Pridopidine for the treatment of motor function in patients with Huntington's disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial.
Huntington's disease is a progressive neurodegenerative disorder, characterised by motor, cognitive, and behavioural deficits. Pridopidine belongs to a new class of compounds known as dopaminergic stabilisers, and results from a small phase 2 study in patients with Huntington's disease suggested that this drug might improve voluntary motor function. We aimed to assess further the effects of pridopidine in patients with Huntington's disease. We undertook a 6 month, randomised, double-blind, placebo-controlled trial to assess the efficacy of pridopidine in the treatment of motor deficits in patients with Huntington's disease. Our primary endpoint was change in the modified motor score (mMS; derived from the unified Huntington's disease rating scale) at 26 weeks. We recruited patients with Huntington's disease from 32 European centres; patients were aged 30 years or older and had an mMS of 10 points or greater at baseline. Patients were randomly assigned (1:1:1) to receive placebo, 45 mg per day pridopidine, or 90 mg per day pridopidine by use of centralised computer-generated codes. Patients and investigators were masked to treatment assignment. We also assessed the safety and tolerability profile of pridopidine. For our primary analysis, all patients were eligible for inclusion in our full analysis set, in which we used the last observation carried forward method for missing values. We used an analysis of covariance model and the Bonferroni method to adjust for multiple comparisons. We used a prespecified per-protocol population as our sensitivity analysis. The α level was 0·025 for our primary analysis and 0·05 overall. This trial is registered with ClinicalTrials.gov, number NCT00665223. At 26 weeks, in our full analysis set the difference in mean mMS was -0·99 points (97·5% CI -2·08 to 0·10, p=0·042) in patients who received 90 mg per day pridopidine (n=145) versus those who received placebo (n=144), and -0·36 points (-1·44 to 0·72, p=0·456) in those who received 45 mg per day pridopidine (n=148) versus those who received placebo. At the 90 mg per day dose, in our per-protocol population (n=114), the reduction in the mMS was of -1·29 points (-2·47 to -0·12; p=0·014) compared with placebo (n=120). We did not identify any changes in non-motor endpoints at either dose. Pridopidine was well tolerated and had an adverse event profile similar to that of placebo. This study did not provide evidence of efficacy as measured by the mMS, but a potential effect of pridopidine on the motor phenotype of Huntington's disease merits further investigation. Pridopidine up to 90 mg per day was well tolerated in patients with Huntington's disease. NeuroSearch A/S.


Identification of enriched PTM crosstalk motifs from large-scale experimental data sets.
Post-translational modifications (PTMs) play an important role in the regulation of protein function. Mass spectrometry based proteomics experiments nowadays identify tens of thousands of PTMs in a single experiment. A wealth of data has therefore become publically available. Evidently the biological function of each PTM is the key question to be addressed; however, such analyses focus primarily on single PTM events. This ignores the fact that PTMs may act in concert in the regulation of protein function, a process termed PTM crosstalk. Relatively little is known on the frequency and functional relevance of crosstalk between PTM sites. In a bioinformatics approach, we extracted PTMs occurring in proximity in the protein sequence from publically available databases. These PTMs and their flanking sequences were subjected to stringent motif searches, including a scoring for evolutionary conservation. Our unprejudiced approach was able to detect a respectable set of motifs, of which about half were described previously. Among these we could add many new proteins harboring these motifs. We extracted also several novel motifs, which through their widespread appearance and high conservation may pinpoint at previously nonannotated concerted PTM actions. By employing network analyses on these proteins, we propose putative functional roles for these novel motifs with two PTM sites in close proximity.


Oral appliance treatment in moderate and severe obstructive sleep apnoea patients non-adherent to CPAP.
The aim of this retrospective study was to evaluate the effect of individually adjusted custom-made mandibular advancement device/oral appliance (OA) in treatment of patients with moderate and severe obstructive sleep apnoea (OSA), who were non-adherent to continuous positive airway pressure (CPAP) therapy. During 2007-2013, 116 patients with moderate (n = 82) and severe (n = 34) OSA non-adherent to CPAP treatment were referred for dental management with an individually adjusted OA at a specialist sleep clinic. Ten of the participants (8·6%) were lost to follow-up, leaving the data set to consist of 106 patients (71 men/35 women, mean age 57 year, range 28-90). Nocturnal respiratory polygraphic recordings were performed at baseline and follow-up. Average time between baseline polygraphy and follow-up was 12 months. A successful OA treatment outcome was based on polygraphy at the follow-up and divided into three groups: 1 = AHI <5; 2 = 5 ≤ AHI <10 and >50% reduction in baseline AHI; and 3. >50% reduction in baseline AHI. If there was a ≤ 50% reduction in baseline AHI at the follow-up, the treatment was considered as a failure. The overall treatment success rate was 75%. There was no significant difference in success rates between patients in the moderate and severe categories (69% and 77%, respectively). Low oxygen saturation (SpO2 nadir) had a high predictive value for OA treatment failure. OA treatment of patients non-adherent to CPAP is efficient and especially promising for the severe OSA group who are at greatest risks for developing serious comorbidities, if left untreated.


Cenpj Regulates Cilia Disassembly and Neurogenesis in the Developing Mouse Cortex.
Primary cilia are microtubule-based protuberances that project from the eukaryotic cell body to sense the extracellular environment. Ciliogenesis is closely correlated to the cell cycle and defects of cilia are related to human systemic diseases such as primary ciliary dyskinesia. However, the role of ciliogenesis in cortical development remains unclear. Here, we demonstrate that Cenpj, a protein that is required for centriole biogenesis, plays a role in regulating cilium disassembly in vivo Depletion of Cenpj in neural progenitor cells results in long cilia and abnormal cilia disassembly. Radial glial cells Cenpj depletion exhibit uncompleted cell division, reduced cell proliferation, and increased cell apoptosis in the developing mouse cerebrum cortex, leading to microcephaly. In addition, Cenpj depletion causes long and thin primary cilia and motile cilia in adult neural stem cells and reduced cell proliferation in the subventricular zone. Furthermore, we show that Cenpj regulates cilia disassembly and neurogenesis through Kif2a, a plus-end-directed motor protein. These data collected from mice of both sexes provide insights into how ciliogenesis plays roles in cortical development and how primary microcephaly is induced by Cenpj mutations in humans.SIGNIFICANCE STATEMENT Autosomal recessive primary microcephaly is a neurodevelopmental disorder with the major symptoms of reduction of circumference of the head, brain volume, and cortex thickness with normal brain architecture in birth. We used conditional Cenpj deletion mice and found that neural progenitor cells (NPCs) exhibited long primary cilia and abnormal cilium appendages. The defective cilium disassembly caused by Cenpj depletion might correlate to reduced cell proliferation, uncompleted cell division, cell apoptosis, and microcephaly in mice. Cenpj also regulates the cilium structure of adult neural stem cells and adult neurogenesis in mice. Additionally, our results illustrate that Cenpj regulates cilia disassembly and neurogenesis through Kif2a, indicating that primary cilia dynamics play a crucial role in NPC mitosis and adult neurogenesis.


An RNA-binding protein specifically interacts with a functionally important domain of the downstream element of the simian virus 40 late polyadenylation signal.
We have identified an RNA-binding protein which interacts with the downstream element of the simian virus 40 late polyadenylation signal in a sequence-specific manner. A partially purified 50-kDa protein, which we have named DSEF-1, retains RNA-binding specificity as assayed by band shift and UV cross-linking analyses. RNA footprinting assays, using end-labeled RNA ladder fragments in conjunction with native gel electrophoresis, have identified the DSEF-1 binding site as 5'-GGGGGAGGUGUGGG-3'. This 14-base sequence serves as an efficient DSEF-1 binding site when placed within a GEM4 polylinker-derived RNA. Finally, the DSEF-1 binding site restored efficient in vitro 3' end processing to derivatives of the simian virus 40 late polyadenylation signal in which it substituted for the entire downstream region. DSEF-1, therefore, may be a sequence-specific binding factor which regulates the efficiency of polyadenylation site usage.


[An unusual late manifestation of hemorrhage caused by vitamin K deficiency].
After an uneventful pregnancy and birth at home without vitamin K-prophylaxis, a 13-day-old breast-fed newborn showed an unexplained swelling of his right elbow and avoided movement of his right arm. One week later a swelling of his left thigh and hip with extensive hematoma led to the diagnosis of vitamin K-deficiency. The initial symptoms can be interpreted as an unusual primary manifestation of late hemorrhagic disease caused by vitamin K-deficiency.


[Health status identification and their relationship with socieconomics and geographic characteristics: a population survey analysis in México].
To estimate the effectiveness of using standardized health vignettes to adjust self-reported health taking into account household and community variables to correct for systematic bias. The national health survey "Evaluación del Desempeño 2002" (Mexican component of the World Health Survey) was used. This survey analyzed subject's health perception based on their responses to hypothetical questions referring to third parties in the vignettes within eight domains. Variations in responses were attributed to socio-demographic, socioeconomic, community, differences of the subjects. To assess those variations, an index for each domain was constructed and used as a variable in a series of linear regression models to estimate the relation between health perceptions, self-reported health, socioeconomic and socio-demographic characteristics. The health perception index derived from the vignettes showed a positive, logarithmic correlation with household expenditure for each health domain, after controlling for socio-demographic, health and community characteristics. No relationship was found between the health status described in the vignettes and self-reported health status. In no case was the explanatory power above 10%. The low explanatory power of the models, and the lack of correlation between self reported health status and the health perception index, suggest that the variability in the vignettes responses cannot be explained by differences in self-reported health status or socioeconomic and socio-demographic characteristics. These results from Mexico suggest that vignette-based methods to correct for systematic variability in perception of own health status are of limited efficacy and reinforce the importance of collecting objective measures of health status in health surveys.


