalities in women than in men. The findings indicate that one in five middle-aged adults in urban Pakistan may have underlying CAD. Women are at greater risk than men. Trial registration number: NCT00327574.     

Healthcare-Associated Pneumonia and Hospital-Acquired Pneumonia: Bacterial Aetiology,Antibiotic Resistance and Treatment Outcomes: A Study From North India

Background

Data regarding the comparative profiling of HCAP and HAP from developing countries like India are scant. We set out to address the microbial aetiology, antibiotic resistance and treatment outcomes in patients with HCAP and HAP.

Methods

318 consenting patients with HCAP (n?=?165, aged 16–90 years; median 60 years; 97 males) or HAP (n?=?153; aged 16–85 years; median 45 years; 92 males) presenting to a tertiary care hospital in North India from 2013 to 2015 were prospectively recruited for the study. Data on patient characteristics, microbial aetiology, APACHE II scores, treatment outcomes and mortality were studied. Clinical outcomes were compared with various possible predictors employing logistic regression analysis.

Results

Patients in HCAP had more comorbidity. Escherichia coli (30, 18%) and Acinetobacter baumannii (62, 41%) were the most commonly isolated bacteria in HCAP and HAP, respectively. Multidrug-resistant bacteria were isolated more frequently in HCAP, only because the incidence of extensively drug-resistant bacteria was markedly high in HAP (p?=?0.00). The mean APACHE II score was lower in HCAP (17.55?±?6.406, range 30) compared to HAP (19.74?±?8.843, range 37; p?=?0.013). The length of stay?≥?5 days (p?=?0.036) and in-hospital mortality was higher in HAP group (p?=?0.002). The most reliable predictors of in-hospital mortality in HCAP and HAP were APACHE II score?≥?17 (OR?=?14, p?=?0.00; HAP: OR?=?10.8, p?=?0.00), and septic shock (OR?=?4.5, p?=?0.00; HAP: OR?=?6.9, p?=?0.00).

Conclusion

The patient characteristics in HCAP, treatment outcomes, bacterial aetiology, and a higher incidence of antibiotic-resistant bacteria, suggest that HCAP although not as severe as HAP, can be grouped as a separate third entity.

     

The ventricular residence time distribution derived from 4D flow particle tracing: a novel marker of myocardial dysfunction

4D flow cardiac magnetic resonance (CMR) imaging allows visualisation of blood flow in the cardiac chambers and great vessels. Post processing of the flow data allows determination of the residence time distribution (RTD), a novel means of assessing ventricular function, potentially providing additional information beyond ejection fraction. We evaluated the RTD measurement of efficiency of left and right ventricular (LV and RV) blood flow. 16 volunteers and 16 patients with systolic dysfunction (LVEF?<?50%) underwent CMR studies including 4D flow. The RTDs were created computationally by seeding virtual ‘particles’ at the inlet plane in customised post-processing software, moving these particles with the measured blood velocity, recording and counting how many exited per unit of time. The efficiency of ventricular flow was determined from the RTDs based on the time constant (RTDc?=???1/B) of the exponential decay. The RTDc was compared to ejection fraction, T1 mapping and global longitudinal strain (GLS). There was a significant difference between groups in LV RTDc (healthy volunteers 1.2?±?0.13 vs systolic dysfunction 2.2?±?0.80, p?<?0.001, C-statistic?=?1.0) and RV RTDc (1.5?±?0.15 vs 2.0?±?0.57, p?=?0.013, C-statistic?=?0.799). The LV RTDc correlated significantly with LVEF (R?=???0.84, P?<?0.001) and the RV RTDc had significant correlation with RVEF (R?=???0.402, p?=?0.008). The correlation between LV RTDc and LVEF was similar to GLS and LVEF (0.926, p?<?0.001). The ventricular residence time correlates with ejection fraction and can distinguish normal from abnormal systolic function. Further assessment of this method of assessment of chamber function is warranted.     

Regulation of basal gastric acid secretion by the glycogen synthase kinase GSK3

Background  

According to previous observations, basal gastric acid secretion is downregulated by phosphoinositol-3-(PI3)-kinase, phosphoinositide-dependent kinase (PDK1), and protein kinase B (PKBβ/Akt2) signaling. PKB/Akt phosphorylates glycogen synthase kinase GSK3. The present study explored whether PKB/Akt-dependent GSK3-phosphorylation modifies gastric acid secretion.