Biologic Activities of the TolC-Like Protein of Neisseria meningitidis as Assessed by Functional Complementation in Escherichia coli

Neisseria meningitidis can produce a TolC-like protein needed for secretion of FrpC but not efflux of antimicrobials. We now report that expression of the meningococcal tolC gene in a TolC-deficient strain of Escherichia coli can restore properties of α-hemolysis and antimicrobial resistance known to involve efflux pumps.Despite considerable progress in understanding the pathophysiology of invasive meningococcal disease and the contribution of bacterial virulence factors, much remains to be learned. In particular, little definitive information is available regarding virulence factors that Neisseria meningitidis secretes to the extracellular fluid during infection and how they might damage host cells and tissues or modulate inflammatory responses that are protective or damaging. Certain strains of N. meningitidis (8), but not of the related pathogen Neisseria gonorrhoeae, produce a type I secretion system similar to the HlyB-HlyD-TolC efflux pump of Escherichia coli (29), known to be important in the extracellular production of α-hemolysin (HlyA) (12, 27, 28). Klee et al. (8) described a DNA island in certain strains of N. meningitidis that contains tandemly linked hylD and tolC genes that we showed (7) are cotranscribed. Wooldridge et al. (29) demonstrated that N. meningitidis contains an unlinked hlyB gene and predicted the presence of a functional HlyB-HlyD-TolC efflux system in N. meningitidis. We (7) recently showed that meningococcal FrpC, which bears amino acid similarity to HlyA (23, 24), but has unknown biological activity (4), is secreted by the HlyB-HlyD-TolC efflux pump.Although N. meningitidis uses TolC in conjunction with HlyB-HlyD for FrpC export (7), as shown previously for its function with the AcrA-AcrB system in E. coli (5), it is not required for efflux of antimicrobials in the meningococcus. Rather, the MtrE proteins of N. meningitidis and N. gonorrhoeae work with the MtrC-MtrD efflux proteins as the outer membrane protein (OMP) channel for export of antimicrobials (3, 7, 17, 21). The AcrA-AcrB-TolC and MtrC-MtrD-MtrE efflux pumps are structurally and functionally similar (21). The amino acid similarity between the TolC OMPs possessed by E. coli and N. meningitidis, their similarity to MtrE (3), and the fact that N. meningitidis has two similar OMPs (MtrE and TolC) led us to further investigate the biologic activity of meningococcal TolC. Accordingly, we asked if this protein could functionally replace TolC used by E. coli in its secretion of HlyA and efflux of antimicrobials. Using a complementation strategy, we found that TolC produced by N. meningitidis can participate in both export functions when expressed in E. coli, suggesting that it has the intrinsic ability to interact with components of bacterial efflux pumps that are involved in antimicrobial resistance and toxin secretion.(A preliminary account of these findings was presented at the 16th International Pathogenic Neisseria Conference, held in Rotterdam, The Netherlands, from 7 to 12 September 2008.)     

Investigation of trace metals in the blood plasma and scalp hair of gastrointestinal cancer patients in comparison with controls

BackgroundGastrointestinal cancer is one of the most common types of cancer which is predominantly associated with the environmental factors. The carcinogenic processes are linked with the imbalances of trace metals in body fluid and tissues.MethodsTrace metals (Cd, Cr, Cu, Fe, Ni, Pb and Zn) are estimated in blood plasma and scalp hair of the cancer patients and controls employing nitric acid–perchloric acid based wet-digestion followed by atomic absorption spectrophotometric method.ResultsThe mean concentrations of Cd, Cr, Cu and Ni were found to be significantly higher in the plasma of patients compared with the controls, however, appreciably higher concentrations of Fe and Zn were observed in the plasma of controls. The average scalp hair concentrations of Zn, Fe, Pb, Cu and Cd were notably higher in the patients than controls. The correlation study revealed significantly different mutual variations of the trace metals in the plasma and scalp hair of the patients and controls. The apportionment of trace metals in the plasma and scalp hair of the patients and controls was also considerably different.ConclusionsThe study revealed that the carcinogenic processes are significantly affecting the trace metal burden and mutual variations in the cancerous patients compared with the controls.     

Use of radiologic imaging to enhance physical diagnosis instruction in the preclinical curriculum

RATIONALE AND OBJECTIVES: To expose students in the premedical years to imaging and its indications, to enhance their understanding of pathologic processes by allowing direct visualization, and to teach physical diagnosis through an integrated, multispecialty approach. MATERIALS AND METHODS: A total of 166 second-year medical students participated in a novel imaging session that accompanied the physical diagnosis course they were concurrently enrolled in. Students were provided a didactic orientation to imaging and taught how to use Picture Archiving and Communications System software. The students then participated in interactive imaging sessions in which they were able to scroll through entire imaging cases of real, anonymized patients with accompanying clinical scenarios and physical examination findings. RESULTS: Of 89 students responding to an online curricular feedback questionnaire, 41% believed that the imaging correlated with the other information taught in the course and 46% found it was helpful to their learning. The majority of students (64%) believed that the sessions helped challenge them to think about physical diagnosis in a different way. CONCLUSION: Physical diagnosis on the wards requires a multispecialty approach and the early introduction of this technique through the integrated mode of teaching we present will benefit students in their clinical years and future careers.     