Expression of HSP105 and HSP60 during germ cell apoptosis in the heat-treated testes of adult cynomolgus monkeys (macaca fascicularis).
To confirm that transient increase in temperature of the testis (43C for 30 minutes once daily for 2 consecutive days) could induce apoptosis of germ cells in non-human primates and to investigate the possible roles of Hsp105 and Hsp60 in regulation of germ cell loss, we conducted the study on eight cynomolgus monkeys. The sperm concentration on day 28 after heat shock decreased to 8.4% of pretreatment levels and recovered to baseline on day 144. Using the TUNEL assay, increased numbers of apoptotic spermatocytes and round spermatids were detected on days 3, 8, and 30 post heat treatment. Hsp105 and Hsp60 mRNA and protein levels were analyzed using in situ hybridization, RT-PCR, immunohistochemical and Western blot methods. Hsp105 was confined to nuclei of spermatids before treatment, decreased dramatically with the loss of spermatids on days 3, 8, and 30, before returning to baseline levels on days 84 and 144. The expression of Hsp60 was high on days 3, 8, 30 and was only detected in Sertoli cells and spermatogonia. These results suggested that exposure of the testis to heat resulted in selective, but reversible damage to the seminiferous epithelium via increased germ cell apoptosis. Temporal changes in the expression pattern of Hsp105 and Hsp60 in relation to germ cell death suggests they may be involved in key processes in regulation of germ cell apoptosis.


[Internal versus topical tetracycline therapy of acne].
The study comprised 49 patients suffering from acne who were treated over a period averaging 4.7 +/- 1.2 months with tetracyclines administered either orally (1000 mg daily for 5 days, then 250 mg daily) or locally (2% alcoholic solution). Randomization was carried out by means of random numbers. The percentage of pustules among the total acne efflorescences was chosen as clinical parameter for the efficacy of the antibiotic therapy. After treatment, both collectives showed the same significant decline of pustulation. The therapy was finally evaluated on a six-point scale both by the doctor and the patient. In total, there could not be detected any significant difference in the evaluation of local and oral medication.


In vivo processing and release into the circulation of GFP fusion protein in arginine vasopressin enhanced GFP transgenic rats: response to osmotic stimulation.
Arginine vasopressin (AVP) is a neurohypophysial hormone synthesized as a part of a prepropeptide precursor containing the signal peptide, AVP hormone, AVP-associated neurophysin II and copeptin in the hypothalamic neurosecretory neurons. A transgenic (Tg) rat line expressing the AVP-eGFP fusion gene has been generated. To establish the AVP-eGFP Tg rat as a unique model for an analysis of AVP dynamics in vivo, we first examined the in vivo molecular dynamics of the AVP-eGFP fusion gene, and then the release of GFP in response to physiological stimuli. Double immunoelectron microscopy demonstrated that GFP was specifically localized in neurosecretory vesicles of AVP neurons in this Tg rat. After stimulation of the posterior pituitary with high potassium we demonstrated the exocytosis of AVP neurosecretory vesicles containing GFP at the ultrastructural level. Biochemical analyses indicated that the AVP-eGFP fusion gene is subjected to in vivo post-translational modifications like the native AVP gene, and is packaged into neurosecretory vesicles as a fusion protein: copeptin1-14 -GFP. Moreover, GFP release into the circulating blood appeared to be augmented after osmotic stimulation, like native AVP. Thus, here we show for the first time the in vivo molecular processing of the AVP-eGFP fusion gene and stimulated secretion after osmotic stimulation in rats. Because GFP behaved like native AVP in the hypothalamo-pituitary axis, and in particular was released into the circulation in response to a physiological stimulus, the AVP-eGFP Tg rat model appears to be a powerful tool for analyzing neuroendocrine systems at the organismal level.


POP levels in breast milk and maternal serum and thyroid hormone levels in mother-child pairs from Uppsala, Sweden.
In experimental studies, it has frequently been observed that the homeostasis of thyroid hormones (THs) is affected by exposure to persistent organic pollutants (POPs), such as dioxins and PCBs. In man, similar effects have been indicated in several epidemiological studies. In order to investigate the possible effect on THs at low background exposures found among the Swedish population the following study was performed. Primiparous women (n=395) in the Uppsala region were recruited between 1996 and 1999. Of these, 325 mothers agreed to donate a serum sample in late pregnancy and breast milk was obtained from 211 women 3 weeks after delivery. Babies were sampled for blood at 3 weeks (n=150) and 3 months (n=115) after birth. In connection to the sampling, questions on personal characteristics were asked. Levels of low (tri- to penta-) chlorinated PCB, di-ortho PCB, p,p'-DDE, (mono-ortho) PCB TEQ and PCDD/DF TEQ were monitored in breast milk and in mother's blood (not PCDD/DF). The results showed that the measured TH levels (thyroid-stimulating hormone - TSH, total tri-iodothyronine - TT3, free thyroxine - FT4) in mothers and children were within the reference range. Some significant associations were seen between POP exposures and TH levels in mother or child after simple regression analysis. Following adjustment for important confounding factors, the significant associations mostly disappeared. However, significantly decreasing TT3 levels with increasing prenatal low-chlorinated PCB exposure were still seen in 3 week old children, and on TT3 in mothers exposed to PCDD/DF. In conclusion, the study clearly shows the importance of adjustment for important confounding factors in the analysis of possible associations between POP exposure and hormonal effects. The remaining associations are weak in both children and mothers and the clinical consequences of these alterations are uncertain. When comparing studies that investigate associations between TH levels and POP levels during the perinatal stage, no obvious between-study concordance was seen regarding the critical dose for hormonal effects to occur.


Simulation of Trauma Incidents : Modelling the Evolution of Patients and Resources.
Mathematical modeling and simulation with medical applications has gained much interest in the last few years, mainly due to the widespread availability of low-cost technology and computational power. This paper presents an integrated platform for the in-silico simulation of trauma incidents, based on a suite of interacting mathematical models. The models cover the generation of a scenario for an incident, a model of physiological evolution of the affected individuals, including the possible effect of the treatment, and a model of evolution in time of the required medical resources. The problem of optimal resource allocation is also investigated. Model parameters have been identified according to the expertise of medical doctors and by reviewing some related literature. The models have been implemented and exposed as web services, while some software clients have been built for the purpose of testing. Due to its extendability, our integrated platform highlights the potential of model-based simulation in different health-related fields, such as emergency medicine and personal health systems. Modifications of the models are already being used in the context of two funded projects, aiming at evaluating the response of health systems to major incidents with and without model-based decision support.


Does X-ray imaging by GPC at emergency care access points in the Netherlands change patient flow and reduce ED crowding? A cohort study.
Organizing out-of-hours emergency care is a challenge in many countries. In the Netherlands, general practitioner cooperatives (GPCs) and emergency departments (EDs) are increasingly working together, creating one emergency care access point (ECAP). This has redirected the majority of patients with musculoskeletal problems from the ED to the GPC in out-of-hours care, due to the treatment of self-referrals by the general practitioner (GP). Only a minority of the GPs at ECAPs have the possibility to request X-rays, and expanding these facilities could reduce patient presentations to the ED even more. The aim of our study was to explore patient flow and possible reductions in ED referrals at an ECAP with X-ray facilities for GPs. This retrospective cohort study examines all patients that visited an ECAP at a general city hospital in the Netherlands and had an X-ray imaging requested by the GPC between January 1, 2014 and December 31, 2014. General practitioner cooperatives could request X-rays between 5 pm and 10 pm on weekdays and between 8 am and 10 pm during weekends. Recorded data included sex, age, number and type of X-ray, X-ray abnormalities, referral to the ED, and treatment. The annual number of patients presenting to the GPC and ED in 2014 were gathered. Patient outcome was stated negative when the X-ray revealed no abnormality. A total of 2243 patients received 2663 X-ray examinations. The mean age was 31 years and 48% was male. A total of 1517 (68%) patients were treated at the GPC without an ED referral, a reduction of 4.5% of the annual ED patients. With a majority (68%) of the patients examined and treated at the GPC, X-ray facilities at ECAPs will substantially reduce ED population, change patient flow, and have a positive effect on ED crowding. Implementing 24/7 X-ray facilities at all ECAPs will further enhance these effects.


MicroRNAs in Breast Cancer: One More Turn in Regulation.
MicroRNAs (miRNAs) are small non-coding RNA molecules that critically regulate the expression of genes. MiRNAs are involved in physiological cellular processes; however, their deregulation has been associated with several pathologies, including cancer. In human breast cancer, differently expressed levels of miRNAs have been identified from those in normal breast tissues. Moreover, several miRNAs have been correlated with pathological phenotype, cancer subtype and therapy response in breast cancer. The resistance to therapy is increasingly a problem in patient management, and miRNAs are emerging as novel therapeutic targets and potential predictive biomarkers for treatment. This review provides an overview of the current situation of miRNAs in breast cancer, focusing on their involvement in resistance and the circulating miRNA. The mechanisms of therapeutic resistance regulated by miRNAs, such as the regulation of receptors, the modification of enzymes of drug metabolism, the inhibition of cell cycle control or pro-apoptotic proteins, the alteration of histone activity and the regulation of DNA repair machinery among others, are discussed for breast cancer clinical subtypes. Additionally, in this review, we summarize the recent knowledge that has established miRNA detection in peripheral body fluids as a suitable biomarker. We review the detection of miRNA in liquid biopsies and its implications for the diagnosis and monitoring of breast cancer. This new generation of cancer biomarkers may lead to a significant improvement in patient management.


Attention within auditory word perception: insights from the phonemic restoration illusion.
Phonemic restoration is a powerful auditory illusion that arises when a phoneme is removed from a word and replaced with noise, resulting in a percept that sounds like the intact word with a spurious bit of noise. It is hypothesized that the configurational properties of the word impair attention to the individual phonemes and thereby induce perceptual restoration of the missing phoneme. If so, this impairment might be unlearned if listeners can process individual phonemes within a word selectively. Subjects received training with the potentially restorable stimuli (972 trials with feedback); in addition, the presence or absence of an attentional cue, contained in a visual prime preceding each trial, was varied between groups of subjects. Cuing the identity and location of the critical phoneme of each test word allowed subjects to attend to the critical phoneme, thereby inhibiting the illusion, but only when the prime also identified the test word itself. When the prime provided only the identity or location of the critical phoneme, or only the identity of the word, subjects performed identically to those subjects for whom the prime contained no information at all about the test word. Furthermore, training did not produce any generalized learning about the types of stimuli used. A limited interactive model of auditory word perception is discussed in which attention operates through the lexical level.


