Onset of action of pimecrolimus cream 1% in the treatment of atopic eczema in infants

BACKGROUND: Data on the efficacy of pimecrolimus cream 1% within the first days of treatment are scarce, as in previous studies, the first postbaseline assessment was performed only after 1 week. OBJECTIVE: We sought to investigate the onset of action of pimecrolimus cream 1% in infants with mild to very severe atopic eczema. METHODS: We used pimecrolimus cream 1% (n = 129) or vehicle cream (n = 66) administered in a double-blind manner for 4 weeks and then open-label pimecrolimus cream 1% for 12 weeks, with a 4-week follow-up period. RESULTS: Pimecrolimus cream 1% reduced the mean Eczema Area and Severity Index at 4 weeks by 71.5% compared with an increase of 19.4% with vehicle ( P < .001). The reduction in the Eczema Area and Severity Index with pimecrolimus cream 1% was significant at day 4 (38.5% vs 17.6% increase with vehicle). Significant improvements in caregivers' assessments of pruritus and sleep loss were observed with pimecrolimus cream 1% by day 2 ( P < .03) and day 3 ( P = .002), respectively, compared with vehicle. Responses to pimecrolimus cream 1% were sustained during the open-label phase, and pimecrolimus cream 1% was well tolerated. Symptoms of atopic eczema returned gradually after discontinuation. CONCLUSION: Pimecrolimus cream 1% was well tolerated and effective in patients with mild to very severe atopic eczema, with rapid onset of action and no disease rebound after discontinuation.     

KCNE1 reverses the response of the human K+ channel KCNQ1 to cytosolic pH changes and alters its pharmacology and sensitivity to temperature

Previous studies have shown that heteromultimeric KCNQ1/KCNE1 (KvLQT1/minK) channels and homomultimeric KCNQ1 (KvLQT1) channels exhibit different current properties, e.g. distinct kinetics and different sensitivities to drugs. In this study we report on the divergent responses to internal pH changes and further characterize some of the current properties of the human isoforms of KCNQ1 and KCNE1 expressed in Chinese hamster ovary (CHO) cells or Xenopus laevis oocytes. Decreasing the bath temperature from 37 degrees C to 20 degrees C increased the half-activation time by a factor of 5 for KCNQ1/KCNE1 currents (IKs) but by only twofold (not significant) for KCNQ1 currents (IK) in CHO cells. Acidification of cytosolic pH (pHi) increased IKs but decreased 1K whereas intracellular alkalinization decreased I(Ks) but increased IK. pHi-induced changes in intracellular Ca2+ activity ([Ca2+]i) did not correlate with the current responses. At 20 degrees C mefenamic acid (0.1 mM) significantly augmented IKs but slightly decreased IK. It changed the slow activation kinetics of I(Ks) to an instantaneous onset. The form of the current/voltage (I/V) curve changed from sigmoidal to almost linear. In contrast, at 37 degrees C, mefenamic acid also increased I(Ks) but slowed the activation kinetics and shifted the voltage activation to more hyperpolarized values without markedly affecting the sigmoidal shape of the I/V curve. The potassium channel blockers clotrimazole and tetrapentylammonium (TPeA) inhibited I(Ks) with a lower potency than I(K). These results show that coexpression of KCNE1 reversed pH regulation of KCNQ1 from inhibition to activation by acidic pHi. In addition, KCNE1 altered the pharmacological properties and sensitivity to temperature of KCNQ1. The pH-dependence of I(Ks) might be of clinical and pathophysiological relevance in the pathogenesis of ischaemic cardiac arrhythmias.     

Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila

Polyglutamine (polyQ) diseases are a growing class of inherited neurodegenerative diseases including Huntington's disease, which are caused by abnormal expansions of the polyQ stretch in each unrelated disease protein. The expanded polyQ stretch is thought to confer toxic properties on the disease proteins through alteration of their conformation leading to pathogenic protein-protein interactions including oligomerization and/or aggregation. Hypothesizing that molecules with selective binding affinity to the expanded polyQ stretch may interfere with the pathogenic properties, we previously identified Polyglutamine Binding Peptide 1 (QBP1) from combinatorial peptide phage display libraries. We show here that a tandem repeat of the inhibitor peptide QBP1, (QBP1)(2), significantly suppresses polyQ aggregation and polyQ-induced neurodegeneration in the compound eye of Drosophila polyQ disease models, which express the expanded polyQ protein under the eye specific promoter. Most importantly, (QBP1)(2) expression dramatically rescues premature death of flies expressing the expanded polyQ protein in the nervous system, resulting in the dramatic increase of the median life span from 5.5 to 52 days. These results suggest that QBP1 can prevent polyQ-induced neurodegeneration in vivo. We propose that QBP1 prevents polyQ oligomerization and/or aggregation either by altering the toxic conformation of the expanded polyQ stretch, or by simply competing with the expanded polyQ stretches for binding to other expanded polyQ proteins. The peptide inhibitor QBP1 is a promising candidate with great potential as a therapeutic molecule against the currently untreatable polyQ diseases.     

