Characteristics of eyes with secondary loss of visual acuity receiving variable dosing ranibizumab for neovascular age-related macular degeneration.

PURPOSE: The aim of this work is to investigate the characteristics of eyes failing to maintain visual acuity (VA) receiving variable dosing ranibizumab for neovascular age-related macular degeneration (nAMD) after three initial loading doses. METHODS: A consecutive series of patients with nAMD, who, after three loading doses of intravitreal ranibizumab (0.5 mg each), were re-treated for fluid seen on optical coherence tomography. After exclusion of eyes with previous treatment, follow-up less than 12 months, or missed visits, 99 patients were included in the analysis. The influence of baseline characteristics, initial VA response, and central retinal thickness (CRT) fluctuations on the VA stability from month 3 to month 24 were analyzed using subgroups and multiple regression analyses. RESULTS: Mean follow-up duration was 21.3 months (range 12-40 months, 32 patients followed-up for ≥24 months). Secondary loss of VA (loss of five letters or more) after month 3 was seen in 30 patients (mean VA improvement from baseline +5.8 letters at month 3, mean loss from baseline -5.3 letters at month 12 and -9.7 at final visit up to month 24), while 69 patients maintained vision (mean gain +8.9 letters at month 3, +10.4 letters at month 12, and +12.8 letters at final visit up to month 24). Secondary loss of VA was associated with the presence of pigment epithelial detachment (PED) at baseline (p 0.01), but not with baseline fibrosis/atrophy/hemorrhage, CRT fluctuations, or initial VA response. Chart analysis revealed additional individual explanations for the secondary loss of VA, including retinal pigment epithelial tears, progressive fibrosis, and atrophy. CONCLUSIONS: Tissue damage due to degeneration of PED, retinal pigment epithelial tears, progressive fibrosis, progressive atrophy, or massive hemorrhage, appears to be relevant in causing secondary loss of VA despite vascular endothelial growth factor suppression. PED at baseline may represent a risk factor.

Characterisation of Culex quinquefasciatus (Diptera: Culicidae) larval habitats at ground level and temporal fluctuations of larval abundance in Córdoba, Argentina

The aims of this study were to characterise the ground-level larval habitats of the mosquito Culex quinquefasciatus, to determine the relationships between habitat characteristics and larval abundance and to examine seasonal larval-stage variations in Córdoba city. Every two weeks for two years, 15 larval habitats (natural and artificial water bodies, including shallow wells, drains, retention ponds, canals and ditches) were visited and sampled for larval mosquitoes. Data regarding the water depth, temperature and pH, permanence, the presence of aquatic vegetation and the density of collected mosquito larvae were recorded. Data on the average air temperatures and accumulated precipitation during the 15 days prior to each sampling date were also obtained. Cx. quinquefasciatus larvae were collected throughout the study period and were generally most abundant in the summer season. Generalised linear mixed models indicated the average air temperature and presence of dicotyledonous aquatic vegetation as variables that served as important predictors of larval densities. Additionally, permanent breeding sites supported high larval densities. In Córdoba city and possibly in other highly populated cities at the same latitude with the same environmental conditions, control programs should focus on permanent larval habitats with aquatic vegetation during the early spring, when the Cx. quinquefasciatus population begins to increase.

Hypertension. La pression artérielle dans la phase aiguë des accidents cérébrovasculaires [Hypertension. Arterial pressure in the acute phase of cerebrovascular accidents]

Blood pressure is abnormally elevated in acute stroke in most patients. This blood pressure increase is usually transient and associated with a poor prognosis. Lowering blood pressure too importantly during this period may worsen the outcome of the patient. Antihypertensive therapy is therefore required only when blood pressure is severely increased, especially in the presence of intracerebral haemorrhage. Initiating treatment before admission to the hospital is not recommended. The medications to be preferred are the blockers of the renin-angiotensin system, the beta-blocker labetalol (which possesses also alpha-blocking properties) and NO donors.

Oseltamivir-resistant influenza A(H1N1)pdm2009 strains found in Brazil are endowed with permissive mutations, which compensate the loss of fitness imposed by antiviral resistance

The 2009 pandemic influenza A virus outbreak led to the systematic use of the neuraminidase (NA) inhibitor oseltamivir (OST). Consequently, OST-resistant strains, carrying the mutation H275Y, emerged in the years after the pandemics, with a prevalence of 1-2%. Currently, OST-resistant strains have been found in community settings, in untreated individuals. To spread in community settings, H275Y mutants must contain additional mutations, collectively called permissive mutations. We display the permissive mutations in NA of OST-resistant A(H1N1)pdm09 virus found in Brazilian community settings. The NAs from 2013 are phylogenetically distinct from those of 2012, indicating a tendency of positive selection of NAs with better fitness. Some previously predicted permissive mutations, such as V241I and N369K, found in different countries, were also detected in Brazil. Importantly, the change D344N, also predicted to compensate loss of fitness imposed by H275Y mutation, was found in Brazil, but not in other countries in 2013. Our results reinforce the notion that OST-resistant A(H1N1)pdm09 strains with compensatory mutations may arise in an independent fashion, with samples being identified in different states of Brazil and in different countries. Systematic circulation of these viral strains may jeopardise the use of the first line of anti-influenza drugs in the future.