Evolutionary analysis of the highly dynamic CHEK2 duplicon in anthropoids.
Segmental duplications (SDs) are euchromatic portions of genomic DNA (> or = 1 kb) that occur at more than one site within the genome, and typically share a high level of sequence identity (>90%). Approximately 5% of the human genome is composed of such duplicated sequences. Here we report the detailed investigation of CHEK2 duplications. CHEK2 is a multiorgan cancer susceptibility gene encoding a cell cycle checkpoint kinase acting in the DNA-damage response signalling pathway. The continuous presence of the CHEK2 gene in all eukaryotes and its important role in maintaining genome stability prompted us to investigate the duplicative evolution and phylogeny of CHEK2 and its paralogs during anthropoid evolution. To study CHEK2 duplicon evolution in anthropoids we applied a combination of comparative FISH and in silico analyses. Our comparative FISH results with a CHEK2 fosmid probe revealed the single-copy status of CHEK2 in New World monkeys, Old World monkeys and gibbons. Whereas a single CHEK2 duplication was detected in orangutan, a multi-site signal pattern indicated a burst of duplication in African great apes and human. Phylogenetic analysis of paralogous and ancestral CHEK2 sequences in human, chimpanzee and rhesus macaque confirmed this burst of duplication, which occurred after the radiation of orangutan and African great apes. In addition, we used inter-species quantitative PCR to determine CHEK2 copy numbers. An amplification of CHEK2 was detected in African great apes and the highest CHEK2 copy number of all analysed species was observed in the human genome. Furthermore, we detected variation in CHEK2 copy numbers within the analysed set of human samples. Our detailed analysis revealed the highly dynamic nature of CHEK2 duplication during anthropoid evolution. We determined a burst of CHEK2 duplication after the radiation of orangutan and African great apes and identified the highest CHEK2 copy number in human. In conclusion, our analysis of CHEK2 duplicon evolution revealed that SDs contribute to inter-species variation. Furthermore, our qPCR analysis led us to presume CHEK2 copy number variation in human, and molecular diagnostics of the cancer susceptibility gene CHEK2 inside the duplicated region might be hampered by the individual-specific set of duplicons.


Water confined in self-assembled ionic surfactant nano-structures.
We present a coarse-grained model for ionic surfactants in explicit aqueous solutions, and study by computer simulation both the impact of water content on the morphology of the system, and the consequent effect of the formed interfaces on the structural features of the absorbed fluid. On increasing the hydration level under ambient conditions, the model exhibits a series of three distinct phases: lamellar, cylindrical and micellar. We characterize the different structures in terms of diffraction patterns and neutron scattering static structure factors. We demonstrate that the rate of variation of the nano-metric sizes of the self-assembled water domains shows peculiar changes in the different phases. We also analyse in depth the structure of the water/confining matrix interfaces, the implications of their tunable degree of curvature, and the properties of water molecules in different restricted environments. Finally, we compare our results with experimental data and their impact on a wide range of important scientific and technological domains, where the behavior of water at the interface with soft materials is crucial.


Partition-based vector filtering technique for suppression of noise in digital color images.
A partition-based adaptive vector filter is proposed for the restoration of corrupted digital color images. The novelty of the filter lies in its unique three-stage adaptive estimation. The local image structure is first estimated by a series of center-weighted reference filters. Then the distances between the observed central pixel and estimated references are utilized to classify the local inputs into one of preset structure partition cells. Finally, a weighted filtering operation, indexed by the partition cell, is applied to the estimated references in order to restore the central pixel value. The weighted filtering operation is optimized off-line for each partition cell to achieve the best tradeoff between noise suppression and structure preservation. Recursive filtering operation and recursive weight training are also investigated to further boost the restoration performance. The proposed filter has demonstrated satisfactory results in suppressing many distinct types of noise in natural color images. Noticeable performance gains are demonstrated over other prior-art methods in terms of standard objective measurements, the visual image quality and the computational complexity.


Noncoding repeat expansions for ALS in Japan are associated with the ATXN8OS gene.
To assess the contribution of noncoding repeat expansions in Japanese patients with amyotrophic lateral sclerosis (ALS). Sporadic ALS in Western countries is frequently associated with noncoding repeat expansions in the C9ORF72 gene. Spinocerebellar ataxia type 8 (SCA8) is another noncoding repeat disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Although the involvement of upper and lower motor neurons in SCA8 has been reported, a positive association between SCA8 and ALS remains unestablished. Spinocerebellar ataxia type 36 is a recently identified disease caused by noncoding repeat expansions in the NOP56 gene and is characterized by motor neuron involvement. We collected blood samples from 102 Japanese patients with sporadic ALS and analyzed the ATXN8OS gene by the PCR-Sanger sequencing method and the C9ORF72 and NOP56 genes by repeat-primed PCR assay. Three patients with ALS (3%) had mutations in the ATXN8OS gene, whereas no patient had a mutation in the C9ORF72 or NOP56 gene. The mutation-positive patients were clinically characterized by neck weakness or bulbar-predominant symptoms. None of our patients had apparent cerebellar atrophy on MRI, but 2 had nonsymptomatic abnormalities in the white matter or putamen. Our finding reveals the importance of noncoding repeat expansions in Japanese patients with ALS and extends the clinical phenotype of SCA8. Three percent seems small but is still relatively large for Japan, considering that the most commonly mutated genes, including the SOD1 and SQSTM1 genes, only account for 2%-3% of sporadic patients each.


Body fat distribution with long-term dietary restriction in adult male rhesus macaques.
Dietary restriction (DR) is the only intervention that has been shown to increase average and median life span in laboratory rodents. The effect of long-term, moderate DR on body composition and fat distribution was evaluated in male rhesus monkeys. Thirty animals (8-14 years of age)fed either 30% less than baseline intake (R, n = 15) or allowed to eat to satiety (C, n = 15), have been assessed semiannually using somatometrics and dual-energy alpha-ray absorptiometry (DXA)for 7.5 years. R subjects have reduced body weight (p <.0001), total body fat (p < .0001), and percentage body fat located in the abdominal region (p < .05). In addition, there has been a sustained reduction in plasma leptin concentrations (p <.001). These findings suggest reduced risk for common morbidities, such as insulin resistance, dyslipidemia, and type 2 diabetes mellitus, that are associated with advancing age and increased levels of bodyfat, especially in the visceral depot.


Undertaking pre-pilot work to gain an empathetic insight into participants' perspectives.
Being an empathetic researcher can be crucial in understanding participants' perspectives. However, while the need for empathy is recognised in qualitative interview research, there is less acknowledgement of its value with other methods of collecting data. Researchers can face various challenges when the instruments and approaches used to collect data are new to them. The value of researchers acting as participants when undertaking pre-pilot work are not be underestimated. To provide a reflective account of the pre-pilot work undertaken by the authors before their main study. Pre-pilot work that involves the researchers as participants can develop cultural competence, as well as empathetic insight into participants' perspectives, thus enabling them to refine and strengthen their main study. It takes time when planning research to incorporate appropriate pre-pilot work that assists personal training and learning. However, this can pay dividends in terms of the empathetic insight gained for the refinement of the proposed study. Pre-pilot work and a reflective approach can strengthen rigour, as well as assist in planning research and collecting data. Experienced researchers may be novices at using specific tools or methods of collecting data. Pre-pilot work enables a greater understanding and deeper appreciation of participants' perspectives.


Monitoring airborne dust in a high density coal-fired power station region in North Yorkshire.
Concerns about the levels of dust deposition in the vicinity of coal-fired power stations in North Yorkshire, in particular Drax Power Station, prompted the commissioning of a detailed monitoring study in the area. This paper describes the first two years' work. The first 12-month study concentrated on the village of Barlow close to Drax Power Station, whilst in the second 12-month study, monitoring sites were spread along a transect passing through the power station belt formed by Ferrybridge, Eggborough and Drax Power Stations. Two monitoring sites were common to both 12-month studies, thus giving two years of continuous monitoring. Pairs of wet Frisbee dust deposit gauges (based on inverted Frisbees) were located at each site. Undissolved particulate matter from each gauge was weighed and characterized by microscopic examination of individual particles. The first 12-month study revealed a downward gradient in dust deposition rate and cenosphere content with distance from Drax Power Station. The high cenosphere content at Barlow, especially at the eastern end, suggested that there was a significant contribution from coal-fired power stations. In the second year, the overall pattern of dust deposition rate and cenosphere content across the power station belt suggested that power stations were contributing to higher levels. In particular, relatively high levels were again found at Barlow. Wind direction correlations point to the fly-ash tip next to Drax Power Station as being the source of cenospheres arriving at Barlow. It is concluded that in both years the fly-ash tip Drax Power Station was making a significant contribution to higher than expected dust deposition rates at Barlow, particularly its eastern end. Other villages in the area may also have been affected by dust originating from coal-fired power stations.


Efficient transfer of genes into senescent cells by adenovirus vectors via highly expressed alpha v beta 5 integrin.
Although various methods for transferring genes into mammalian cells have been established, none have been successful with senescent cells. In this report, we present evidence of the efficient transfer of a gene into human senescent fibroblasts using an adenoviral vector. By employing a recombinant adenovirus vector harboring the beta-galactosidase gene (Ad-CAG beta NR), we observed a good correlation between the proportion of beta-galactosidase positive cells and population doubling of the infected cells. In addition, 1.5- to 6.0-fold greater beta-galactosidase activity was observed in senescent fibroblasts (population doubling [PD] = 58) than in young cells (PD = 15). Western blotting analysis revealed that, compared with young fibroblasts, senescent fibroblasts expressed larger amounts of alpha v beta 5 and alpha v beta 3 integrins which were thought to form part of the adenovirus receptor. These results suggest that higher expression of alpha v beta 5 and alpha v beta 3 integrins in senescent cells renders them more sensitive to adenovirus infection than young cells. Thus, adenovirus vectors may prove to be useful in gene therapy strategies directed against senescence-related disorders.


