Phosphoinositide-3 Kinase gamma Activity Contributes to Sepsis and Organ Damage by Altering Neutrophil Recruitment

Rationale Sepsis is a leading cause of death in the intensive care unit, characterized by a systemic inflammatory response (SIRS) and bacterial infection, which can often induce multiorgan damage and failure. Leukocyte recruitment, required to limit bacterial spread, depends on phosphoinositide-3 kinase gamma (PI3K gamma) signaling in vitro; however, the role of this enzyme in polymicrobial sepsis has remained unclear. Objectives: This study aimed to determine the specific role of the kinase activity of PI3K gamma in the pathogenesis of sepsis and multiorgan damage. Methods. PI3K gamma wild-type, knockout, and kinase-dead mice were exposed to cecal ligation and perforation induced sepsis and assessed for survival; pulmonary, hepatic, and cardiovascular damage; coagulation derangements; systemic inflammation; bacterial spread; and neutrophil recruitment. Additionally, wild-type mice were treated either before or after the onset of sepsis with a PI3K gamma inhibitor and assessed for survival, neutrophil recruitment, and bacterial spread. Measurements and Main Results: Both genetic and pharmaceutical PI3K gamma kinase inhibition significantly improved survival, reduced multiorgan damage, and limited bacterial decompartmentalization, while modestly affecting SIRS. Protection resulted from both neutrophil-independent mechanisms, involving improved cardiovascular function, and neutrophil-dependent mechanisms, through reduced susceptibility to neutrophil migration failure during severe sepsis by maintaining neutrophil surface expression of the chemokine receptor, CXCR2. Furthermore, PI3K gamma pharmacological inhibition significantly decreased mortality and improved neutrophil migration and bacterial control, even when administered during established septic shock. Conclusions: This study establishes PI3K gamma as a key molecule in the pathogenesis of septic infection and the transition from SIRS to organ damage and identifies it as a novel possible therapeutic target.

Histological effects of intratympanic gentamicin on the vestibular organ of guinea pigs

Background: Transtympanic administration of gentamicin may be suitable to achieve unilateral vestibular ablation, in order to control unilateral Meniere`s disease. In low doses, gentamicin appears to affect selectively the vestibular system, with relative sparing of the cochlea. An experimental study on guinea pigs was conducted to determine what single dose of gentamicin would produce a unilateral vestibular organ lesion when applied to the middle ear. Study design: Experimental and prospective. Methods: Four groups of guinea pigs received different gentamicin doses ( 1, 5, 10 and 25 mg) administered to the middle ear. The animals` vestibular organs were then assessed by scanning electron microscopy, in order to quantify the level of vestibular damage. Results: Study of the utricular macula and the ampullar crista of the lateral semicircular canal revealed vestibular neuroepithelial lesions in all infused ears. Conclusions: The severity of the vestibular neuroepithelial lesions was dose-dependent. Lower gentamicin doses were observed to damage vestibular structures more than cochlear structures.

Protective effects of carvedilol on systemic vascular damage induced by angiotensin II: Organ-specific effects independent of antihypertensive effects

Background: The protective effect of carvedilol on multiple organ damage induced by angiotensin II (Ang II) remains unclear. The aim of this study was to evaluate the protective effect of carvedilol on the heart, liver, and kidney in rats infused with Ang II. Material/Methods: Wistar rats were randomly distributed into three groups: control (no treatment), continuously infused with Ang II (150 eta g/min for 72 hr), and treated with Ang II + carvedilol (90 mg/kg/d). Histological sections of the myocardium, kidney, and liver were analyzed for the presence of necrosis. Results: Ang II induced arterial hypertension which was not affected by carvedilol treatment (tail-cuff blood pressures, control: 125 +/- 13.6, Ang II: 163 +/- 27.3, Ang II + CV: 178 +/- 39.8 mmHg, p<0.05). Also, there were perivascular inflammation and necrosis in the myocardium, kidney, and hepatocytes necrosis around the terminal vein. Carvedilol treatment fully prevented damage to the heart and kidney and attenuated liver lesions induced by the Ang II infusion. Conclusions: The protective effect of carvedilol on perivascular damage induced by Ang II infusion depended on the target organ. The prevention of heart damage occurred independently of the antihypertensive effects of carvedilol.

