Safety and efficacy of aliskiren in the treatment of hypertension and associated clinical conditions

Aliskiren is the first known representative of a new class of non-peptide orally active renin inhibitors that blocks the renin-angiotensin-aldosterone-system (RAAS) at its rate-limiting step. It induces a net reduction in plasma renin activity (PRA), angiotensin II and aldosterone levels. Aliskiren is effective in reducing blood pressure (BP) and is well tolerated. The incidence of adverse events and the number of study discontinuations as a result of adverse events during aliskiren treatment were relatively low and generally not dissimilar from placebo. In placebo-controlled studies, aliskiren showed a dose-related systolic/diastolic BP lowering effect at doses between 75 and 300 mg/day. When compared to active treatments, aliskiren was generally as effective as hydrochlorothiazide, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers, in reducing BP. Aliskiren exhibits synergistic effects when combined with drugs that lead to a reactive increase in the PRA, such as diuretics, ACE inhibitors or ARBs. Although in clinical studies aliskiren proved to reduce proteinuria, the early termination of the Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) confirms previous concerns about the full suppression of the RAAS, in this case with aliskiren combined with ACE-inhibitors or ARBs, in patients with diabetes and concomitant renal impairment. This review summarizes the available data on its safety profile and its clinical development for treatment of arterial hypertension, diabetes and nephropathy.     

The pro-myogenic environment provided by whole organ scale acellular scaffolds from skeletal muscle

In the pursuit of a transplantable construct for the replacement of large skeletal muscle defects arising from traumatic or pathological conditions, several attempts have been made to obtain a highly oriented, vascularized and functional skeletal muscle. Acellular scaffolds derived from organ decellularization are promising, widely used biomaterials for tissue engineering. However, the acellular skeletal muscle extra cellular matrix (ECM) has been poorly characterized in terms of production, storage and host-donor interactions. We have produced acellular scaffolds at the whole organ scale from various skeletal muscles explanted from mice. The acellular scaffolds conserve chemical and architectural features of the tissue of origin, including the vascular bed. Scaffolds can be sterilely stored for weeks at?+4°C or?+37°C in tissue culture grade conditions. When transplanted in wt mice, the grafts are stable for several weeks, whilst being colonized by inflammatory and stem cells. We demonstrate that the acellular scaffold per se represents a pro-myogenic environment supporting de novo formation of muscle fibers, likely derived from host cells with myogenic potential. Myogenesis within the implant is enhanced by immunosuppressive treatment. Our work highlights the fundamental role of this niche in tissue engineering application and unveils the clinical potential of allografts based on decellularized tissue for regenerative medicine.     

Co-circulation of genetically distinct human metapneumovirus and human bocavirus strains in young children with respiratory tract infections in Italy

The discovery of human Metapneumovirus (hMPV) and human Bocavirus (hBoV) identified the etiological causes of several cases of acute respiratory tract infections in children. This report describes the molecular epidemiology of hMPV and hBoV infections observed following viral surveillance of children hospitalized for acute respiratory tract infections in Milan, Italy. Pharyngeal swabs were collected from 240 children ≤3 years of age (130 males, 110 females; median age, 5.0 months; IQR, 2.0-12.5 months) and tested for respiratory viruses, including hMPV and hBoV, by molecular methods. hMPV-RNA and hBoV-DNA positive samples were characterized molecularly and a phylogenetical analysis was performed. PCR analysis identified 131/240 (54.6%) samples positive for at least one virus. The frequency of hMPV and hBoV infections was similar (8.3% and 12.1%, respectively). Both infections were associated with lower respiratory tract infections: hMPV was present as a single infectious agent in 7.2% of children with bronchiolitis, hBoV was associated with 18.5% of pediatric pneumonias and identified frequently as a single etiological agent. Genetically distinct hMPV and hBoV strains were identified in children examined with respiratory tract infections. Phylogenetic analysis showed an increased prevalence of hMPV genotype A (A2b sublineage) compared to genotype B (80% vs. 20%, respectively) and of the hBoV genotype St2 compared to genotype St1 (71.4% vs. 28.6%, respectively). Interestingly, a shift in hMPV infections resulting from A2 strains has been observed in recent years. In addition, the occurrence of recombination events between two hBoV strains with a breakpoint located in the VP1/VP2 region was identified.     

Gender differences in a cohort study of 604 bipolar patients: the role of predominant polarity

Background

Some clinical differences between gender regarding the course and outcome of bipolar disorders have already been described and some others remain still controversial.

Aims

To explore gender differences regarding clinical and socio-demographic characteristics amongst bipolar patients with particular attention to predominant polarity and depressive symptoms.

Method

Data were collected from DSM-IV type I and II bipolar patients (n = 604), resulting from the systematic follow-up of the Bipolar Disorders Program, Hospital Clinic of Barcelona, over an average follow-up of 10 years. Socio-demographic and clinical variables were collected in order to detect gender-related differences.