[Ampicillin pharmacokinetics in pregnant women with acute pyelonephritis].
The pharmacokinetics of ampicillin was studied in 38 patients with acute pyelonephritis in the second and third trimesters of pregnancy after the first and the last (28th-32nd) intramuscular injections of the antibiotic. The ampicillin levels in the blood and urine were determined with the agar diffusion method. The pharmacokinetic parameters were estimated in a one-compartmental model by computer The ampicillin levels in the blood and urine of the patients did not practically differ at all the investigation periods (0.5-6 hours after the antibiotic administration) in the second and third trimesters of pregnancy. During the treatment, the rate of ampicillin elimination from the host increased and the period of half-elimination from the blood decreased. The antibiotic levels in the urine within 4-6 hours after the last injection were practically lower in the second trimester of pregnancy as compared with the second trimester. The therapy resulted in an increase in the antibiotic renal clearance, which returned to normal in the second trimester of pregnancy and remained under normal in the third trimester of pregnancy. The increase was due to an approximately 2-fold acceleration of the rate of ampicillin secretion by the renal tubules. The total clearance of ampicillin practically increased in the second trimester of pregnancy and remained decreased in the third trimester of pregnancy. The estimation performed in accordance with the Krueger-Timmer principles on the basis of the characteristic features of the pharmacokinetics of ampicillin shown in the study provides recommendation of the following scheme for pyelonephritis treatment in pregnant women: 500 mg of ampicillin injected intramuscularly every 6 hours followed by gradual decreasing of the intervals between the injections to 4 hours as the rate of ampicillin elimination increases.


Prevalence of hypercalcaemia in patients on maintenance lithium therapy monitored in primary care.
The purpose of this study was to ascertain the prevalence of hypercalcaemia and hyperparathyroidism in individuals on long term lithium therapy who were monitored by their general practitioners and living within the West Galway mental health catchment area. We also wished to assess the extent of screening for calcium dysfunction in this patient cohort.Current guidelines do not specify the need for calcium monitoring in patients on lithium therapy. We conducted a retrospective analysis of clinical and laboratory data collected as part of regular monitoring for patients on long term lithium treatment. Three hundred and thirty three patients had serum lithium levels monitored over a 2 year period. Fifteen patients (5.3%) had lithium associated hypercalcaemia. The mean duration of lithium treatment for those with hypercalcaemia was 15 years and these patients had a mean serum calcium level of 2.7mmol/L. Eighty six (14%) patients did not have a calcium level monitored over the 2 year period. Three patients (1%) were found to have hyperparathyroidism. This survey supports the need for regular monitoring of serum calcium levels in patients on maintenance lithium treatment.


Identification of an enhancer required for the expression of a mouse major urinary protein gene in the submaxillary gland.
The MUP1.5b gene was previously found to be expressed specifically in the submaxillary gland and at high levels when introduced into mice as a transgene including 4.7 kb of 5'-flanking DNA and 0.3 kb of 3'-flanking DNA. To localize regulatory elements responsible for this tissue-specific pattern of expression, we tested the expression of three additional MUP1.5b transgenes including various amounts of 5'-flanking DNA. These experiments indicated that sequences between -1.85 and -3.46 kb from the transcription initiation site were required for high-level expression in the submaxillary gland. The presence of regulatory elements in this region was also suggested by the detection of a DNase I-hypersensitive site, seen only in submaxillary gland nuclei, at position -2.5 kb upstream from the MUP1.5a gene, a member of the same MUP gene subfamily and virtually identical to the MUP1.5b gene. Further evidence for enhancer activity was provided by the ability of the 1.6-kb DNA fragment including sequences between -1.85 and -3.46 kb to stimulate the expression of an otherwise inactive MUP1.5b-chloramphenicol acetyltransferase fusion gene specifically in the submaxillary gland. The nucleotide sequence of this 1.6-kb DNA fragment was found to be identical for the MUP1.5a and MUP1.5b genes. Together, these results provide the first localization of a cis-acting regulatory sequence involved in the differential tissue-specific expression of the MUP gene family.


Bleeding and coagulation problems in the dental patient. Hereditary disease and medication-induced risks.
This article addresses the unique problems of hereditary and medically induced coagulation problems in dental patients. Both general practitioners and specialists need to have a full understanding of normal events that lead to clot formation to appreciate how treatments and medications administered can adversely affect the final outcome in this patient group.


[Antipsychotics in treatment of eating disorders patient: a study with risperidone].
The use of antipsychotic drugs in the treatment of eating disorders (ED) patients is a controversial issue. Although a few studies support the systematic use of antipsychotics, they are frequently used, mainly in severe disorders with other associated psychopathological symptoms. 27 ED patients were included in the study, 7 dropped-out prematurely or did not complete the pharmacological treatment. All the patients were interviewed and diagnosed according to the Structured Clinical Interview for the DSM-IV (SCID-I) and the personality diagnosis was carried out with the Spanish version of the International Personality Disorders Examination (IPDE). The clinical assessment was performed with the Clinical Global Impression (CGI) scale and the Change Severity Assessment (CSA) at baseline and three months after the beginning of the treatment with risperidone. A significant proportion of patients showed clear clinical and general state improvement in areas like physical state, eating behavior, family and social relationships and work ability. Risperidone associated to the previous therapeutic treatment in patient with a severe ED, with comorbid disorders and where other pharmacological treatments have not been effective, could be a useful option.


Management of bilateral pneumothoraces after talc pleurodesis and unilateral lung volume reduction surgery.
Lung volume reduction surgery (LVRS) is one of the surgical options in the treatment of advanced emphysema and may also be considered as a 'bridge' operation to lung transplantation in selected patients. Although its long-term effects are still debatable, some patients significantly benefit from this operation. Secondary spontaneous pneumothorax is one of the commonest complications of severe emphysema that necessitates an emergency drainage procedure. However, there is no satisfactory information regarding the management of this complication occurring after LVRS in the literature. This paper reports a case of bilateral pneumothorax three months after a unilateral LVRS that was performed following a contra-lateral talc pleurodesis for recurrent pneumothorax.


RNA Helicase A/DHX9 Forms Unique Cytoplasmic Antiviral Granules That Restrict Oncolytic Myxoma Virus Replication in Human Cancer Cells.
RNA helicase A/DHX9 is required for diverse RNA-related essential cellular functions and antiviral responses and is hijacked by RNA viruses to support their replication. Here, we show that during the late replication stage in human cancer cells of myxoma virus (MYXV), a member of the double-stranded DNA (dsDNA) poxvirus family that is being developed as an oncolytic virus, DHX9, forms unique granular cytoplasmic structures, which we named "DHX9 antiviral granules." These DHX9 antiviral granules are not formed if MYXV DNA replication and/or late protein synthesis is blocked. When formed, DHX9 antiviral granules significantly reduced nascent protein synthesis in the MYXV-infected cancer cells. MYXV late gene transcription and translation were also significantly compromised, particularly in nonpermissive or semipermissive human cancer cells where MYXV replication is partly or completely restricted. Directed knockdown of DHX9 significantly enhanced viral late protein synthesis and progeny virus formation in normally restrictive cancer cells. We further demonstrate that DHX9 is not a component of the canonical cellular stress granules. DHX9 antiviral granules are induced by MYXV, and other poxviruses, in human cells and are associated with other known cellular components of stress granules, dsRNA and virus encoded dsRNA-binding protein M029, a known interactor with DHX9. Thus, DHX9 antiviral granules function by hijacking poxviral elements needed for the cytoplasmic viral replication factories. These results demonstrate a novel antiviral function for DHX9 that is recruited from the nucleus into the cytoplasm, and this step can be exploited to enhance oncolytic virotherapy against the subset of human cancer cells that normally restrict MYXV. IMPORTANCE The cellular DHX9 has both proviral and antiviral roles against diverse RNA and DNA viruses. In this article, we demonstrate that DHX9 can form unique antiviral granules in the cytoplasm during myxoma virus (MYXV) replication in human cancer cells. These antiviral granules sequester viral proteins and reduce viral late protein synthesis and thus regulate MYXV, and other poxviruses, that replicate in the cytoplasm. In addition, we show that in the absence of DHX9, the formation of DHX9 antiviral granules can be inhibited, which significantly enhanced oncolytic MYXV replication in human cancer cell lines where the virus is normally restricted. Our results also show that DHX9 antiviral granules are formed after viral infection but not by common nonviral cellular stress inducers. Thus, our study suggests that DHX9 has antiviral activity in human cancer cells, and this pathway can be targeted for enhanced activity of oncolytic poxviruses against even restrictive cancer cells.


From molecules to macrostructures: recent development of bioinspired hard tissue repair.
Enamel, dentin and bone are calcified hard tissues in the human body that play significant roles in food mastication and movement support. Generally, hard tissues lack the ability of self-repair, except for the regeneration ability of bone for small-scale defects. Fabrication of man-made repair materials is therefore highly demanded. In this review, following a bioinspired strategy, we describe the composition and multiscale structures of different hard tissues, and highlight the key points for the reconstruction of hard tissues. Finally, bioinspired tissue repair techniques ranging from molecule-induced mineralization, to microscale assembly to macroscaffold fabrication are summarised.


Evaluation of the potential toxicity of unmodified and modified cyclodextrins on murine blood-brain barrier endothelial cells.
In this study, we investigated the cytotoxic effects of unmodified α-cyclodextrin (α-CD) and modified cyclodextrins, including trimethyl-β-cyclodextrin (TRIMEB) and hydroxypropyl-β-cyclodextrin (HPβCD), on immortalized murine microvascular endothelial (cEND) cells of the blood-brain barrier (BBB). A CellTiter-Glo viability test, performed on the cEND cells showed significant differences among the different cyclodextrins. After 24 hr of incubation, TRIMEB was the most cytotoxic, and HPβCD was non-toxic. α-CD and TRIMEB exhibited greater cytotoxicity in the Dulbecco's modified Eagle's medium than in heat-inactivated human serum indicating protective properties of the human serum. The predicted dynamic toxicity profiles (Td) for α-CD and TRIMEB indicated higher cytotoxicity for these cyclodextrins compared to the reference compound (dimethylsulfoxide). Molecular dynamics simulation of cholesterol binding to the CDs suggested that not just cholesterol but phospholipids extraction might be involved in the cytotoxicity. Overall, the results demonstrate that HPβCD has the potential to be used as a candidate for drug delivery vector development and signify a correlation between the in vitro cytotoxic effect and cholesterol binding of cyclodextrins.


Urine cytology. Part II: renal cytology.
Properly collected urine samples examined by qualified cytologists can aid in the diagnosis and management of various infectious and inflammatory renal parenchymal diseases. Patients with proteinuria, hematuria or bacteriuria will benefit most from renal cytologic examination. Exfoliative cells from renal parenchymal tumors often do not communicate with the collecting system. Some disseminated neoplasms, such as lymphoma or myeloma, can be diagnosed and followed by cytologic study.


