Monitoring the trend of the transmission rate of vertically acquired HIV infection: a simple method applied to Italian data.

The objective of this study was to develop and validate a method for estimating and monitoring over time the transmission rate of vertically acquired HIV infection at the population level. We estimated the annual number of children born to HIV-infected women in Italy in 1991-1994 by multiplying the seroprevalence rates, provided by Anonymous Unlinked HIV Serosurveys among Italian Newborns, by the annual number of births, provided by the Italian National Institute of Statistics. The number of HIV-infected children was estimated by applying a simplified back-calculation method to the incident cases of vertically acquired AIDS reported to the AIDS surveillance registry, using seven different estimates of the distribution of the incubation period identified through a literature search. The annual vertical transmission rates were estimated by dividing the estimated number of children with vertically acquired HIV infection by the estimated number of births to an HIV-infected mother. Depending on the chosen distribution of the incubation period, the estimated transmission rate for the four-year period ranges from 0.10 to 0.30. Five of the seven incubation distributions provided a rate falling within the very narrow interval 0.18-0.20. The method provided estimates of vertical transmission rates consistent with those of longitudinal studies performed in European countries. The method presented here could be useful for monitoring the impact of interventions aimed at reducing HIV vertical transmission rate.     

Genetic trends of abdominal fat content in a male broiler chicken line

Data of chickens from a broiler-breeding program were collected and used to determine the genetic trends of absolute and relative abdominal fat content. The genetic trends were estimated by the regression of trait genetic value averages on hatch-years. Genetic values from 32,485 individuals were used for regression analysis. The genetic trend estimate for absolute abdominal fat content was +0.39 g per year, indicating that abdominal fat deposition in the analyzed line, in absolute terms, tended to increase, making the existing excess fat deposition in the broilers even worse. However, the genetic trend of relative abdominal fat content was not significant, indicating that there is no increase on abdominal fat content when it is corrected for body weight.     

Role of dipeptidyl peptidase IV in regulating activity of Na+/H+ exchanger isoform NHE3 in proximal tubule cells

We recently reported that NHE3 exists in multimeric complexes with dipeptidyl peptidase IV (DPPIV) in renal brush-border membranes. To examine the possible role of DPPIV in modulating NHE3 activity, we evaluated whether specific competitive inhibitors that bind to the active site of DPPIV affect NHE3 activity in the OKP line of opossum kidney proximal tubule cells. The DPPIV inhibitors diprotin A and P32/98 significantly reduced NHE3 activity, whereas the inactive isomer P34/98 had no effect. DPPIV inhibitors did not reduce the activity of another brush-border transport process, Na-phosphate cotransport. Effects of DPPIV inhibitors on NHE3 activity were not associated with detectable changes in amount or apparent molecular weight of NHE3 or in NHE3 surface expression. To investigate the signaling mechanisms involved in modulation of NHE3 activity by DPPIV, we used inhibitors of protein kinase pathways known to regulate NHE3. Whereas the PKA inhibitor H-89 failed to block the effect of DPPIV inhibitors, the tyrosine kinase inhibitor genistein alone caused a decrement in NHE3 activity very similar in magnitude to that caused by P32/98. We also found that the effects of genistein and P32/98 on NHE3 activity were not additive. In contrast, forskolin/IBMX and P32/98 had additive inhibitory effects on NHE3 activity. These findings suggested that the effect of DPPIV inhibitors to reduce NHE3 activity results from inhibition of a tyrosine kinase signaling pathway rather than by activation of PKA. We conclude that DPPIV plays an unexpected role in modulating Na⁺/H⁺ exchange mediated by NHE3 in proximal tubule cells. sodium/hydrogen exchange; diprotin A; P32/98; tyrosine kinase     

Effects of an adenosine analogue administration on the striatal NMDA receptors in an experimental model of epilepsy

Specific [3H]-MK801 binding to rat NMDA receptors following the administration of the convulsant drug 3-mercaptopropionic acid (MP) and the adenosine analogue cyclopentyladenosine (CPA) was studied in striatal membrane fractions. MP administration (150 mg/kg, i.p.) caused an increase of 53% and 82% in [3H]-MK801 binding during seizure and the postseizure period respectively. Administration of CPA (2 mg/kg, i.p.) raised [3H]-MK801 binding by 72%. When CPA was administered 30 min before MP and rats sacrificed at seizure (CPA + MPc), an increase of 64%, was observed. Saturation results indicate that receptor sites increased their maximal binding capacity (Bmax) in all treatments while the apparent dissociation constant (Kd) remained unchanged. MP administration brought about an increase of 52% and 42% in [3H]-MK801 binding sites during seizure and postseizure respectively. Administration of CPA raised receptor density by 75%. When CPA was administered 30 min before MP and rats sacrificed at seizure (CPA + MPc), an increase of 62%, was observed. These results show that striatal NMDA receptors have a selective role in seizure activity in the basal ganglia and that the adenosine analogue administration may modify [3H]-MK801 binding in a way similar to that of the convulsant drug.     

The effect of budesonide/formoterol maintenance and reliever therapy on the risk of severe asthma exacerbations following episodes of high reliever use: an exploratory analysis of two randomised,controlled studies with comparisons to standard therapy

Background

Divergent strategies have emerged for the management of severe asthma. One strategy utilises high and fixed doses of maintenance treatment, usually inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA), supplemented by a short-acting β₂-agonist (SABA) as needed. Alternatively, budesonide/formoterol is used as both maintenance and reliever therapy. The latter is superior to fixed-dose treatment in reducing severe exacerbations while achieving similar or better asthma control in other regards. Exacerbations may be reduced by the use of budesonide/formoterol as reliever medication during periods of unstable asthma. We examined the risk of a severe exacerbation in the period after a single day with high reliever use.

