12th C. L. Oakley lecture. Pathogenesis of Clostridium difficile infection of the gut

On the basis of the above findings it is possible to propose a sequence of events following exposure to C. difficile. Exposure of neonates to C. difficile leads to transient colonisation which is almost invariably asymptomatic; the reasons why colonisation is asymptomatic are not known. Exposure of antibiotic-treated adults to C. difficile does not invariably lead to colonisation; however, in those instances where colonisation occurs, it may be transient and asymptomatic or transient and symptomatic. The transient nature of the colonisation could be because the infecting strain is poorly virulent, or because the degree of compromise of the intestinal flora is insufficient to permit establishment and full expression of virulence. It is likely that it is easier to fully compromise the intestinal flora of the elderly so that they more readily become fully susceptible to colonisation by C. difficile. In a fully susceptible host and with a highly virulent strain, the following sequence of events could occur. The organism may associate with the intestinal mucosa possible via fimbriae, and form a microcolony of capsulate cells protected by a glycocalyx. The toxins, or other factors, produced may facilitate the interaction with mucosa and toxin A will result in increased vascular and mucosal permeability resulting in intra-luminal accumulation of serum-albumin-rich fluid. Although C. difficile does not appear to be capable of using serum albumin nutritionally, it may utilise other serum proteins, and the serum proteins in general may compete with host proteases and help prevent degradation of the toxins produced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pseudomonas aeruginosa in a neonatal intensive care unit: molecular epidemiology and infection control measures

Background  

Pseudomonas aeruginosa, a non-fermentative, gram-negative rod, is responsible for a wide variety of clinical syndromes in NICU patients, including sepsis, pneumonia, meningitis, diarrhea, conjunctivitis and skin infections. An increased number of infections and colonisations by P. aeruginosa has been observed in the neonatal intensive care unit (NICU) of our university hospital between 2005 and 2007.     

Functional status and well-being of centenarians

Data regarding a sample of 109 centenarians are presented, living in the region of central Italy. Physical and psychosocial variables were analyzed by a questionnaire based on a multidimensional conceptualization of health. Objective and laboratory data were collected and functional capacity was complemented by clinical diagnoses and judgements as well as by self-reported health problems and functional limitations. The results reveal that people can reach their maximum life span while maintaining good levels of functional capacity in spite of the chronological age. One major aspect of functional status in upper ranges of human life span is the everyday competence in the activities of daily living (ADL). In this regard, 26.6% of centenarians are classified as having no ADL-dependency (level A: 34.6% of males and 24.0% of females); the most frequent type of dependency was in bathing (65.1%; 46.2% of males, 71.1% of females) and in continence (45.9%; 50% of males, 44.6% of females). The Mini Mental State Examination (MMSE) showed a mean score of 19.86 +/- 5.93 (21.04 +/- 5.33 of males; 19.49 +/- 6.10 of females). The Geriatric Depression Scale (GDS) mean score was 8.22 +/- 4.89 (7.60 +/- 5.05 of males, 8.40 +/- 4.87 of females).     

Long-term use of HU210 adversely affects spermatogenesis in rats by modulating the endocannabinoid system

Recent societal acceptance of cannabinoids as recreational and therapeutic drugs has posed a potential hazard to male reproductive health. Mammals have a highly sophisticated endogenous cannabinoid (ECS) system that regulates male (and female) reproduction and exo-cannabinoids may influence it adversely. Therefore it is imperative to determine their effects on male reproduction so that men can make informed choices as to their use. Here, an animal model was used to administer HU210, a synthetic analogue of Δ9-tetrahydrocannabinol (THC) and potent cannabinoid receptor (CB) agonist to determine its effects on reproductive organ weights, spermatogenesis, testicular histology and sperm motility. Its effects on the physiological endocannabinoid system were also investigated. Spermatogenesis was markedly impaired with reductions in total sperm count after 2?weeks of exposure. Spermatogenic efficiency was depleted, and Sertoli cell number decreased as exposure time increased with seminiferous tubules showing germ cell depletion developing into atrophy in some cases. Sperm motility was also adversely affected with marked reductions from 2?weeks on. HU210 also acted on the sperm's endocannabinoid system. Long-term use of exo-cannabinoids has adverse effects on both spermatogenesis and sperm function. These findings highlight the urgent need for studies evaluating the fertility potential of male recreational drug users. HU210, a selective agonist for CB1 and CB2 cannabinoid receptors impairs spermatogenesis and sperm motility and deregulates the endocannabinoid system.     

Microbial and metabolic profile of achlorhydric stomach: comparison of pernicious anaemia and hypogammaglobulinaemia.

The microbial flora and some of its metabolites and enzymes in the stomach were compared in patients with achlorhydria, pernicious anaemia, and primary hypogammaglobulinaemia and in patients with dyspepsia with normal gastric acidity. Detailed analysis of the flora of the gastric juice and of the mucosa from the antrum, body, and fundus in six patients with hypogammaglobulinaemia (mean pH 8.2), seven patients with pernicious anaemia (mean pH 7.3), and five patients with dyspepsia (mean pH 1.9) yielded 22 different genera of bacteria, mainly from the patients with achlorhydria, the most common being streptococci, micrococci, staphylococci, veillonella, and lactobacilli. A similar flora was found associated with the mucosa at all three sites. Various metabolites were also looked for. beta Glucoronidase and C14 lipase were found in patients with hypogammaglobulinaemia but not in those with pernicious anaemia or dyspepsia. Volatile fatty acids were not found. Relatively high concentrations of ethanol were found in the patients with hypogammaglobulinaemia compared with those with pernicious anaemia (p = 0.02). Similar concentrations of dimethylamine were found in all three groups, but the concentrations of trimethylamine were much higher in patients with pernicious anaemia and hypogammaglobulinaemia. The high concentrations of some microbial enzymes and ethanol differentiated the group with hypogammaglobulinaemia from the rest, and these may bear some relation to the high incidence of gastric cancer in patients with hypogammaglobulinaemia.     

Discovery of huperzine A-tacrine hybrids as potent inhibitors of human cholinesterases targeting their midgorge recognition sites

We describe herein the development of novel huperzine A-tacrine hybrids characterized by 3-methylbicyclo[3.3.1]non-3-ene scaffolds. These compounds were specifically designed to establish tight interactions, through different binding modes, with the midgorge recognition sites of human acetylcholinesterase (hAChE: Y72, D74) and human butyrylcholinesterase (hBuChE: N68, D70) and their catalytic or peripheral sites. Compounds 5a-c show a markedly improved biological profile relative to tacrine and huperzine A.