[Ascorbic acid consumption and serum levels in smokers and non-smokers adult men in Hermosillo, Sonora, México].
Ascorbic acid is one of the important antioxidant nutrients that can aid in the prevention of oxidative cellular damage. Adequate dietary intake is essential as humans can not synthesize this vitamin. It has been reported that smokers require higher dietary intakes to maintain their serum levels. The objective of this study was to determine serum levels of ascorbic acid in young male smokers and non smokers in the city of Hermosillo, Sonora, Mexico. In addition, their dietary intake of ascorbic acid was determined by a 24 h dietary recall. The dietary intake of ascorbic acid in 12 smokers was 64 +/- 11 mg/d and in 13 non smokers it was 70 +/- 12 mg/d. The smokers in this study did not meet the dietary recommendation of 100 mg/d. Serum ascorbic acid values in smokers and non smokers were 24.2 +/- 6.9 mumol/L and 30.9 +/- 3.7 mumol/L respectively. No significant difference was found among the 2 groups. Although the average serum ascorbic acid values fell within the range considered normal, 50% of the smokers had individual values that were below 23 mumol/L, indicating that these subjects have hipovitaminosis. A positive correlation between intake and serum levels was obtained for smokers (r = 0.71; p = 0.03). The results of this study suggest smokers may be at increased risk for chronic diseases due to their low intake and low serum levels of ascorbic acid.


The vasodilator-stimulated phosphoprotein is regulated by cyclic GMP-dependent protein kinase during neutrophil spreading.
The expression and phosphorylation state of the vasodilator-stimulated phosphoprotein (VASP), a membrane-associated focal adhesion protein, was investigated in human neutrophils. Adhesion and spreading of neutrophils induced the rapid phosphorylation of VASP. The phosphorylation of VASP was dependent on cell spreading, as VASP was expressed as a dephosphorylated protein in round adherent cells and was phosphorylated at the onset of changes in cell shape from round to spread cells. Immunofluorescence microscopy demonstrated that VASP was localized at the cell cortex in round cells and redistributed to focal adhesions at the ventral surface of the cell body during cell spreading. Dual labeling of spread cells indicated that VASP was colocalized with F-actin in filopodia and in focal adhesions, suggesting that the phosphorylation of VASP during cell spreading may be involved in focal adhesion complex organization and actin dynamics. VASP is a prominent substrate for both cGMP-dependent protein kinase (cGK) and cAMP-dependent protein kinase. Evidence suggested that cGK regulated neutrophil spreading, as both VASP phosphorylation and neutrophil spreading were inhibited by Rp-8-pCPT-cGMPS (cGK inhibitor), but not KT5720 (cAMP-dependent protein kinase inhibitor). In contrast, neutrophil spreading was accelerated when cGMP levels were elevated with 8-Br-cGMP, a direct activator of cGK. Furthermore, the same conditions that lead to VASP phosphorylation during neutrophil adherence and spreading induced significant elevations of cGMP in neutrophils. These results indicate that cGMP/cGK signal transduction is required for neutrophil spreading, and that VASP is a target for cGK regulation.


Comparative pathobiology of low and high pathogenicity H7N3 Chilean avian influenza viruses in chickens.
Chickens were intranasally inoculated with Chilean H7N3 avian influenza (AI) viruses of low pathogenicity (LP) (H7N3/LP), high pathogenicity (HP) (H7N3/HP), and a laboratory derivative (02-AI-15-#9) (H7N3/14D) from the LPAI virus to determine pathobiologic effects. All chickens inoculated with H7N3/HP AI virus became infected and abruptly died 2 or 3 days postinoculation, but a few showed moderate depression before death. The H7N3/HP AI virus produced focal hemorrhages of the comb, petechial hemorrhage at the esophageal-proventricular junction and proventricular mucosa, edema and congestion of the lung, petechiation of the spleen, and generalized decrease in body fat. Histologically, severe necrosis, hemorrhage, and inflammation were primarily identified in lungs and the lymphoid tissues. All tissues sampled from the H7N3/HP AI group were positive for the AI viral antigen, predominantly in endothelium of blood vessels throughout most tissues and less frequently in histiocytes and cellular debris of lymphoid tissues. Even less consistently, cardiac myocytes, hepatocytes, Kupffer cells, glandular epithelial cells, microglial cells, and neurons became infected. These studies suggest the Chilean H7N3/LP AI virus was poorly infectious for chickens and may have been recently introduced from a nongalliform host. By contrast, the H7N3/HP AI virus was highly infectious and lethal for chickens. The H7N3/HP AI virus had a strong tropism for the cardiovascular system, principally vascular endothelium, which is similar to the viral tropism demonstrated previously with other H5 and H7 HPAI viruses. Interestingly, the H7N3/LP AI virus on intravenous inoculation replicated in cardiac myocytes, a feature of HPAI and not LPAI viruses, which further supports the theory that the H7N3/LP AI virus was in transition from LP to HP.


Glial cell line-derived neurotrophic factor and endothelial cells promote self-renewal of rabbit germ cells with spermatogonial stem cell properties.
Previous studies suggest that exogenous factors crucial for spermatogonial stem cell (SSC) self-renewal are conserved among several mammalian species. Since glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2) are critical for rodent SSC self-renewal, we hypothesized that they might promote self-renewal of nonrodent SSCs. Therefore, we cultured testicular germ cells from prepubertal rabbits in the presence of GDNF and FGF2 and found they proliferated indefinitely as cellular clumps that displayed characteristics previously identified for rodent SSCs. The rabbit germ cells could not be maintained on mouse embryonic fibroblast (STO) feeders that support rodent SSC self-renewal in vitro but were rather supported on mouse yolk sac-derived endothelial cell (C166) feeder layers. Proliferation of rabbit germ cells was dependent on GDNF. Of critical importance was that clump-forming rabbit germ cells colonized seminiferous tubules of immunodeficient mice, proliferated for at least 6 mo, while retaining an SSC phenotype in the testes of recipient mice, indicating that they were rabbit SSCs. This study demonstrates that GDNF is a mitogenic factor promoting self-renewal that is conserved between rodent and rabbit SSCs; with an evolutionary separation of ∼ 60 million years. These findings provide a foundation to study the mechanisms governing SSC self-renewal in nonrodent species.


In Vitro Anti-Inflammatory Activity of Methyl Derivatives of Flavanone.
Inflammation plays an important role in the immune defense against injury and infection agents. However, the inflammatory chronic process may lead to neurodegenerative diseases, atherosclerosis, inflammatory bowel diseases, or cancer. Flavanones present in citrus fruits exhibit biological activities, including anti-oxidative and anti-inflammatory properties. The beneficial effects of flavanones have been found based on in vitro cell cultures and animal studies. A suitable in vitro model for studying the inflammatory process are macrophages (RAW264.7 cell line) because, after stimulation using lipopolysaccharide (LPS), they release inflammatory cytokines involved in the immune response. We determined the nitrite concentration in the macrophage cell culture and detected ROS using chemiluminescence. Additionally, we measured the production of selected cytokines using the Bio-Plex Magnetic Luminex Assay and the Bio-PlexTM 200 System. For the first time, we have shown that methyl derivatives of flavanone inhibit NO and chemiluminescence generated via LPS-stimulated macrophages. Moreover, the tested compounds at 1-20 µM dose-dependently modulate proinflammatory cytokine production (IL-1β, IL-6, IL-12p40, IL-12p70, and TNF-α) in stimulated RAW264.7 cells. The 2'-methylflavanone (5B) and the 3'-methylflavanone (6B) possess the strongest anti-inflammatory activity among all the tested flavanone derivatives. These compounds reduce the concentration of IL-6, IL-12p40, and IL12p70 compared to the core flavanone structure. Moreover, 2'-methylflavanone reduces TNF-α, and 3'-methylflavanone reduces IL-1β secreted by RAW264.7 cells.


Regulation of collagen synthesis by ascorbic acid.
After prolonged exposure to ascorbate, collagen synthesis in cultured human skin fibroblasts increased approximately 8-fold with no significant change in synthesis of noncollagen protein. This effect of ascorbate appears to be unrelated to its cofactor function in collagen hydroxylation. The collagenous protein secreted in the absence of added ascorbate was normal in hydroxylysine but was mildly deficient in hydroxyproline. In parallel experiments, lysine hydroxylase (peptidyllysine, 2-oxoglutarate:oxygen 5-oxidoreductase, EC 184.108.40.206) activity increased 3-fold in response to ascorbate administration whereas proline hydroxylase (prolyl-glycyl-peptide, 2-oxoglutarate:oxygen oxidoreductase, EC 188.8.131.52) activity decreased considerably. These results suggest that collage polypeptide synthesis, posttranslational hydroxylations, and activities of the two hydroxylases are independently regulated by ascorbate.


Informal Dementia Caregiving Among Indigenous Communities in Ontario, Canada.
Recent studies suggest dementia is an emerging health issue for Indigenous peoples in Canada. In this article, we explore findings concerning informal dementia caregiving in Indigenous communities. Our research has been carried out in partnership with Indigenous communities in Ontario, Canada, over the past 4 years. Semistructured in-depth interviews were carried out with informal Indigenous caregivers (primarily family) to Indigenous people with dementia at 7 geographically and culturally diverse research sites (n = 34). We use a critical interpretive and postcolonial lens to explore common caregiving experiences and patterns to gain insight into Indigenous models of care and better understand how to appropriately support Indigenous families dealing with a dementia diagnosis. Themes from the interview data are explored through a storyline beginning with why and how participants came to the caregiving role; the challenges, struggles, and decisions along the way; and reflections on the rewards and benefits of caring for a loved one with dementia. The findings suggest that underlying Indigenous values created a consistent family caregiving model across the Indigenous cultures and geographic contexts included in the study. Family caregiving was found to facilitate cultural continuity through intergenerational contact and the transmission of cultural knowledge. Diverse community contexts presented significant challenges most immediately attributable to the nature of relations between Indigenous and non-Indigenous Canadians and the continued colonial policies governing access to services.


