Increased intracellular survival of Salmonella Typhimurium ST313 in HIV-1-infected primary human macrophages is not associated with Salmonella hijacking the HIV compartment.

BACKGROUND: Non-typhoidal Salmonella (NTS) causes a severe invasive syndrome (iNTS disease) described in HIV-positive adults. The impact of HIV-1 on Salmonella pathogenesis and the molecular basis for the differences between these bacteria and classical diarrhoeal S. Typhimurium remains unclear. RESULTS: Here, we show that iNTS-associated S. Typhimurium Sequence Type 313 (ST313) bacteria show greater intracellular survival in primary human macrophages, compared with a 'classical' diarrhoeal S. Typhimurium ST19 isolate. The increased intracellular survival phenotype of ST313 is more pronounced in HIV-infected macrophages. We explored the possibility that the bacteria take advantage of the HIV-associated viral-containing compartments created in human macrophages that have low pH. Confocal fluorescence microscopy and focussed ion beam-scanning electron microscopy tomography showed that Salmonella did not co-localise extensively with HIV-positive compartments. CONCLUSION: The capacity of ST313 bacteria to survive better than ST19 bacteria within primary human macrophages is enhanced in cells pre-infected with HIV-1. Our results indicate that the ST313 bacteria do not directly benefit from the niche created by the virus in HIV-1-infected macrophages, and that they might take advantage from a more globally modified host cell. SIGNIFICANCE: A better understanding of the interplay between HIV-1 and Salmonella is important not only for these bacteria but also for other opportunistic pathogens.

Mitochondrial functions and rare diseases.

Mitochondria are dynamic cellular organelles responsible for a large variety of biochemical processes as energy transduction, REDOX signaling, the biosynthesis of hormones and vitamins, inflammation or cell death execution. Cell biology studies established that 1158 human genes encode proteins localized to mitochondria, as registered in MITOCARTA. Clinical studies showed that a large number of these mitochondrial proteins can be altered in expression and function through genetic, epigenetic or biochemical mechanisms including the interaction with environmental toxics or iatrogenic medicine. As a result, pathogenic mitochondrial genetic and functional defects participate to the onset and the progression of a growing number of rare diseases. In this review we provide an exhaustive survey of the biochemical, genetic and clinical studies that demonstrated the implication of mitochondrial dysfunction in human rare diseases. We discuss the striking diversity of the symptoms caused by mitochondrial dysfunction and the strategies proposed for mitochondrial therapy, including a survey of ongoing clinical trials.

Stimulation of insulin release in the absence of extracellular calcium by isobutylmethylxanthine and its inhibition by somatostatin.

It has been suggested that somatostatin may inhibit insulin release by interfering with pancreatic islet calcium uptake. To further investigate this hypothesis, the effect of somatostatin on insulin release was examined under conditions where islet uptake of calcium would be unlikely to occur. The phosphodiesterase inhibitor, isobutylmethylxanthine (0.75 mM), was found to stimulate biphasic insulin release from rat pancreases perfused in vitro in the absence of added extracellular calcium on a background of 0.3 mM EGTA And 8 mM glucose; these results support previous suggestions that methylxanthine phosphodiesterase inhibitors may stimulate insulin release by increasing islet cytosol free calcium through translocation of bound (stored) intraislet calcium. Somatostatin (1.0 muM) completely inhibited both phases of isobutylmethylxanthine-stimulated insulin release. Since uptake of extracellular calcium by islets was unlikely under the present experimental conditions, these results suggest that somatostatin inhibition of insulin release is probably due to interference with a cAMP-dependent translocation of intraislet calcium, or to interference with some other effects of cAMP or an effect of calcium itself rather than to interference with islet calcium uptake.

Reduction in infarct size by synchronized selective coronary venous retroperfusion of arterialized blood.

The effectiveness of selective synchronized pulsatile coronary venous retroperfusion for the temporary metabolic support of a region of acutely ischemic myocardium has previously been demonstrated. This study was designed to determine the degree of reduction in ultimate infarct size that may be achieved when coronary venous retroperfusion initiated early after coronary occlusion is combined with later anterograde reperfusion. In 10 baboons, the proximal left anterior descending coronary artery was occluded for 4 hours at which time anterograde reperfusion was restored. In five baboons (Group A), coronary venous retroperfusion was initiated 15 minutes after occlusion. Five baboons (Group B) underwent an identical procedure without coronary venous retroperfusion. Epicardial electrograms were recorded from 24 sites overlying the ischemic region. At 24 hours, hearts were excised and serial transverse sections of the left ventricle were stained with nitroblue tetrazolium for stereometric determination of infarct size. In Group A 12 +/- 5.4 percent (mean +/- standard error of the mean) of epicardial sites with S-T segment elevation at 15 minutes after occlusion showed subsequent Q waves, compared with 96 +/- 2.3 percent in Group B (p less than 0.01). In Group A 4.8 +/- 1.7 percent of the left ventricular mass was infarcted, compared with 30.6 +/- 4.2 percent in Group B (p less than 0.01). The results demonstrated the effectiveness of coronary venous retroperfusion in preserving ischemic myocardium such that anterograde reperfusion resulted in a mean reduction of 84 percent in ultimate infarct size.