Salmonella antibiotic-mutant strains reduce fecal shedding and organ invasion in broiler chicks

We investigated the exposure to antibiotics in the production of antibiotic-mutant strains of Salmonella. Ten isolates of poultry origin were assayed for antibiotic susceptibilities. One strain of Salmonella Enteritidis, one of Salmonella Heidelberg, and one of Salmonella Typhimurium were selected to induce antimicrobial resistance. Each strain was exposed to high concentrations of streptomycin, rifampicin, and nalidixic acid, respectively. Parent and antibiotic-mutant strains were assayed for antibiotic susceptibilities using a commercial microdilution test and the disk susceptibility test. The strains were assessed for virulence genes and evaluated for fecal shedding, cecal colonization, organ invasion, and mean Salmonella counts after inoculation in 1-day-old chicks. The study revealed that exposure to high concentrations of streptomycin produced the antibiotic-mutant strain SE/LABOR/USP/08 and the exposure to rifampicin produced the antibiotic-mutant SH/LABOR/USP/08. These strains showed significantly reduced fecal shedding (P = 0.05) and organ invasion, persisting less than the parental strains and showing no clinical signs in inoculated chicks. High concentrations of nalidixic acid produced the antibiotic-mutant strain ST/LABOR/USP/08, which did not show any differences compared with the parent strain. Likewise, SE/LABOR/USP/08 did not show the expression of plasmid-encoded fimbriae (pefA) and plasmid virulence protein (spvC), suggesting that after exposure to streptomycin, the parent isolate lost the original gene expression, reducing fecal shedding and organ invasion in inoculated chicks.

Prevention of Salmonella Typhimurium colonization and organ invasion by combination treatment in broiler chicks

The effects in broiler chicks of treatment with a competitive exclusion (CE) product, an experimental dietary probiotic, and the abiotic beta-glucan on cecal colonization, organ invasion, and serum and intestinal IgG and IgA levels to Salmonella challenge was evaluated. Four groups of 1-d-old chicks were treated by oral gavage on d 1 with an appropriate dose of a commercial CE product. Three groups received daily doses of probiotic, beta-glucan, or both, for 6 d. Three other groups were fed daily from d 1 onwards with probiotic, beta-glucan, or both. Subgroups of 30 chicks from each group were challenged on d 1, 9, 16, or 23 with 10(7) cfu/mL of Salmonella Typhimurium (1769NR) and killed 7 d later. Control groups were maintained untreated and remained unchallenged (negative control), or were challenged with Salmonella Typhimurium (1769NR; positive control), as described above. Cecum, liver, and spleen samples were examined for the presence of Salmonella, whereas serum and intestinal fluid samples were assayed for total antibody (IgG and IgA) concentrations. Data were analyzed by 1-way ANOVA, and means were compared using Duncan`s multiple range test. In comparison with other treatments, those involving CE product and beta-glucan, with or without probiotic during the first week, resulted in a superior inhibition of cecal colonization and organ invasion by Salmonella and also offered a higher level of protection (P < 0.05). During the second week, treatments containing experimental dietary probiotic and beta-glucan, with or without CE product, resulted in an inhibition of liver invasion (P < 0.05). The IgA levels were significantly higher (P < 0.05) in intestinal fluid compared with serum, whereas IgG had low levels. The results in the first and third week indicate that combination treatments involving CE product, probiotic, and beta-glucan are a more effective control of Salmonella colonization than the corresponding individual preparations.

Dual origin of mesenchymal stem cells contributing to organ growth and repair

In many adult tissues, mesenchymal stem cells (MSCs) are closely associated with perivascular niches and coexpress many markers in common with pericytes. The ability of pericytes to act as MSCs, however, remains controversial. By using genetic lineage tracing, we show that some pericytes differentiate into specialized tooth mesenchyme-derived cells-odontoblasts-during tooth growth and in response to damage in vivo. As the pericyte-derived mesenchymal cell contribution to odontoblast differentiation does not account for all cell differentiation, we identify an additional source of cells with MSC-like properties that are stimulated to migrate toward areas of tissue damage and differentiate into odontoblasts. Thus, although pericytes are capable of acting as a source of MSCs and differentiating into cells of mesenchymal origin, they do so alongside other MSCs of a nonpericyte origin. This study identifies a dual origin of MSCs in a single tissue and suggests that the pericyte contribution to MSC-derived mesenchymal cells in any given tissue is variable and possibly dependent on the extent of the vascularity.

Expression of glycoproteins in the vomeronasal organ reveals a novel spatiotemporal pattern of sensory neurone maturation