Pharmacokinetic modeling of the dosing interval dependency for the interaction between itraconazole and triazolam.
Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A with an elimination half-life of more than 30 hours. Therefore, itraconazole may cause persistent CYP3A inhibition. Triazolam is primarily metabolized by CYP3A and its plasma concentration is increased remarkably by itraconazole. Although separating their dosages by 24 hours has been shown to reduce the interaction, an appropriate dosage interval remains to be determined. The aim of this study was to identify an appropriate dosage schedule to avoid their interaction. We developed a pharmacokinetic model based on the assumption that both itraconazole and hydroxyitraconazole competitively and reversibly inhibit the first-pass metabolism and systemic elimination of triazolam. The developed model was simultaneously fitted to the plasma concentration profiles of triazolam, taken from the literature, by using the plasma concentration-time profiles of itraconazole and hydroxyitraconazole as input functions to estimate their in vivo Ki values. Subsequently, we simulated the plasma concentration profiles of triazolam administered after itraconazole therapy with various dosing intervals. The model could explain and simulate the interaction between itraconazole-triazolam using a variety of dosage intervals between the administrations. The developed model may provide useful information with regard to the appropriate interval for triazolam administration during itraconazole therapy.


Intravenous iron does not effectively correct preoperative anaemia in cardiac surgery: a pilot randomized controlled trial.
Preoperative anaemia is a strong predictor of blood transfusion requirements and must be assessed for appropriate optimization before elective surgery. Iron therapy is a transfusion-sparing approach effective for increasing haemoglobin concentrations. However, its role in elective cardiac surgery and the optimal route of administration remain unknown. This single-centre, non-blinded, randomized, controlled trial compared the effectiveness of intravenous ferric carboxymaltose therapy with oral iron for anaemic patients undergoing elective cardiac surgery. Fifty anaemic patients scheduled for elective cardiac surgery were randomized to receive either oral or intravenous iron therapy 3-8 weeks preoperatively. Changes in haemoglobin concentration were measured. Blood transfusion and postoperative outcome data were collected. Preoperative median increases in haemoglobin were 1.0 g/l (interquartile range -3.25 to 7.25 g/l) and 3.0 g/l (interquartile range -1.25 to 6.25 g/l) for patients receiving intravenous and oral iron, respectively (P = 0.42). The median first 12-h blood loss was significantly higher in the intravenous group (655 ml; interquartile range 162-1540 ml) compared to the oral group (313 ml; interquartile range 150-1750 ml; P < 0.007). Median increments in serum ferritin were superior for the intravenous group (median difference 313 µg/l; interquartile range 228-496) compared to the oral group (median difference 5.5 µg/l; interquartile range -1.4 to 19.4; P < 0.001). Increases in ferritin after intravenous iron administration were significantly greater than those after oral iron administration. There was no significant difference in haemoglobin increments between groups. Despite significantly higher intraoperative blood loss in the group receiving intravenous iron, blood transfusion requirements for both groups were not statistically different. ISRCTN22158788.


Intrascrotal Muscular Myxoma - A Case Report.
Myxomas are gelatinous tumours that commonly appear as circumscribed masses situated within muscles. It can occur at various sites. However, mostly found in cardiac muscles and skeletal muscles of extremities. Published cases of intrascrotal myxoma are rare in literature. A 28-year-old male was admitted to our General Surgery Department with a history of a gradually enlarging mass in the scrotum and scrotal discomfort since two years. After cytological and imaging investigations, a scrotal exploration was performed with plexiform neurofibroma as the preoperative diagnosis. Histopathological examination of the specimen revealed features of intramuscular myxoma. Although a relatively rare diagnosis, intramuscular myxoma should be considered as a differential diagnosis of testicular and paratesticular tumours.


Is sleep-disordered breathing an independent risk factor for hypertension in the general population (13,057 subjects)?
OBJECTIVES Sleep-disordered breathing has been hypothesized to have a close relationship with hypertension but previous studies have reported mixed results. This is an important health issue that requires further clarification because of the potential impact on the prevention and control of hypertension. The relationship between hypertension and three forms of sleep-disordered breathing (chronic snoring, breathing pauses and obstructive sleep apnea syndrome (OSAS)) was assessed using representative samples of the non-institutionalized population of the UK, Germany and Italy (159 million inhabitants). The samples were comprised of 13,057 individuals aged 15-100 years who were interviewed about their sleeping habits and their sleep symptoms over the telephone using the Sleep-EVAL system. OSAS was found in 1.9% (95% CI: 1.2% to 2.3%) of the UK sample, 1.8% (95% CI: 1.4% to 2.2%) of the German sample and 1.1% (95% CI: 0.8% to 1.4%) of the Italian sample. OSAS was an independent risk factor (odds ratio (OR): 9.7) for hypertension after controlling for possible confounding effects of age, gender, obesity, smoking, alcohol consumption, life stress, and, heart and renal disease. Results from three of the most populated countries in Western Europe indicate that OSAS is an independent risk factor for hypertension. Snoring and breathing pauses during sleep appeared to be non-significant predictive factors.


Zinc absorption and zinc status are reduced after Roux-en-Y gastric bypass: a randomized study using 2 supplements.
Micronutrient deficiencies are common in patients undergoing gastric bypass. The effect of this type of surgery on zinc absorption and zinc status is not well known. The objective was to evaluate the effects of Roux-en-Y gastric bypass (RYGBP) on zinc status and zinc absorption at different stages after surgery. We hypothesized that zinc status would be significantly impaired after surgery and that this impairment would be less severe in subjects receiving increased supplemental zinc. We also hypothesized that zinc absorption would be lower after surgery. Anthropometric and body-composition variables and dietary and biochemical indexes of zinc status and zinc absorption were determined in 67 severe and morbidly obese women [mean (±SD) age: 36.9 ± 9.8 y; BMI (in kg/m(2)): 45.2 ± 4.7] who underwent RYGBP. The subjects were randomly assigned to 1 of 2 vitamin-mineral supplementation groups. Measurements were made before and 6, 12, and 18 mo after surgery. Fifty-six subjects completed the 18-mo follow-up. Mean plasma zinc, erythrocyte membrane alkaline phosphatase activity, and the size of the rapidly exchangeable zinc pool decreased after RYGBP. Percentage zinc absorption decreased significantly from 32.3% to 13.6% at 6 mo after RYGBP and to 21% at 18 mo after surgery. No effect of supplement type was observed. Zinc status is impaired after RYGBP, despite the finding that dietary plus supplemental zinc doubled recommended zinc intakes in healthy persons. Zinc absorption capacity is significantly reduced soon after RYGBP, with no major changes until 18 mo after surgery.


Discharge patterns of cat pontine brain stem neurons during desynchronized sleep.
1. Discharge pattern has been characterized by autocorrelation analysis of stationary portions of extracellularly recorded discharge trains of cat pontine brain stem neurons during spontaneously occurring desynchronized sleep episodes. 2. Neurons localized to the area implicated in control of the desynchronized phase of sleep, the gigantocellular tegmental field (FTG), show the most phasic or clustered discharge pattern, as evinced by initial peaks in the autocorrelations. At the peak, the FTG population average discharge probability is 3 times that expected had the discharges been evenly distributed over time. The initial peak extends beyond a lag of 3 s, indicating runs of clustered discharge extending beyond this duration. Neurons in other reticular tegmental fields, the tegmental reticular nucleus and pontine gray, show a more sustained or tonic discharge pattern. 3. Discharge patterns of a given cell are consistent from one desynchronized sleep episode to the next; units with phasic discharge patterns remain phasic, and tonic patterns remain tonic. 4. There is a three-way correlation among FTG units recorded at sites with many giant cells, units with high discharge rate increases on transition to desynchronized sleep, and units with a markedly phasic discharge pattern. This implicates the giant cells as the source of both the distinctive discharge rate and pattern changes of neurons during desynchronized sleep. 5. Stereotyped, regular discharge patterns are not characteristic of FTG or other units, suggesting they are not pacemakers and that endogenous activation of pacemaker cells is unlikely to be a mechanism for generation of the marked discharge rate increases on transition to desynchronized sleep that are found in FTG units. The irregular, clustered discharge pattern of FTG is more compatible with generation of discharge rate increases through interaction with other cells. The markedly phasic discharge of FTG units is also consistent with a driving role in generation of the phasic electrophysiologic events of desynchronized sleep.


MAAGs (Medical Audit Advisory Groups): the Eli Lilly National Clinical Audit Centre.
Outlines the framework for promoting audit in general practice, created as one part of the health service reforms. Medical Audit Advisory Groups (MAAGs) were set up in each district with the aim of participation in audit of all general practitioners by April 1992. The activities undertaken have included those recommended by the Department of Health; the most significant of these being the appointment of lay facilitators who are able to assist general practitioners and primary care teams co-operate over efforts to improve the quality of care, and may offer one means of introducing some of the methods of total quality management into general practice. Discusses the problems which remain: audit is not yet sufficiently systematic, interface audit with secondary care is at a very early stage, the ways to involve managers and patients in audit remain to be clarified, and there is little evidence of the consequences of audit in terms of improved care. The Eli Lilly National Clinical Audit Centre has been set up within the Department of General Practice, University of Leicester, in order to address these issues.


Highly conserved upstream sequences for transcription factor genes and implications for the regulatory network.
Identifying evolutionarily conserved blocks in orthologous genomic sequences is an effective way to detect regulatory elements. In this study, with the aim of elucidating the architecture of the regulatory network, we systematically estimated the degree of conservation of the upstream sequences of 3,750 human-mouse orthologue pairs along 8-kb stretches. We found that the genes with high upstream conservation are predominantly transcription factor (TF) genes. In particular, developmental process-related TF genes showed significantly higher conservation of the upstream sequences than other TF genes. Such extreme upstream conservation of the developmental process-related TF genes suggests that the regulatory networks involved with developmental processes have been evolutionarily well conserved in both human and mouse lineages.


Tissue factor expression in mesothelial cells: induction both in vivo and in vitro.
Exudative pleural effusions are characterized by a high protein content and frequently progress to loculation and fibrosis. To test the hypothesis that tissue factor (TF) plays an integral role in this process, we investigated the expression of TF by human mesothelial cells (HMC) both in vivo and in vitro, and measured the effect of serum on HMC expression of TF in vitro. In vivo TF expression was not detected in HMC of normal pleura, but was detected in HMC of pleura overlying inflamed lung. In vitro, quiescent HMC demonstrated negligible levels of TF expression; however, upon serum stimulation there was a marked induction in both TF protein level and activity, peaking at 8-9 h. In contrast, treating quiescent HMC with plasma resulted in a further small, but significant, decrease in TF expression. This serum-induced rise in TF was also reflected in TF mRNA levels and did not require de novo protein synthesis. These results suggest that induction of HMC TF expression may be important in triggering both the intrapleural activation of prothrombin and the deposition of fibrin characteristic of inflammatory effusions.