Heritable dentin defects: Nosology,pathology, and treatment

Heritable dentin defects have been divided into 2 main categories: dentinogenesis imperfecta (DI) and dentin dysplasia (DD). Recent studies have shown that they share many features in common. Of the connective tissue diseases, only osteogenesis imperfecta (OI) has been linked to these disorders. So far, no definitive relation between the type of OI and the dental involvement can be established. Familial occurrence of DI with OI cannot be comprehensively explained by mutations in type I collagen genes. No information about the gene defects in DD is available. At the ultrastructural level, the organization of the normally cross-striated collagen fibers in the dentin matrix varies markedly in patients affected by DI.     

The activity of erythrocyte enzymes in rats subjected to running exercises

Summary The studies were carried out on male Wistar rats subjected to running within an electric rotating drum. The animals were divided into four experimental groups, differing one from another as to the duration of training. Each training session lasted 30 days. In the first group the daily run lasted 3 min, in the second group 5 min; in the third group, a 1 min run on the first day, and one min longer on each successive day; in the fourth group a 2 min run on the first day and for two min longer on each successive day.The determinations made prior to and after training included the peripheral blood erythrocyte (Er) and reticulocyte (Ret.) count, the hemoglobin concentration (Hb) and packed cell volume (PCV) and, determined by spectrophotometric methods, the activity of pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase (GR). Training induced an improvement of all enzymatic activities. The heavier the physical exertion, the more intensive was the enzymatic activity of red blood cells, due to the intensification of bone marrow erythropoetic activity under physical exertion and the appearance of young red cells in peripheral blood. All the experimental groups revealed a drop in erythrocyte count (Er), hemoglobin concentration (Hb), and hematocrit values (PCV), as well as an increase in the reticulocytes count (Ret) and in the activity of all the enzymes investigated. In the fourth group anemia was detected: prolonged endurance training decreased the RBC by 24.2%, Hb by 31.1%, PCV by 26.2% and increased the reticulocyte count by 881.6%. Pronounced loading with physical effort leads to shifts in the glucose utilization ratio along particular erythrocyte metabolic pathways. This change in enzymatic activities may prove to be one of the causes of faster elimination of old RBCs.     

Identification of 26 new constitutional RB1 gene mutations in Spanish, Colombian, and Cuban retinoblastoma patients

Constitutional mutations in the RB1 gene predispose to retinoblastoma development. Hence genetic screening of retinoblastoma patients and relatives is important for genetic counseling purposes. In addition, RB1 gene mutation studies may help decipher the molecular mechanisms leading to tumors with different degrees of penetrance or expressivity. In the course of genetically screening of 107 hereditary and non-hereditary retinoblastoma patients (11 familiar bilateral, 4 familiar unilateral, 49 sporadic bilateral and 43 sporadic unilateral) and kindred from Spain, Colombia and Cuba, using direct PCR sequencing, we observed 45 distinct mutations and four RB1 deletions in 53 patients (9 familiar bilateral, 2 familiar unilateral, 31 sporadic bilateral and 11 sporadic unilateral). Most of these mutations (26/45, 57%) have not been reported before. In 32 patients, the predisposing mutations correspond to nonsense (mainly CpG transitions) and small insertions or deletions whose expected outcome is a truncated Rb protein that lacks the functional pockets and tail. Five single aminoacid replacements and seventeen mutations affecting splicing sites were also observed in retinoblastoma patients. Two of these sixteen mutations are of unclear pathogenic nature.     