Methods

Episodes of high reliever use were quantified and exacerbations occurring post-index day with these episodes were examined post hoc in two double-blind studies comparing the efficacy and safety of budesonide/formoterol maintenance and reliever therapy (Symbicort SMART™, Turbuhaler®) 160/4.5 μg twice daily plus as needed with similar or higher maintenance doses of ICS/LABA plus SABA or formoterol.

Results

Budesonide/formoterol maintenance and reliever therapy significantly reduced the risk of episodes of high reliever use (>6 inhalations/day) vs. all alternative ICS/LABA regimens. With conventional fixed-dose treatment the need for exacerbation treatment within 21 days ranged from 6.0–10.1% of days post-index for all regimens compared with 2.5–3.4% of days with budesonide/formoterol maintenance and reliever therapy.

Conclusions

Budesonide/formoterol maintenance and reliever therapy reduces the incidence of high reliever episodes and the exacerbation burden immediately following these episodes vs. alternative ICS/LABA plus SABA regimens at up to double the maintenance dose of ICS.

Trial registration

These studies do not have registration numbers as they were conducted before clinical trial registration was required     

Head and Neck Manifestations of Paracoccidioidomycosis: An Epidemiological Study of 36 Cases in Brazil

Background

Paracoccidioidomycosis is a systemic mycosis caused by the dimorphic fungus Paracoccidioides brasiliensis. It is the principal systemic mycosis in Brazil, with higher incidence rates in the southern, southeastern, and midwestern regions. It primarily involves the lungs, but head and neck manifestations are common, and differential diagnosis with granulomatous and neoplastic diseases should therefore be considered.

Methods

We conducted a retrospective analysis of medical records of paracoccidioidomycosis cases with head and neck manifestations in southern Brazil over a 10-year period, from 1998 to 2008.

Results

A total of 36 cases of paracoccidioidomycosis were confirmed by histopathological examination, fungal investigation, or culture. Most cases consisted of men with smoking and/or chronic drinking habits and with poor hygiene and nutrition.

Conclusions

Paracoccidioidomycosis is endemic to southern Brazil. Most cases with mucocutaneous manifestations affect the head and neck region. Given that risk factors and clinical manifestations are similar to those of head and neck carcinomas, a differential diagnosis has to be done.     

Deciphering the mechanisms of the Na+/H+ exchanger-3 regulation in organ dysfunction

The Na(+)/H(+) exchanger-3 (NHE3) belongs to the mammalian NHE protein family and catalyzes the electro-neutral exchange of extracellular sodium for intracellular proton across cellular membranes. Its transport function is of essential importance for the maintenance of the body's salt and water homeostasis as well as acid-base balance. Indeed, NHE3 activity is finely regulated by a variety of stimuli, both acutely and chronically, and its transport function is fundamental for a multiplicity of severe and world-wide infection-pathological conditions. This review aims to provide a concise overview of NHE3 physiology and discusses the role of NHE3 in clinical conditions of prominent importance, specifically in hypertension, diabetic nephropathy, heart failure, acute kidney injury, and diarrhea. Study of NHE3 function in models of these diseases has contributed to the deciphering of mechanisms that control the delicate ion balance disrupted in these disorders. The majority of the findings indicate that NHE3 transport function is activated before the onset of hypertension and inhibited thereafter; NHE3 transport function is also upregulated in diabetic nephropathy and heart failure, while it is reported to be downregulated in acute kidney injury and in diarrhea. The molecular mechanisms activated during these pathological conditions to regulate NHE3 transport function are examined with the aim of linking NHE3 dysfunction to the analyzed clinical disorders.     

Structural and functional characterization of a novel nonglycosidic type I NKT agonist with immunomodulatory properties

Activation of type I NKT (iNKT) cells by CD1d-presented agonists is a potent immunotherapeutic tool. α-Galactosylceramide (α-GalCer) is the prototypic agonist, but its excessive potency with simultaneous production of both pro- and anti-inflammatory cytokines hampers its potential therapeutic use. In search for novel agonists, we have analyzed the structure and function of HS44, a synthetic aminocyclitolic ceramide analog designed to avoid unrestrained iNKT cell activation. HS44 is a weaker agonist compared with α-GalCer in vitro, although in vivo it induces robust IFN-γ production, and highly reduced but still functional Th2 response. The characteristic cytokine storm produced upon α-GalCer activation was not induced. Consequently, HS44 induced a very efficient iNKT cell-dependent antitumoral response in B16 animal model. In addition, intranasal administration showed the capacity to induce lung inflammation and airway hyperreactivity, a cardinal asthma feature. Thus, HS44 is able to elicit functional Th1 or Th2 responses. Structural studies show that HS44 binds to CD1d with the same conformation as α-GalCer. The TCR binds to HS44 similarly as α-GalCer, but forms less contacts, thus explaining its weaker TCR affinity and, consequently, its weaker recognition by iNKT cells. The ability of this compound to activate an efficient, but not massive, tailored functional immune response makes it an attractive reagent for immune manipulation.     

Investigation on the Anticonvulsant Potential of Luteolin and Micronized Luteolin in Adult Zebrafish (Danio rerio)

Neurochemical Research - Epilepsy affects around 50 million people worldwide, and an important number of patients (30%) fail to respond to any available antiepileptic drug. Previous studies have...