Regulation of motilin release: studies with ex vivo perfused canine jejunum.
The regulatory process of motilin release was studied in segments of canine jejunum isolated and perfused ex vivo. The secretion of motilin in the effluent venous system of the isolated intestine was measured by radioimmunoassay in response to various pharmacological agents injected intra-arterially. Muscarinie agonist and antagonist, respectively, increased and decreased the release of motilin. The stimulatory effect of carbachol was still documented after tetrodotoxin (10(-5) M) was injected in the system to block neural influence on M cells. Bombesin and morphine also increased the release of motilin. The effect of bombesin was still documented in the presence of atropine or tetrodotoxin, but the stimulatory morphine effect was blocked by atropine. Both phenylephrine and octreotide decreased the release of motilin stimulated by carbachol in a jejunal segment pretreated and denervated with tetrodotoxin. Therefore, a revised model for the regulation of motilin release from M cells of intestinal mucosa can now be proposed. Cholinergic and bombesin receptors are present on M cells to encode a stimulatory signal, whereas adrenergic and somatostatin receptors are responsible for inhibitory transmission. The stimulatory effect of morphine is mediated via a muscarinic transmitter.


Peptic stricture: surgical treatment.
The results reported in this group of patients managed by modified Collis gastroplasty and partial fundoplication appear to be satisfactory and enduring over a reasonably long period of regular follow-up. It is difficult, however, to compare the results of any of these operations with results reported by others. In this context, the following quote is taken from an earlier publication [1]: "A critical review of the literature, however, indicates that accurate and meaningful comparison of the results of the various procedures recommended for correcting the problem of short esophagus is almost impossible. There is little uniformity in attempts to grade the severity of the pathology in patients with strictures, details of the techniques of stricture dilatation are usually scanty or absent, and few studies have reported the more objective results of postoperative function tests using manometry and pH measurements. Very few reports document a significant number of patients who have been followed for 5 to 10 years or longer. Further resolution of the controversy awaits reports in which case selection has been clearly defined and the long-term follow-up data are recorded with sufficient detail and uniformity."


Appendicitis and situs inversus viscerum in a 32-year-old female nigerian: a case report.
Situs inversus is a relatively rare congenital abnormality in which the internal organs are disposed in a mirror image of the normal. It is said to be an autosomal recessive genetic condition. Its prevalence varies with population. In the United States, Situs inversus is found in 0.01% of the population. The incidence in Nigeria is unknown. We present the case of a young lady with situs inversus discovered during management for appendicitis. As is often the case in situs situations, there was initial confusion and some significant delay in offering needed treatment due to the unusual disposition of the organs.


Attenuative effects of tamarixetin against polystyrene microplastics-induced hepatotoxicity in rats by regulation of Nrf-2/Keap-1 pathway.
Polystyrene microplastics (PS-MPs) are environmental contaminants due to their potential to induce damages in multiple organs specifically liver. Tamarixetin (TMT) is a naturally occurring flavonoid present in Tamarix ramosissima plant that exhibits multiple pharmacological properties. Therefore, the present research was designed to evaluate the palliative role of TMT against PS-MPs instigated liver dysfunction in rats. The exposure to PS-MPs reduced the expressions of nuclear factor erythroid 2-related factor 2 and antioxidant genes, while increasing the expression of Kelch-like ECH-associated protein 1. PS-MPs exposed rats exhibited considerably (p < .05) higher alkaline phosphatase (ALP), aspartate aminotransferase (AST) as well as alanine aminotransferase (ALT) contents. Additionally, PS-MPs treatment resulted in a notable decrease in anti-oxidants activity, that is, glutathione S-transferase (GST), superoxide dismutase (SOD), heme oxygenase-1 (HO-1), glutathione reductase (GSR), glutathione peroxidase (GPx), catalase (CAT) and glutathione (GSH) content, whereas upregulating reactive oxygen species (ROS) and malondialdehyde (MDA) contents. Moreover, PS-MPs intoxication noticeably increased (p < .05) the inflammatory indices (interleukin-1ß [IL-1ß], nuclear factor kappa B [NF-κB], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α] levels, and cyclooxygenase-2 [COX-2] activity). Besides, Caspase-3 and Bax expressions were upregulated and Bcl-2 expression was decreased after PS-MPs exposure. Additionally, the histomorphological examination revealed notable hepatic damage in PS-MPs treated group. However, TMT treatment substantially (p < .05) recovered all the PS-MPs-induced damages and histopathological changes. Taken together, it can be deduced that TMT might be used as a pharmacological agent to ameliorate hepatic damage.


Family voices: life for family carers of people with intellectual disabilities in Ireland.
Families in Ireland remain the main providers of support for people with Intellectual disabilities, and the aim of this study was to map their life experiences whilst involving their family members as co-researchers. This qualitative, participatory study involved 10 focus groups attended by 70 parents and siblings of people with intellectual disabilities. Data were analysed using thematic analysis. Caring for a family member with intellectual disabilities was found to be a dynamic and adaptive process. The well-being of the family and the challenges they face throughout their lives was the central theme identified. This was affected by: the availability of appropriate supports for families and having to advocate for them, communication and relationships with services and professionals, the availability of information and attitudes towards disability and governmental support. Strategies are suggested as to how services can better support family carers in Ireland in their role. These include families being provided with flexible and timely support for families at critical times; being offered services, support, entitlements and information without having to fight for them; knowing that their family member with intellectual disabilities is well cared for, listened to and provided with opportunities to develop and be part of the community; and carers being shown respect, listened to and involved in decisions.


Surveillance data confirm multiyear predictions of rotavirus dynamics in New York City.
Prediction skill is a key test of models for epidemic dynamics. However, future validation of models against out-of-sample data is rare, partly because of a lack of timely surveillance data. We address this gap by analyzing the response of rotavirus dynamics to infant vaccination. Syndromic surveillance of emergency department visits for diarrhea in New York City reveals a marked decline in diarrheal incidence among infants and young children, in line with data on rotavirus-coded hospitalizations and laboratory-confirmed cases, and a shift from annual to biennial epidemics increasingly affecting older children and adults. A published mechanistic model qualitatively predicted these patterns more than 2 years in advance. Future efforts to increase vaccination coverage may disrupt these patterns and lead to further declines in the incidence of rotavirus-attributable gastroenteritis.


Inclusion of brown midrib dwarf pearl millet silage in the diet of lactating dairy cows.
Brown midrib brachytic dwarf pearl millet (Pennisetum glaucum) forage harvested at the flag leaf visible stage and subsequently ensiled was investigated as a partial replacement of corn silage in the diet of high-producing dairy cows. Seventeen lactating Holstein cows were fed 2 diets in a crossover design experiment with 2 periods of 28 d each. Both diets had forage:concentrate ratios of 60:40. The control diet (CSD) was based on corn silage and alfalfa haylage, and in the treatment diet, 20% of the corn silage dry matter (corresponding to 10% of the dietary dry matter) was replaced with pearl millet silage (PMD). The effects of partial substitution of corn silage with pearl millet silage on dry matter intake, milk yield, milk components, fatty acid profile, apparent total-tract digestibility of nutrients, N utilization, and enteric methane emissions were analyzed. The pearl millet silage was higher in crude protein and neutral detergent fiber and lower in lignin and starch than the corn silage. Diet did not affect dry matter intake or energy-corrected milk yield, which averaged 46.7 ± 1.92 kg/d. The PMD treatment tended to increase milk fat concentration, had no effect on milk fat yield, and increased milk urea N. Concentrations and yields of milk protein and lactose were not affected by diet. Apparent total-tract digestibility of dry matter decreased from 66.5% in CSD to 64.5% in PMD. Similarly, organic matter and crude protein digestibility was decreased by PMD, whereas neutral- and acid-detergent fiber digestibility was increased. Total milk trans fatty acid concentration was decreased by PMD, with a particular decrease in trans-10 18:1. Urinary urea and fecal N excretion increased with PMD compared with CSD. Milk N efficiency decreased with PMD. Carbon dioxide emission was not different between the diets, but PMD increased enteric methane emission from 396 to 454 g/d and increased methane yield and intensity. Substituting corn silage with brown midrib dwarf pearl millet silage at 10% of the diet dry matter supported high milk production in dairy cows. When planning on farm forage production strategies, brown midrib dwarf pearl millet should be considered as a viable fiber source.


Traumatic injury to the superior mesenteric artery.
Superior mesenteric artery (SMA) injuries are rare and devastating injuries incurring very high mortality rates. It is the purpose of this study to review our experience with these injuries, to analyze Fullen's classification based on anatomical zone and injury grade for its predictive value, and to correlate the American Association for the Surgery of Trauma-Organ Injury Scale (AAST-OIS) for abdominal vascular injury with mortality. Retrospective study was made over a 65-month period of all patients sustaining SMA injuries in an urban level I trauma center. Thirty-five patients, mean age 31, had a mean Revised Trauma Score of 5.86 and a mean Injurity Severity Score of 23. Mechanisms of injury were penetrating 27 (77%) and blunt 8 (23%). Mean admission systolic blood pressure was 85 mm Hg. Mean estimated blood loss was 8,500 mL and mean total fluid replacement 17,000 mL. Operating room findings were retroperitoneal hematoma in 34 (97%) and "black bowel" in 2 (6%). Number of associated injuries was nonvascular, mean 4.2, and vascular, mean 1.5. Surgical management consisted of ligation in 18 (51%), primary repair in 14 (40%), and interposition graft in 2 (6%). Overall mortality was 19 of 35 (54%). Mortality versus Fullen's zones was zone I, 100%, zone II, 43%, and zones III and IV, 25%. Mortality versus Fullen's ischemia grade was grade 1, 89%, grade 2, 58%, grade 3, 100%, and grade 4, 19%. Mortality versus AAST-OIS: was grade 1, 0%, grade II, 20%, grade III, 0%, grade IV, 59%, and grade V, 88%. SMA injuries are highly lethal. Most deaths are due to exsanguination. A higher number of associated vascular injuries increases mortality. "Black bowel" is an uncommon finding. Both Fullen's anatomical zones and the AAST-OIS for abdominal vascular injuries correlate with mortality. Fullen's ischemia grade does not.