Bioavailability of four ursodeoxycholic acid preparations.

BACKGROUND: Ursodeoxycholic acid (UDCA) is the drug of choice for treating primary biliary cirrhosis and dissolving cholesterol gallstones. OBJECTIVES: The objective of this study was to compare the bioavailability of four commercially available ursodeoxycholic acid formulations in standardized doses. METHODS: Twenty-four healthy subjects were studied in groups of four, and received each of the different UDCA preparations in random order, with a 1-week washout or more in-between. Serum UDCA levels were determined for a 6-h period. The mean area under the curve (AUC), Cmax and Tmax were determined for each drug formulation, and the results compared. Dose proportionality was determined using the Canadian Ursofalk tablet using either 250 mg, 500 mg or 750 mg dosing. The intraparticipant variability was assessed by asking each participant to repeat the last drug that they took the second time, 1 week later. RESULTS: The mean AUC was 68.99 micromol/1.6 h-1 for the USA UDCA tablet, 59.34 micromol/1.6 h-1 for the Canadian UDCA tablet, 55.55 micromol/1.6 h-1 for Ursolvan capsules, and 46.66 micromol/1.6 h-1 for Actigall capsules. The mean Cmax values were 24.29, 17.85, 16.63 and 413.32 nmol/mL, respectively. The mean Tmax was 1.82, 2.3, 2.79 and 3.39 h, respectively. Linear aggression analysis assessing the direct proportionality of AUC on the dose for the Canadian UDCA tablet gave an estimate of 0.063 + 0.0164 (standard error, P-value=0.0117), e.g. if the dose increases from 250 mg to 500 mg, the serum ursodeoxycholic acid increases by 250 x 0.063=15.75. There was excellent reproducibility for the AUC for the North American tablets (0.97, 0.88) compared to the two capsules (0.32, 0.15). CONCLUSIONS: The significantly higher AUC and Cmax and shorter Tmax for the Canadian Ursofalk tablets compared to the UDCA capsule preparations supports better bioavailability.

A comparison of nursing home-acquired pneumonia patients with patients with community-acquired pneumonia and nursing home patients without pneumonia.

OBJECTIVES: To determine the factors responsible for mortality and characteristics unique to patients with nursing home acquired pneumonia (NHAP). DESIGN: A prospective study of 71 patients with NHAP, 79 patients admitted from nursing homes for conditions other than pneumonia (NP), and 93 patients with community-acquired pneumonia (CAP). SETTING: A teaching hospital that serves as the community hospital for the City of Halifax. RESULTS: The 32% in-hospital mortality rate for NHAP was higher than the 14% rate for CAP (P < .05) but not significantly higher than the 23% mortality rate for NP patients. The most important determinants for long-term (52 weeks) outcome were complications during hospital stay, odds ratio for mortality 3.55, and self sufficiency at time of admission, odds ratio for mortality 0.306. While bacteremia rates were similar at 8% for NHAP, 13% for CAP, and 17% for NP, there was a trend toward a higher rate of pneumococcal bacteremia in the CAP group. CAP patients were more likely to receive ventilatory support, 13% versus 3% for NHAP and 4% for no pneumonia patients despite similar levels of hypoxemia in the two pneumonia groups. CONCLUSIONS: The in-hospital mortality rate for NHAP is higher than that for CAP. The 1-year survival rate is determined by self-sufficiency at time of admission and absence of complications during hospital stay and is not group (e.g., nursing home) dependent.

The Dartmouth Health Promotion Study: a failed quest for synergy in school health promotion.

The Dartmouth Health Promotion Study was a longitudinal, quasi-experimental field study with a qualitative research arm, designed to learn whether coordinating school health instruction, health services, and a healthful environment enhanced the program's effect on the heart health and mental health of children. The research strategy-the Coordinated Approach-was applied to approximately 300 children in each of two cohorts in grades four to six attending nine trial schools; a further 600 children attended 10 comparison schools in Dartmouth and nine distal comparison schools. Although the qualitative analysis demonstrated that positive feelings were engendered in most areas of the study, when either the classroom or the individual was used as the unit of analysis, the Coordinated Approach did not have a more favorable effect on the heart or mental health of children than did the standard school health program. Thus, the effect of an existing school health program was not directly enhanced through coordinating its components.

Teaching an illiterate transplant patient.

