Impaired Striatal Akt Signaling Disrupts Dopamine Homeostasis and Increases Feeding

DOI is broken and has been reportedThe prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address “food-abuse” disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake. Methodology/Principal Findings We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia. Conclusions/Significance Acquired disruption of brain insulin action may confer risk for and/or underlie “food-abuse” disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to “the fast food lifestyle” creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.National Institutes of Health (U.S.) (grant DA14684)National Institutes of Health (U.S.) (grant DK085712

Molecular epidemiology of pneumococci obtained from Gambian children aged 2–29 months with invasive pneumococcal disease during a trial of a 9-valent pneumococcal conjugate vaccine

BACKGROUND: The study describes the molecular epidemiology of Streptococcus pneumoniae causing invasive disease in Gambian children METHODS: One hundred and thirty-two S. pneumoniae isolates were recovered from children aged 2-29 months during the course of a pneumococcal conjugate vaccine trial conducted in The Gambia of which 131 were characterized by serotyping, antibiotic susceptibility, BOX-PCR and MLST. RESULTS: Twenty-nine different serotypes were identified; serotypes 14, 19A, 12F, 5, 23F, and 1 were common and accounted for 58.3% of all serotypes overall. MLST analysis showed 72 sequence types (STs) of which 46 are novel. eBURST analysis using the stringent 6/7 identical loci definition, grouped the isolates into 17 clonal complexes and 32 singletons. The population structure of the 8 serotype 1 isolates obtained from 4 vaccinated and 2 unvaccinated children were the same (ST 618) except that one (ST3336) of the isolates from an unvaccinated child had a novel ST which is a single locus variant of ST 618. CONCLUSION: We provide the first background data on the genetic structure of S. pneumoniae causing IPD prior to PC7V use in The Gambia. This data will be important for assessing the impact of PC7V in post-vaccine surveillance from The Gambia

Epidemiologic and clinical characteristics of community-acquired invasive bacterial infections in children aged 2-29 months in The Gambia.

BACKGROUND: The incidence of community-acquired bacteremia (CAB) in Africa is several-fold higher than in industrialized countries. We report here the incidence of invasive bacterial infections in rural Gambia and compare the clinical characteristics of children with pneumococcal infection with those of children with extraintestinal nontyphoidal salmonella infection (NTS) or other bacterial infections. METHODS: As part of a pneumococcal conjugate vaccine trial, we investigated children aged 2-29 months who presented with signs suggestive of invasive bacterial infections. RESULTS: The incidence of invasive bacterial infections in all subjects was 1009 (95% CI, 903-1124) cases per 100,000 person-years. It was 1108 (95% CI, 953-1282) among children who had not received pneumococcal conjugate vaccine. Incidence decreased with increasing age but remained relatively high in 24- to 29-month-olds for pneumococcal infections. Pneumococcal infection was more frequent than NTS infections in the hot dry season. Respiratory symptoms and signs, consolidation on chest radiograph, and a primary diagnosis of pneumonia were more frequent in children with pneumococcal infection than in those with NTS or other infections. Diarrhea, laboratory evidence of malaria infection, and a primary diagnosis of malaria were more common in children with NTS infections. CONCLUSIONS: Bacterial infections continue to cause significant morbidity in rural Africa. Although vaccines could greatly reduce the pneumococcal burden, a high index of suspicion and appropriate use of antimicrobials are needed to manage other causes of invasive bacterial infections

Molecular epidemiology of community-acquired invasive non-typhoidal Salmonella among children aged 2 29 months in rural Gambia and discovery of a new serovar, Salmonella enterica Dingiri.

Sixty-two invasive non-typhoidal Salmonella (NTS) isolates from children aged 2-29 months in rural Gambia were examined for serovar prevalence and antimicrobial susceptibility, and characterized using multilocus sequence typing (MLST) of seven genes, aroC, dnaN, hemD, hisD, purE, sucA and thrA. Salmonella enterica serovar Enteritidis was the most common serovar (80.6 %), followed by S. enterica serovar Typhimurium (8.0 %). Thirty-three per cent of the isolates were resistant to all eight antimicrobials tested, including ampicillin (74.2 %), cotrimoxazole (64.5 %) and tetracycline (63 %). A total of 40.3 % of the NTS cases had an initial clinical diagnosis of malaria, whilst 27.3 % had a diagnosis of clinical pneumonia and 18 % had a diagnosis of septicaemia. MLST of NTS resulted in ten different sequence types (STs), of which five were novel, representing five different NTS serovars. In general, STs were restricted to the same serovar. One type (ST11) encompassed 80.6 % of the NTSs. A new NTS serovar named S. enterica serovar Dingiri was discovered. S. Dingiri was isolated from a 6-month-old male with an initial clinical diagnosis of malaria but a final clinical diagnosis of anaemia and septicaemia. S. Dingiri, which possesses an antigenic formula of 17:z:1,6, was sensitive to ampicillin, cefotaxime, chloramphenicol, ciprofloxacin, cotrimoxazole and tetracycline but resistant to gentamicin, and was ST338