Viral aetiology of common colds of outpatient children at primary care level and the use of antibiotics

Although antibiotics are ineffective against viral respiratory infections, studies have shown high rates of prescriptions worldwide. We conducted a study in Brazil to determine the viral aetiologies of common colds in children and to describe the use of antibiotics for these patients. Children up to 12 years with common colds were enrolled from March 2008-February 2009 at a primary care level facility and followed by regular telephone calls and medical consultations. A nasopharyngeal wash was obtained at enrollment and studied by direct fluorescence assay and polymerase chain reaction for nine different types of virus. A sample of 134 patients was obtained, median age 2.9 years (0.1-11.2 y). Respiratory viruses were detected in 73.9% (99/134) with a coinfection rate of 30.3% (30/99). Rhinovirus was the most frequent virus (53/134; 39.6%), followed by influenza (33/134; 24.6%) and respiratory syncytial virus (8/134; 13.4%). Antibiotic prescription rate was 39.6% (53/134) and 69.8% (37/53) were considered inappropriate. Patients with influenza infection received antibiotics inappropriately in a greater proportion of cases when compared to respiratory syncytial virus and rhinovirus infections (p = 0.016). The rate of inappropriate use of antibiotics was very high and patients with influenza virus infection were prescribed antibiotics inappropriately in a greater proportion of cases.

Assessing heterogeneity of effects on blood pressure in a meta-analysis of pharmacist interventions trials

Background: Recent reviews of randomized control trials have shown that pharmacist interventions improve cardiovascular diseases (CVD) risk factors in outpatients. Various interventions were evaluated in different settings, and a substantial heterogeneity was observed in the effect estimates. To better express uncertainties in the effect estimates, prediction intervals (PI) have been proposed but are, however, rarely reported. Objective: Pooling data from two systematic reviews, we estimated the effect of pharmacist interventions on systolic blood pressure (BP), computed PI, and evaluated potential causes of heterogeneity. Methods: Data were pooled from systematic reviews assessing the effect of pharmacist interventions on CVD risk factors in patients with or without diabetes, respectively. Effects were estimated using random effect models. Results: Systolic BP was the outcome in 31 trials including 12 373 patients. Pharmacist interventions included patient educational interventions, patient-reminder systems, measurement of BP, medication management and feedback to physician, or educational intervention to health care professionals. Pharmacist interventions were associated with a large reduction in systolic BP (-7.5 mmHg; 95% CI: -9.0 to -5.9). There was a substantial heterogeneity (I2: 66%). The 95% PI ranged from -13.9 to -1.0 mmHg. The effect tended to be larger if the intervention was conducted in a community pharmacy and if the pharmacist intervened at least monthly. Conclusion: On average, the effect of pharmacist interventions on BP was substantial. However, the wide PI suggests that the effect differed between interventions, with some having modest effects and others very large effects on BP. Part of the heterogeneity could be due to differences in the setting and in the frequency of the interventions.

Simultaneous loss of beta- and gamma-catenin does not perturb hematopoiesis or lymphopoiesis.

Hematopietic stem cells (HSCs) maintain life-long hematopoiesis in the bone marrow via their ability to self-renew and to differentiate into all blood lineages. Although a central role for the canonical wnt signaling pathway has been suggested in HSC self-renewal as well as in the development of B and T cells, conditional deletion of beta-catenin (which is considered to be essential for Wnt signaling) has no effect on hematopoiesis or lymphopoiesis. Here, we address whether this discrepancy can be explained by a redundant and compensatory function of gamma-catenin, a close homolog of beta-catenin. Unexpectedly, we find that combined deficiency of beta- and gamma-catenin in hematopoietic progenitors does not impair their ability to self-renew and to reconstitute all myeloid, erythroid, and lymphoid lineages, even in competitive mixed chimeras and serial transplantations. These results exclude an essential role for canonical Wnt signaling (as mediated by beta- and/or gamma-catenin) during hematopoiesis and lymphopoiesis.