RSR is now several years posttransplant. He has a serum creatinine of 2.1 mg/dl and his hypertension remains borderline with additional medication. He is seen regularly by his local nephrologist and once a year at the transplant center. In RSR's case, collaboration with physicians, nurses, and home health helped this patient achieve the goal of self-care. Illiteracy was no barrier to achieving this goal when assessing the patient's skills, developing a plan that uses those skills, and working together as a team to implement the plan.

Interatrial groove tear: an unusual complication of balloon atrial septostomy.

The authors present an unusual complication of the balloon atrial septostomy procedure performed in a neonate with D-transposition of the great arteries. Cardiac tamponade developed shortly after the balloon atrial septostomy procedure and the infant was found to have a tear in the superior aspect of the left atrium, parallel to the interatrial groove. The tear was successfully sutured and may have been caused by the greater pull-back force needed if the catheter balloon is maximally distended for the first pull-back.

Epilepsy rehabilitation: evaluating specialized versus general agency outcome.

This 1982 study was a retrospective comparison of vocational outcome between eight state rehabilitation agencies and the University of Washington Epilepsy Center's Vocational Unit for the years 1977-1978. Hypotheses included: (a) A significantly higher portion of those with epilepsy will find employment through a specialized (i.e., Epilepsy Center) versus a general rehabilitation program. (b) A specialized program will have a significantly lower proportion of program dropouts. (c) Those finding jobs through a specialized program will earn higher salaries and have better job retention than those employing a general agency program. On several comparisons the specialized program outperformed the general agencies--higher proportion of successful job placements and lower proportions of dropouts and those remaining in process (all chi2 tests significant at the p less than 0.001 level). Placement rates for specialized programs have traditionally approximated 50%, whereas these state agencies placed from 9 to 21%. Salary level and job retention differences were inconclusive. Data implications are discussed.

Ventricular parasystole in a newborn infant.

A case of ventricular parasystole is presented which appeared in an otherwise healthy newborn infant. The dysrhythmia persisted until 10 months of age. In contrast to its occurrence in adults, this rare dysrhythmia appears not to be associated with primary cardiac disease in children.

Evidence for multigene control of cryptorchidism in swine.

The mode of inheritance of cryptorchidism was investigated in Duroc swine. Matings of cryptorchid males with females whose full-sib brothers were cryptorchids were done. Sixteen of these litters were farrowed, and 54 males were born, of which 8 were cryptorchid. Two hypotheses were examined: first, that this trait is controlled by homozygosity of a recessive gene at a single locus; second, that it is controlled by homozygosity of recessive genes at two loci. The single-locus recessive hypothesis was rejected (P less than .01), but the two-locus model was not. Culling to reduce the incidence of cryptorchidism is discussed.

An electrocardiographic model of myocardial ischemic injury.

Previous electrocardiographic models of myocardial ischemic injury have assumed that transmembrane potential changes are uniform throughout a region of ischemia such that injury currents arise exclusively at the boundary between normal and ischemic myocardium. In such models, the distribution and amplitude of ST segment deflections are considered to arise from a polarized surface interfacing normal and ischemic myocardium. This concept in modeling ischemic injury was derived from the application of principles of electric field theory which had been successfully applied previously to ventricular activation in which QRS potentials are considered to arise from polarized surfaces representing the relatively narrow interfaces between depolarized and nondepolarized myocardium. The present paper outlines the limitations of modeling ischemic injury as a polarized surface in terms of the failure of the predictions of such a model to be supported by the experimentally observed: 1) distribution and relative amplitude of epicardial ST segment elevation overlying a region of ischemia; 2) directional changes in epicardial ST segment elevation that occur with changes in the size of an ischemic region; and 3) nonuniform distribution of transmembrane potential changes which occur within a region of ischemia. A new electrocardiographic model of ischemic injury is formulated which accounts for the nonuniform distribution of transmembrane potential changes which occur throughout a region of ischemia. The model accurately describes experimental observations regarding ST segment deflections which had remained inconsistent with previous models.

Selective effects of somatostatin-14, -25 and -28 on in vitro insulin and glucagon secretion.

The widely occurring tetradecapeptide somatostatin (SRIF-14) has been variously implicated as a neurotransmitter, a neurohormone, a cybernin (local regulatory factor) and a hormone. In the first isolation of SRIF-14 from hypothalamic extracts and subsequent extracts of other tissues, peptides of higher molecular weight but with similar activity have been noted. Recently two such peptides have been characterized as the 28-amino acid SRIF-28 (from porcine gastro-intestinal tract and porcine and ovine hypothalamus and the 25-amino acid SRIF-25 (from ovine hypothalamus), each of which consists of an N-terminal extension of SRIF-14. We now report that SRIF-28 and SRIF-25 are more potent than SRIF-14 in the inhibition of insulin release, but that SRIF-14 preferentially inhibits glucagon release. This suggests that SRIF-28 and SRIF-25 are not mere biosynthetic precursors of SRIF-14 and that their differential release may be physiologically important.