Histopathological findings in rabbits after experimental acute exposure to the Loxosceles intermedia (brown spider) venom

Loxoscelism, the term used to describe envenomation with brown spiders, is characterized by a dermonecrotic lesion at the bite site. In the present investigation we submitted albino rabbits to an acute experimental envenomation protocol using Loxosceles intermedia (brown spider) venom, with in order to determine the pathogenesic features of the lesion induced by this spider, which is the cause of several accidents throughout the world. Rabbits received intradermal injections of the venom and were monitored over the first 4 h, and then at 12 h and 1, 2 and 5 days after envenomation. Histological specimens from 3 rabbits per time point were collected from euthanized animals and processed for histological examination by light microscopy. Major findings observed during the first 4 h were oedema, haemorrhage, degeneration of blood vessel walls, plasma exudation, thrombosis, neutrophil accumulation in and around blood vessels with an intensive diapedesis, a diffuse collection of inflammatory cells (polymorphonuclear leucocytes) in the dermis, and subcutaneous muscular oedema. Over the following hours and up to 5 days after envenomation the changes progressed to massive neutrophil infiltration (with no other leucocytes) into the dermis and even into subcutaneous muscle tissue, destruction of blood vessels, thrombosis, haemorrhage, myonecrosis, and coagulative necrosis on the 5th day.     

Social Inequalities in Changes in Diet in Adolescents during Confinement Due to COVID-19 in Spain: The DESKcohort Project

Adolescence is a critical period in the consolidation of healthy lifestyles that can last into adulthood. To analyze changes in food consumption and eating behaviors in high-school adolescents during the first confinement, a cross-sectional study was conducted at the end of confinement in Spain. Changes in the frequency or quantity of consumption of different types of food and food-related behaviors were analyzed. Socioeconomic and health-related variables were also considered. To determine whether dietary changes were related to socioeconomic position (SEP), Poisson regression models with robust variance were estimated. Overall, there were some changes towards a healthier diet such as an increase in fruit consumption (38.9%) and a decrease in the consumption of soft drinks (49.8%), sweets and pastries (39.3%), and convenience foods (49.2%). Some changes, however, were related to less healthy behaviors, such as a more irregular pattern of meal distribution (39.9%) or an increase in snacking between meals (56.4%). Changes towards less healthy eating were also related to students’ SEP. The risk of worsening the diet was found to be 21% higher in adolescents from a more disadvantaged SEP. Future public policies could be adapted to avoid increasing nutritional and health inequalities.     

Effects of Coronavirus Disease Pandemic on Tuberculosis Notifications,Malawi

The coronavirus disease (COVID-19) pandemic might affect tuberculosis (TB) diagnosis and patient care. We analyzed a citywide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi did not have an official COVID-19 lockdown but closed schools and borders on March 23, 2020. In an interrupted time series analysis, we noted an immediate 35.9% reduction in TB notifications in April 2020; notifications recovered to near prepandemic numbers by December 2020. However, 333 fewer cumulative TB notifications were received than anticipated. Women and girls were affected more (30.7% fewer cases) than men and boys (20.9% fewer cases). Fear of COVID-19 infection, temporary facility closures, inadequate personal protective equipment, and COVID-19 stigma because of similar symptoms to TB were mentioned as reasons for fewer people being diagnosed with TB. Public health measures could benefit control of both TB and COVID-19, but only if TB diagnostic services remain accessible and are considered safe to attend.     

Being on hemodialysis during the COVID‐19 outbreak: A mixed‐methods’ study exploring the impacts on dialysis adequacy,analytical data,and patients’ experiences

For individuals with end‐stage renal disease (ESRD), the novel coronavirus can present several additional challenges in disease self‐management. This study aimed to explore the impacts of the COVID‐19 pandemic in non‐COVID‐19 patients with ESRD undergoing in‐center hemodialysis (HD). A mixed‐methods study was conducted with a purposive sample recruited from one dialysis unit in Portugal. Quantitative data were collected retrospectively from patients' medical records from February 2020 (T1—before the outbreak) and from April 2020 (T2—during lockdown). Semi‐structured interviews were conducted with 20 patients (66.9 ± 11.9 years old) undergoing HD for an average of 46.1 months (±39.5) in April 2020. Overall results suggested that dialysis adequacy and serum albumin levels decreased significantly at T2, while phosphorus levels increased. The findings from thematic analysis suggested several psychosocial negative impacts and impacts on disease and treatment‐related health behaviors (eg, difficulties managing dietary restrictions during the lockdown and diminished physical activity), which can partially explain these quantitative results. However, some patients were also able to find positive impacts in this experience and problem‐focused and emotional strategies were identified to cope with the demands of COVID‐19. Several recommendations have been made to mitigate patients’ emotional, relational, and educational unmet needs during the current pandemic and in the event of new outbreaks.