Avoiding transcription factor competition at promoter level increases the chances of obtaining oscillations

Background: The ultimate goal of synthetic biology is the conception and construction of genetic circuits that are reliable with respect to their designed function (e.g. oscillators, switches). This task remains still to be attained due to the inherent synergy of the biological building blocks and to an insufficient feedback between experiments and mathematical models. Nevertheless, the progress in these directions has been substantial. Results: It has been emphasized in the literature that the architecture of a genetic oscillator must include positive (activating) and negative (inhibiting) genetic interactions in order to yield robust oscillations. Our results point out that the oscillatory capacity is not only affected by the interaction polarity but by how it is implemented at promoter level. For a chosen oscillator architecture, we show by means of numerical simulations that the existence or lack of competition between activator and inhibitor at promoter level affects the probability of producing oscillations and also leaves characteristic fingerprints on the associated period/amplitude features. Conclusions: In comparison with non-competitive binding at promoters, competition drastically reduces the region of the parameters space characterized by oscillatory solutions. Moreover, while competition leads to pulse-like oscillations with long-tail distribution in period and amplitude for various parameters or noisy conditions, the non-competitive scenario shows a characteristic frequency and confined amplitude values. Our study also situates the competition mechanism in the context of existing genetic oscillators, with emphasis on the Atkinson oscillator.

The loss of GLUT2 expression in the pancreatic beta-cells of diabetic db/db mice is associated with an impaired DNA-binding activity of islet-specific trans-acting factors.

GLUT2 expression is reduced in the pancreatic beta-cells of several diabetic animals. The transcriptional control of the gene in beta-cells involves at least two islet-specific DNA-binding proteins, GTIIa and PDX-1, which also transactivates the insulin, somatostatin and glucokinase genes. In this report, we assessed the DNA-binding activities of GTIIa and PDX-1 to their respective cis-elements of the GLUT2 promoter using nuclear extracts prepared from pancreatic islets of 12 week old db/db diabetic mice. We show that the decreased GLUT2 mRNA expression correlates with a decrease of the GTIIa DNA-binding activity, whereas the PDX-1 binding activity is increased. In these diabetic animals, insulin mRNA expression remains normal. The adjunction of dexamethasone to isolated pancreatic islets, a treatment previously shown to decrease PDX-1 expression in the insulin-secreting HIT-T15 cells, has no effect on the GTIIa and PDX-1 DNA-binding activities. These data suggest that the decreased activity of GTIIa, in contrast to PDX-1, may be a major initial step in the development of the beta-cell dysfunction in this model of diabetes.

Factors associated with loss of handgrip strength in long-lived elderly

Objective To investigate the prevalence of reduced grip strength and associated factors in long-lived elderly, who are users of primary health care. Method Cross-sectional quantitative study, data were collected during the period of January to December of 2013, by applying tests and questionnaires. The convenience sampling was comprised of 157 seniors. Results The findings indicate that the reduction in grip strength presents a moderate prevalence (25.5%), predominantly among females (19.1%), in the age group of 80-89 years (18.5%) and in those with lower educational levels (15.9%). The association between reduced grip strength and the variables of age and body mass index showed a statistical significance. Conclusion Investigations about the handgrip strength are essential for identifying clinical conditions of Brazilian long-lived elderly, and contribute to the development of plans towards the management of frailty.

Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias.

Microsatellites are important highly polymorphic genetic markers dispersed in the human genome. Using a panel of 22 (CA)n repeat microsatellite markers mapped to recurrent breakpoint cluster regions specifically involved in leukemia, we investigated 114 adult leukemias (25 acute lymphocytic leukemia [ALL], 32 acute myeloid leukemia [AML], 36 chronic lymphocytic leukemia [CLL], and 21 chronic myeloid leukemia [CML] in chronic phase) for somatic mutations at these loci. In each patient, DNA from fresh leukemia samples was analyzed alongside normal constitutive DNA from buccal epithelium. We detected loss of heterozygosity (LOH) in 81 of 114 patients (ALL 16/25, AML 25/32, CLL 30/36, CML 10/21). Deletions were most often seen in ALL at 11q23 and 19p13; in AML at 8q22 and 11q23; in CLL at 13q14.3, 11q13, and 11q23; and in CML at 3q26. Only six deletions were reported in 74 karyotypes analyzed, whereas in these same cases, 91 LOH events were detected by microsatellites. Of 26 leukemias with a normal karyotype, 16 nevertheless showed at least one LOH by microsatellite analysis. Replication errors were found in 10 of 114 patients (8.8%). Thus, microsatellite instability is rare in leukemia in contrast to many solid tumors. Our findings suggest that in adult leukemia, LOH may be an important genetic event in addition to typical chromosomal translocations. LOH may point to the existence of tumor suppressor genes involved in leukemogenesis to a degree that has hitherto been underestimated.