The main olfactory and the accessory olfactory systems are both anatomically and functionally distinct chemosensory systems. The primary sensory neurones of the accessory olfactory system are sequestered in the vomeronasal organ (VNO), where they express pheromone receptors, which are unrelated to the odorant receptors expressed in the principal nasal cavity. We have identified a 240 kDa glycoprotein (VNO240) that is selectively expressed by sensory neurones in the VNO but not in the main olfactory neuroepithelium of mouse. VNO240 is first expressed at embryonic day 20.5 by a small subpopulation of sensory neurones residing within the central region of the crescent-shaped VNO, Although VNO240 was detected in neuronal perikarya at this age, it was not observed in the axons in the accessory olfactory bulb until postnatal day 3.5, This delayed appearance in the accessory olfactory bulb suggests that VNO240 is involved in the functional maturation of VNO neurones rather than in axon growth and targeting to the bulb, During the first 2 postnatal weeks, the population of neurones expressing VNO240 spread peripherally, and by adulthood all primary sensory neurones in the VNO appeared to be expressing this molecule. Similar patterns of expression were also observed for NOC-1, a previously characterized glycoform of the neural cell adhesion molecule NCAM, To date, differential expression of VNO-specific molecules has only been reported along the rostrocaudal axis or at different apical-basal levels in the neuroepithelium. This is the first demonstration of a centroperipheral wave of expression of molecules in the VNO, These results indicate that mechanisms controlling the molecular differentiation of VNO neurones must involve spatial cues organised, not only about orthogonal axes, but also about a centroperipheral axis, Moreover, expression about this centroperipheral axis also involves a temporal component because the subpopulation of neurones expressing VNO240 and NOC-1 increases during postnatal maturation. (C) 2001 John Wiley & Sons, Inc.

Adipose tissue as an endocrine organ

Adipose tissue is a highly active endocrine organ secreting a range of soluble products with both local and distant actions. These hormones have important roles in metabolism, reproduction, cardiovascular function and immunity. It is now evident that adipose endocrine function directly influences other organ systems, including the brain, liver and skeletal muscle. The endocrine function of adipose tissue is significantly regulated by nutritional status, and both are inextricably linked to the energy storage role of adipose tissue. This chapter highlights the endocrinology of adipose tissue by concentrating on functional aspects of the secreted products. The data of particular relevance to humans are highlighted, and areas in need of future research are suggested.

Catheter effects in organ perfusion experiments

In a typical isolated organ perfusion experiment, a substance is injected upstream of an organ and then collected at some distance downstream. To reach the organ from the injection site, and then from the organ to the collector, a solute passes through catheters, usually tubes with circular cross-sections. Catheters cause distortion to the concentration-time profile of the perfusion. In this paper, we analyse catheter distribution kinetics from a mathematical point of view, develop the function most suitable for modeling this distribution and successfully apply this function to experimental data. (C) 2002 Academic Press.

Normal values for pelvic organ descent in health nulligravid young caucasian women

Translabial ultrasound is increasingly being used for the assessment of women presenting with pelvic floor dysfunction and incontinence (1,2). However, there is little information on normal values for bladder neck descent, with the two available studies disagreeing widely (3,4). No data has so far been published on mobility of the central and posterior compartment which can now also be assessed by ultrasound (5). This study presents normal values for urethral, bladder, cervical and rectal mobility in a cohort of young, stress continent, nulliparous nonpregnant women. Methods 118 nonpregnant nulliparous Caucasian women between 18 and 23 years of age were recruited for an ongoing twin study of pelvic floor function. Translabial ultrasound assessment of pelvic organ mobility was undertaken supine and after bladder emptying (6,7). The best of at least three effective Valsalva manoeuvres was used for evaluation, with no attempts at standardization of Valsalva pressure. Parameters of anterior compartment mobility were obtained by the use of on-screen calipers; cervical and rectal descent were evaluated on printouts. All examinations were carried out under direct supervision of the first author or by personnel trained by him for at least 100 consecutive assessments. Results The median age of participants in this study was 20 (range 18- 23). Mean body mass index was 23 (range 16.9- 36.7). Of 118 women, 2 were completely unable to perform a Valsalva manoeuvre despite repeated efforts at teaching and were excluded from analysis, as were ten women who complained of urinary stress incontinence, leaving 106 datasets. Average measurements for the parameters ‘retrovesical angle at rest’ (RVA-R) and on Valsalva (RVA-S), urethral rotation, bladder neck mobility, cysto-cele descent, cervical descent and descent of the rectal ampulla are given in Table 1.

Dynamics and orchestral effects in late Eighteenth-Century portuguese organ music: the works of José Marques e Silva (1782-1837) and the organs of António Xavier Machado e Cerveira (1756-1828)