Hemodialysis in diabetics: complications in insulin-dependent patients accepted for renal transplantation.
The hemodialysis complications in 67 insulin-dependent diabetic patients accepted for renal transplantation were compared with those in 67 nondiabetic hemodialysis patients. Eleven of the 67 diabetic patients died before receiving a renal transplant-four of myocardial infarction, three of dialysis-related causes, and four of infections. One of the 67 nondiabetic patients died of infection before transplantation. The diabetic patients experienced more complications on dialysis than did the nondiabetic patients; they were more hypertensive and required more ultrafiltration during dialysis. In addition, the diabetic patients had a higher incidence of hypertensive episodes during dialysis, as well as a high incidence of predialysis hyperglycemia. These findings suggest that diabetic patients with renal failure should be dialyzed more frequently and transplanted as soon as possible in order to decrease the complications associated with hemodialysis.


Efficacy of protocol implementation on incidence of wound infection in colorectal operations.
We reported previously a 26% incidence of surgical site infection (SSI) in patients undergoing elective colorectal resection. Multiple risk factors have been identified, including obesity, improper administration of prophylactic antibiotics, hypothermia, and poor glycemic control. We hypothesized that implementation of a multidisciplinary wound management protocol targeting these risk factors would reduce the incidence of SSI. Previously reported baseline data were collected from February 2000 to January 2002. Beginning September 2004, the protocol was implemented, including appropriate administration of prophylactic antibiotics 0 to 60 minutes before incision, continued antibiotic administration for < or = 24 hours postoperatively, maintenance of intraoperative normothermia (> 36 degrees C), improved glycemic control (goal <200 mg/dL 48 hours postoperatively) in diabetic patients, and placement of penrose drains in the subcutaneous space of patients with a body mass index > or = 25. Data were collected on patients undergoing elective colorectal resection from January 2005 to August 2005 and compared with baseline. One hundred seventy-five and 132 patients during the baseline and study periods, respectively, met criteria for inclusion. Compliance with administration of prophylactic antibiotics increased from 68% to 91% (p < or = 0.0001), and compliance with cessation within 24 hours increased from 71% to 93% (p < or = 0.0001). Compliance with normothermia increased from 64% to 71% (p = 0.25). Incidence of SSI fell from 25.6% to 15.9% (p < or = 0.05). After implementation of a multidisciplinary wound-management protocol, incidence of SSI improved 39%. These results demonstrate that compliance with a prospectively designed protocol for perioperative care can effectively reduce operative morbidity in patients undergoing colorectal operations.


A phenomenologic study of the interface of caring and technology in intermediate care: toward a reflexive ethics for clinical practice.
A phenomenologic research study of nurse caring was conducted in an intermediate care unit of a hospital. Three narratives from the data are presented as examples to illuminate the meaning of the experience of caring for technologically dependent patients. Results revealed that vulnerability, suffering, and the ethical situations of moral blurring and moral blindness were the dynamics of caring for these patients. Identification of these phenomena cells for a new reflexive ethics in health care to increase understanding of how deep values in relation to the status of vulnerable human beings, and how moral interactions among patients, families, and caregivers, shape ethical decisions.


Levels and interactions of p27, cyclin D3, and CDK4 during the formation and maintenance of the corpus luteum in mice.
The cyclin-dependent kinase (CDK) inhibitor p27, the regulator of the cell cycle, is required for proper functioning of luteinizing/luteinized cells in vivo. Since different members of the CDK family may be targeted by p27 during luteinization-associated cell cycle exit, this in vivo study further analyzed the organization of the network of cell cycle regulators that may underlie both the establishment and maintenance of the luteal phenotype. Most importantly, it shows that the luteinization process is associated with down-regulation of CDK2 and cyclin D1, and up-regulation of p27 and cyclin D3. Both p27 and cyclin D3 proteins not only accumulated during initial phases of luteinization, but they remained elevated until termination of the luteal function. Along with its accumulation, p27 lost physical contact with CDK2 and instead became associated with CDK4. In fully luteinized cells, all cyclin D3 was incorporated into complexes with p27, some complexes being p27/cyclin D3/CDK4 trimers. Despite the significant amounts of CDK4 and CDK6, only nonphosphorylated forms of retinoblastoma protein were detectable in fully luteinized cells. Together, our data indicate that while inhibition of proliferation is underlaid by the progressive loss of positive regulators of the cell cycle, including cyclins and CDK2, maintenance of the luteal phenotype is driven by up-regulated levels of p27 and cyclin D3, at least partially owing to formation of p27/cyclin D3/CDK4 trimers.


Tumors of the kidney.
The most frequent renal tumours of animals are renal cell carcinoma and nephroblastoma. Renal cell carcinomas are seen mainly in dogs and cattle and nephroblastoma is encountered in pigs, puppies, and calves. Renal cell carcinomas are usually papillary in the dog. They show a marked propensity for vascular invasion, penetration of the posterior vena cava, and subsequent pulmonary metastasis. Nephroblastoma, which is morphologically identical to Wilms' tumour of children, is almost always a benign tumour in animals. It is one of the most frequent neoplasms of pigs, possibly owing to the fact that most pigs are slaughtered (and examined) when a few months old. Lymphosarcoma involving the kidney is particularly frequent in the cat, but is also seen in other species as part of a generalized disease.


Effects of acepromazine and butorphanol on tiletamine-zolazepam anesthesia in llamas.
To evaluate sedative, antinociceptive, and physiologic effects of acepromazine and butorphanol during tiletamine-zolazepam (TZ) anesthesia in llamas. 5 young adult llamas. Llamas received each of 5 treatments IM (1-week intervals): A (acepromazine, 0.05 mg/kg), B1 (butorphanol, 0.1 mg/kg), AB (acepromazine, 0.05 mg/kg, and butorphanol, 0.1 mg/kg), B2 (butorphanol, 0.2 mg/kg), or C (saline [0.9% NaCl] solution). Sedation was evaluated during a 30-minute period prior to anesthesia with TZ (2 mg/kg, IM). Anesthesia and recovery characteristics and selected cardiorespiratory variables were recorded at intervals. Antinociception was assessed via a toe-clamp technique. Sedation was not evident following any treatment. Times to sternal and lateral recumbency did not differ among treatments. Duration of lateral recumbency was significantly longer for treatment AB than for treatment C. Duration of antinociception was significantly longer for treatments A and AB, compared with treatment C, and longer for treatment AB, compared with treatment B2. Treatment B1 resulted in a significant decrease in respiratory rate, compared with treatment C. Compared with treatment C, diastolic and mean blood pressures were lower after treatment A. Heart rate was increased with treatment A, compared with treatment B1 or treatment C. Although severe hypoxemia developed in llamas anesthetized with TZ alone and with each treatment-TZ combination, hemoglobin saturation remained high and the hypoxemia was not considered clinically important. Sedation or changes in heart and respiratory rates were not detected with any treatment before administration of TZ. Acepromazine alone and acepromazine with butorphanol (0.1 mg/kg) prolonged the duration of antinociception in TZ-treated llamas.


Controllable digital resistive switching for artificial synapses and pavlovian learning algorithm.
The fundamental unit of the nervous system is a synapse, which is involved in transmitting information between neurons as well as learning, memory, and forgetting processes. Two-terminal memristors can fulfil most of these requirements; however, their poor dynamic changes in resistance to input electric stimuli remain an obstacle, which must be improved for accurate and quick information processing. Herein, we demonstrate the synaptic properties of ZnO-based memristors, which were significantly enhanced (∼340 times) by geometrical modulation due to the localized electric field enhancement. Specifically, by inserting Ag-nanowires and Ag-dots into the ZnO/Si interface, the resistive switching could be controlled from a digital to analog mode. A finite element simulation revealed that the presence of Ag could enhance the localized electric field, which in turn improved the migration of ionic species. Further, the device showed a variety of comprehensive synaptic functions, for instance, paired-pulse facilitation and transformation from short-term plasticity to long-term plasticity, including the Pavlovian associative learning process in a human brain. Our study presents a novel architecture to enhance the synaptic sensitivity, and its uses in practical applications, including the artificial learning algorithm.


Using prefrailty to detect early disability.
In an aging population, new strategies are required to identify individuals at risk of adverse health outcomes. Frailty syndrome is related to negative health events. This increased risk may be used to identify individuals in which interventions can delay the onset of physical and functional complications. The aim of the study was to determine the relationship between the onset of frailty and the beginning of functional disability. This was a cross-sectional observational study with consecutive sampling to analyze 146 patients aged seventy and older who come to the primary care center. The level of frailty was registered according to fatigue, resistance, ambulation, illnesses, and loss of weight scale. Disability for Instrumental Activities of Daily Live dependency, comorbidity, and social risk factors was registered too. The prevalence of frailty and prefrailty was 17.8% and 39%, respectively, and were associated with age, level of disability, and the presence of gastrointestinal disease. Prefrail patients had initial levels of dependency, while those who were not frail were mostly independent. Frailty syndrome is easily detectable. The intermediate stage known as prefrailty is related to the start of the functional disability. The syndrome screening identifies individuals at risk in whom we can potentially intervene to delay the onset of the syndrome and delay functional disability. Control of comorbidity in frail patients must be studied. Screening age could be set in patients between 75 and 81 years old.


Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.
We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly glucagon-like peptide 1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated hemoglobin A1c [HbA1c] 7.0-10.5% [53-91 mmol/mol]) were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change in HbA1c from baseline to week 20. Mean changes in HbA1c from baseline to week 20 ranged from -1.41% to -1.67% with mazdutide (-1.35% with dulaglutide and 0.03% with placebo; all P < 0.0001 vs. placebo). Mean percent changes in body weight from baseline to week 20 were dose dependent and up to -7.1% with mazdutide (-2.7% with dulaglutide and -1.4% with placebo). At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants. The most common adverse events with mazdutide included diarrhea (36%), decreased appetite (29%), nausea (23%), vomiting (14%), and hypoglycemia (10% [8% with placebo]). In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reductions.