Clinical epidemiology of ulcerative colitis in Arabs based on the Montréal classification

AIM: To determine the clinical, epidemiological and phenotypic characteristics of ulcerative colitis (UC) in Saudi Arabia by studying the largest cohort of Arab UC patients.METHODS: Data from UC patients attending gastroenterology clinics in four tertiary care centers in three cities between September 2009 and September 2013 were entered into a validated web-based registry, inflammatory bowel disease information system (IBDIS). The IBDIS database covers numerous aspects of inflammatory bowel disease. Patient characteristics, disease phenotype and behavior, age at diagnosis, course of the disease, and extraintestinal manifestations were recorded.RESULTS: Among 394 UC patients, males comprised 51.0% and females 49.0%. According to the Montréal classification of age, the major chunk of our patients belonged to the A2 category for age of diagnosis at 17-40 years (68.4%), while 24.2% belonged to the A3 category for age of diagnosis at > 40 years. According to the same classification, a majority of patients had extensive UC (42.7%), 35.3% had left-sided colitis and 29.2% had only proctitis. Moreover, 51.3% were in remission, 16.6% had mild UC, 23.4% had moderate UC and 8.6% had severe UC. Frequent relapse occurred in 17.4% patients, infrequent relapse in 77% and 4.8% had chronic disease. A majority (85.2%) of patients was steroid responsive. With regard to extraintestinal manifestations, arthritis was present in 16.4%, osteopenia in 31.4%, osteoporosis in 17.1% and cutaneous involvement in 7.0%.CONCLUSION: The majority of UC cases were young people (17-40 years), with a male preponderance. While the disease course was found to be similar to that reported in Western countries, more similarities were found with Asian countries with regards to the extent of the disease and response to steroid therapy.     

Gene-gene,gene-environment,gene-nutrient interactions and single nucleotide polymorphisms of inflammatory cytokines

Inflammation plays a significant role in the etiology of type 2 diabetes mellitus(T2DM).The rise in the pro-inflammatory cytokines is the essential step in glucotoxicity and lipotoxicity induced mitochondrial injury,oxidative stress and beta cell apoptosis in T2 DM.Among the recognized markers are interleukin(IL)-6,IL-1,IL-10,IL-18,tissue necrosis factor-alpha(TNF-α),C-reactive protein,resistin,adiponectin,tissue plasminogen activator,fibrinogen and heptoglobins.Diabetes mellitus has firm genetic and very strong environmental influence; exhibiting a polygenic mode of inheritance.Many single nucleotide polymorphisms(SNPs) in various genes including those of pro and antiinflammatory cytokines have been reported as a risk for T2 DM.Not all the SNPs have been confirmed by unifying results in different studies and wide variations have been reported in various ethnic groups.The inter-ethnic variations can be explained by the fact that gene expression may be regulated by gene-gene,gene-environment and gene-nutrient interactions.This review highlights the impact of these interactions on determining the role of single nucleotide polymorphism of IL-6,TNF-α,resistin and adiponectin in pathogenesis of T2 DM.     

Effects of Obesity and Hypertension on Pulse Wave Velocity in Children

Pulse wave velocity (PWV) is a biomarker of arterial stiffness. Findings from prior studies are conflicting regarding the impact of obesity on PWV in children. The authors measured carotid‐femoral PWV in 159 children aged 4 to 18 years, of whom 95 were healthy, 25 were obese, 15 had hypertension (HTN), and 24 were both obese and hypertensive. Mean PWV increased with age but did not differ by race or sex. In adjusted analyses in children 10 years and older (n=102), PWV was significantly higher in children with hypertension (PWV±standard deviation, 4.9±0.7 m/s), obesity (5.0±0.9 m/s), and combined obesity‐hypertension (5.2±0.6 m/s) vs healthy children (4.3±0.7 m/s) (each group, P<.001 vs control). In our study, obesity and HTN both significantly and independently increased PWV, while African American children did not have a higher PWV than Caucasian children.     

Inflammatory myofibroblastic tumor of the lung in an adolescent boy

Inflammatory myofibroblastic tumors of the lung are rare, here, an unusual case is described. A 14-year-old boy presented with a history of weight loss and clubbing and was found to have a solitary circumscribed mass in right lower lobe treated with lobectomy. This case indicates the need for early and complete removal of the inflammatory myofibroblastic tumor of the lung.     

Hypohidrotic ectodermal dysplasia (HED)

Hypohidrotic Ectodermal Dysplasia (HED) is a hereditary congenital disorder of ectodermal origin. It is characterized by lack of sweat glands (hypohidrosis), nail dystrophy(onychodysplasia), alopecia (hypotrichosis), defective palms and soles (palmoplantar hyperkeratosis) and the oral presentations of partial absence of teeth (hypodontia) or complete absence of teeth (anodontia). Hypodontia of primary and permanent dentition is one of the most frequently occurring oral symptoms in HED patients. These features of poor aesthetic affect the social and the psychological well-being of the patient. This case report describes the prosthetic rehabilitation of a HED patient.     

Serum ghrelin levels are inversely correlated with body mass index,age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome

Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index (BMI) of 31.3 kg/m2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r = 0.36, P = 0.007), insulin (r = 0.55, P < 0.001), and BMI (r = 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean +/- SD; 429 +/- 374 vs. 270 +/- 102 pmol/liter; P = 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3- to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean +/- SD; 429 +/- 374 vs. 139 +/- 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3- to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.