A maioria dos órgãos históricos portugueses data dos finais do século XVIII ou do princípio do século XIX. Durante este período foi construído um invulgar número de instrumentos em Lisboa e nas áreas circundantes por António Xavier Machado e Cerveira (1756-1828) e outros organeiros menos prolíficos. O estudo desses órgãos, muitos dos quais (restaurados ou não) se encontram próximos das condições originais, permite a identificação de um tipo de instrumento com uma morfologia específica, claramente emancipada do chamado «órgão ibérico». No entanto, até muito recentemente, não era conhecida música que se adaptasse às idiossincrasisas daqueles instrumentos. O recente estudo das obras para órgão de José Marques e Silva (1782-1837) permitiu clarificar esta situação. Bem conhecido durante a sua vida como organista e compositor, José Marques e Silva foi um dos ultimos mestres do Seminário Patriarcal. A importância da sua produção musical reside não só num substancial número de obras com autoria firmemente estabelecida – escritas, na maior parte, para coro misto com acompanhamento de órgão obbligato – mas também na íntima relação entre a sua escrita e a morfologia dos órgãos construídos em Portugal durante a sua vida. Este artigo enfatiza a importância de José Marques e Silva (indubitavelmente, o mais significativo compositor português para órgão do seu tempo) sublinhando a relevância das suas obras para órgão solo, cujo uso extensivo de escrita idiomática e indicações de registação fazem delas um dos mais importantes documentos só início do século XIX sobre a prática organística em Portugal.

The organ verses of Frei Jerónimo da Madre de Deus: Portuguese organ music in the time of D. João V

Contrastando com o importante legado dos mestres organistas portugueses dos séculos XVI e XVII, a música portuguesa para órgão pós-1700 parece quase inexistente (excluindo raros exemplos, como as quatro sonatas para órgão de Carlos Seixas). Seja devido à destruição causada pelo grande terramoto de Lisboa em 1755, ou a outras causas, a ausência de fontes é surpreendente, considerando os testemunhos de actividade musical durante aquele período. Este artigo lida com uma fonte até hoje relativamente ignorada: o manuscrito CLI/1-4 nº 7 da Biblioteca do Palácio Ducal de Vila Viçosa (Versos / Sobre o Canto Chão / Para Orgão / De Fr. Jeronimo da M.dre de DS.). Esta colecção de vinte versos para órgão de Jerónimo da Madre de Deus é, de longe, a maior obra portuguesa para órgão da primeira metade do século XVIII até hoje conhecida. Claramente pensadas para o órgão, estas curtas peças testemunham a transformação da escrita para tecla em Portugal durante o reinado de D. João V (nomeadamente através da absorção de influências italianas) e fornecem informações preciosas sobre o tipo de instrumento em que eram tocadas.

Biochemistry of adipose tissue: an endocrine organ

Adipose tissue is no longer considered to be an inert tissue that stores fat. This tissue is capable of expanding to accommodate increased lipids through hypertrophy of existing adipocytes and by initiating differentiation of pre-adipocytes. Adipose tissue metabolism exerts an impact on whole-body metabolism. As an endocrine organ, adipose tissue is responsible for the synthesis and secretion of several hormones. These are active in a range of processes, such as control of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and inflammatory process mediators (tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example). This paper reviews some of the biochemical and metabolic aspects of adipose tissue and its relationship to inflammatory disease and insulin resistance.

Intra-hospital organ and tissue donation coordination project: cost-effectiveness and social benefits

OBJECTIVE To evaluate the viability of a professional specialist in intra-hospital committees of organ and tissue donation for transplantation. METHODS Epidemiological, retrospective and cross-sectional study (2003-2011 and 2008-2012), which was performed using organ donation for transplants data in the state of Sao Paulo, Southeastern Brazil. Nine hospitals were evaluated (hospitals 1 to 9). Logistic regression was used to evaluate the differences in the number of brain death referrals and actual donors (dependent variables) after the professional specialist started work (independent variable) at the intra-hospital committee of organ and tissue donation for transplantation. To evaluate the hospital invoicing, the hourly wage of the doctor and registered nurse, according to the legislation of the Consolidation of Labor Laws, were calculated, as were the investment return and the time elapsed to do so. RESULTS Following the nursing specialist commencement on the committee, brain death referrals and the number of actual donors increased at hospital 2 (4.17 and 1.52, respectively). At hospital 7, the number of actual donors also increased from 0.005 to 1.54. In addition, after the nurse started working, hospital revenues increased by 190.0% (ranging 40.0% to 1.955%). The monthly cost for the nurse working 20 hours was US$397.97 while the doctor would cost US$3,526.67. The return on investment was 275% over the short term (0.36 years). CONCLUSIONS This paper showed that including a professional specialist in intra-hospital committees for organ and tissue donation for transplantation proved to be cost-effective. Further economic research in the area could contribute to the efficient public policy implementation of this organ and tissue harvesting model.

Paracoccidioidomycosis in organ transplant recipient: case report

Paracoccidioidomycosis is a common disease in Latin America but it is rare in organ transplant recipient patients. We report on a case of such mycosis in a renal transplant recipient. The patient presented with a large lung cavity on the left lower lobe, a rare radiological presentation of paracoccidioidomycosis. Unusual clinical and radiological manifestations of Paracoccidioides brasiliensis infection can occur in immunocompromised patients.