Results

Bipolar women are more likely than men to show a predominance of depressive polarity as well as a depressive onset whilst men would be more likely to suffer from comorbid substance use disorders. Women significantly have a higher lifetime prevalence of psychotic depression and a higher prevalence of axis II comorbid disorders. Bipolar women are also more likely to have a family history of suicide and a lifetime history of attempted suicide. Suicide attempts are more often violent amongst bipolar men. In a backward logistic regression model, two variables were responsible for most gender-related clinical differences: type of predominant polarity - more likely to be depressive amongst women - (B = − 0.794, p = 0.027, Exp(B) = 0.452; CI =  0.223-0.915), alcohol abuse (B = − 1.095, p = 0.000, Exp(B) = 2990; CI =  1.817-4.919) and cocaine abuse (B = 0.784, p = 0.033, Exp(B) = 2.189; CI =  1.066-4.496) - more prevalent amongst men.

Conclusion

The main characteristic featuring bipolar women is depression, both at illness onset and as a predominant polarity all along the illness course. This may have important diagnostic and therapeutic implications.     

Using small RNA sequences to diagnose, sequence, and investigate the infectivity characteristics of vegetable-infecting viruses

In a virus-infected plant, small interfering RNAs (siRNAs) corresponding to the viral genome form a large proportion of the small RNA population. It is possible to reassemble significant portions of the virus sequence from overlapping siRNA sequences and use these to identify the virus. We tested this technique with a resistance-breaking and a non-resistance-breaking strain of tomato spotted wilt virus (TSWV). We were able to assemble contigs covering 99% of the genomes of both viruses. The abundance of TSWV siRNAs allowed us to detect TSWV at early time points before the onset of symptoms, at levels too low for conventional detection. Combining traditional and bioinformatic detection methods, we also measured how replication of the resistance-breaking strain differed from the non-resistance-breaking strain in susceptible and resistant tomato varieties. We repeated this technique in identification of a squash-infecting geminivirus and also used it to identify an unspecified tospovirus.     

Mammalian target of rapamycin expression and laryngeal squamous cell carcinoma prognosis: novel preliminary evidence

Marioni G, Staffieri A, Giacomelli L, Lionello M, Guzzardo V, Busnardo A & Blandamura S
(2011) Histopathology  58, 1148–1156
Mammalian target of rapamycin expression and laryngeal squamous cell carcinoma prognosis: novel preliminary evidence Aims: The mammalian target of rapamycin (mTOR) has a key role in regulating cancer cell proliferation, apoptosis, cell migration, and angiogenesis. The aim of this study was to assess the relationships between mTOR and clinicopathological and prognostic parameters in laryngeal squamous cell carcinoma (SCC). Methods and results: Mammalian target of rapamycin expression was determined in 103 consecutive operable laryngeal SCCs. Among the mTOR‐positive cases, the locoregional recurrence rate was higher (P = 0.048) and the disease‐free survival (DFS) rate was shorter (P = 0.031) in patients with mTOR expression >50.7%. In the N₀ subgroup, the disease recurrence rate was higher (P = 0.034) and the DFS was shorter (P = 0.009) in patients with mTOR expression >50.7%. In mTOR‐positive patients, multivariate analysis showed that N stage (P = 0.0001) and mTOR status (P = 0.042) were independent indicators of a poor prognosis. Conclusions: mTOR appeared to be a significant predictor of DFS in univariate and multivariate models. mTOR expression in laryngeal SCC may be useful for the detection of patients at higher risk for recurrence, and N₀ patients at higher risk for early locoregional recurrence who might benefit from more aggressive therapy. The role of mTOR inhibitors in multimodality or multitarget strategies against laryngeal SCC warrants investigation.     

Preventing the ubiquitin-proteasome-dependent degradation of frataxin, the protein defective in Friedreich's ataxia

Friedreich's ataxia (FRDA) is a devastating orphan disease, with no specific treatment. The disease is caused by reduced expression of the protein frataxin, which results in mitochondrial defects and oxidative damage. Levels of residual frataxin critically affect onset and progression of the disease. Understanding the molecular mechanisms that regulate frataxin stability and degradation may, therefore, be exploited for the design of effective therapeutics. Here we show that frataxin is degraded by the ubiquitin-proteasome system and that K(147) is the critical residue responsible for frataxin ubiquitination and degradation. Accordingly, a K(147)R substitution generates a more stable frataxin. We then disclose a set of lead compounds, computationally selected to target the molecular cleft harboring K(147), that can prevent frataxin ubiquitination and degradation, and increase frataxin levels in cells derived from FRDA patients. Moreover, treatment with these compounds induces substantial recovery of aconitase activity and adenosine-5'-triphosphate levels in FRDA cells. Thus, we provide evidence for the therapeutic potential of directly interfering with the frataxin degradation pathway.