The Impact of Obesity on Disease Severity and Outcomes Among Hospitalized Children With COVID-19.
To describe the impact of obesity on disease severity and outcomes of coronavirus disease 2019 (COVID-19) among hospitalized children. This retrospective cohort study from the Society of Critical Care Medicine Viral Respiratory Illness Universal Study registry included all children hospitalized with COVID-19 from March 2020 to January 2021. Obesity was defined by Centers for Disease Control and Prevention BMI or World Health Organization weight for length criteria. Critical illness definition was adapted from National Institutes of Health criteria of critical COVID. Multivariate mixed logistic and linear regression was performed to calculate the adjusted odds ratio of critical illness and the adjusted impact of obesity on hospital length of stay. Data from 795 patients (96.4% United States) from 45 sites were analyzed, including 251 (31.5%) with obesity and 544 (68.5%) without. A higher proportion of patients with obesity were adolescents, of Hispanic ethnicity, and had other comorbidities. Those with obesity were also more likely to be diagnosed with multisystem inflammatory syndrome in children (35.7% vs 28.1%, P = .04) and had higher ICU admission rates (57% vs 44%, P < .01) with more critical illness (30.3% vs 18.3%, P < .01). Obesity had more impact on acute COVID-19 severity than on multisystem inflammatory syndrome in children presentation. The adjusted odds ratio for critical illness with obesity was 3.11 (95% confidence interval: 1.8-5.3). Patients with obesity had longer adjusted length of stay (exponentiated parameter estimate 1.3; 95% confidence interval: 1.1-1.5) compared with patients without obesity but did not have increased mortality risk due to COVID-19 (2.4% vs 1.5%, P = .38). In a large, multicenter cohort, a high proportion of hospitalized children from COVID-19 had obesity as comorbidity. Furthermore, obesity had a significant independent association with critical illness.


Assessing patient beliefs in a clinical trial of Hypericum perforatum in major depression.
Little is known about the beliefs of patients suffering from major depression as to the causes of their illness and effective treatments. This study introduces a new instrument for capturing these beliefs, the Explanatory Model for Depression (EMD) Questionnaire, and explores the beliefs of patients participating in a clinical trial of an alternative medicine, Hypericum perforatum. Although the EMD was originally conceptualized as having five factors pertaining to models of the illness and treatment approaches, the data suggest that patient beliefs are aligned on two factors pertaining to internal and external locus of control. Strong beliefs on either of the EMD locus of control subscales are associated with more severe depression. More importantly, strong beliefs on the external locus of control subscale are associated with less improvement over the 8-week period of observation. These results support the role of patients' beliefs in their recovery from depression and suggest that patients who believe the causes of their depression are outside of their control are less likely to improve over time. It is important to note that beliefs did not mediate the effect of treatment on depression in this study, perhaps because patients were blinded to their treatment condition. Future studies should explore whether patient beliefs have an even greater impact when patients are aware of the treatment they are receiving and can determine whether that treatment is consistent with their beliefs.


A rapid, automated enzymatic fluorometric assay for determination of D-arabinitol in serum.
A rapid enzymatic fluorometric assay for measuring D-arabinitol in serum was developed using recombinant D-arabinitol dehydrogenase from Candida albicans (rArDH). rArDH was produced in Escherichia coli and purified by dye-ligand affinity chromatography. rArDH was highly specific for D-arabinitol, cross-reacting only with xylitol (4.9%) among all polyols tested. A Cobas Fara II centrifugal autoanalyzer (Roche) was used to measure NADH fluorometrically when rArDH and NAD were added to serum extracts, and D-arabinitol concentrations were calculated from standard curves derived from pooled human serum containing known amounts of D-arabinitol. The method was precise (mean intra-assay coefficients of variation [CVs], 0.8%, and mean interassay CVs, 1.6%) and rapid (3.5 min per assay) and showed excellent recovery of added D-arabinitol in serum (mean recovery rate, 101%). The mean and median D-arabinitol/creatinine ratios were 2.74 and 2.23 microM/mg/dl, respectively, for the 11 patients with candidemia compared to 1.14 and 1.23 microM/mg/dl, respectively, for 10 healthy controls (P < 0.01). These results confirm earlier studies showing that serum D-arabinitol measurement may help to promptly diagnose invasive candidiasis. The technique shows a significant improvement in terms of accuracy, cost, simplicity, specificity, and speed compared with gas chromatography, mass spectrometry, and earlier enzymatic assays.


A comparison of physicians' and patients' attitudes toward pharmaceutical industry gifts.
To compare physicians' and their patients' attitudes toward pharmaceutical gifts. Survey of physicians and their patients. Two tertiary-care medical centers, one military and one civilian. Two hundred sixty-eight of 392 consecutively surveyed physicians, 100 of 103 randomly selected patients at the military center, and 96 patients in a convenience sample at the civilian center completed the survey. Participants rated 10 pharmaceutical gifts on whether they were appropriate for physicians to accept and whether they were likely to influence prescribing. Patients found gifts less appropriate and more influential than did their physicians. About half of the patients were aware of such gifts; of those unaware, 24% responded that this knowledge altered their perception of the medical profession. Asked whether they thought their own physician accepted gifts, 27% said yes, 20% no, and 53% were unsure. For patients, feeling that gifts were inappropriate was best predicted by a belief that gifts might influence prescribing, while for physicians, the best predictor was knowledge of guidelines. Patients feel pharmaceutical gifts are more influential and less appropriate than do their physicians. Physicians may want to consider this in deciding whether to accept particular gifts. Broader dissemination of guidelines may be one means of changing physician behavior. At the same time, future guidelines should further consider the potentially different viewpoints of patients and physicians.


Dexmedetomidine attenuates sympathoadrenal response to tracheal intubation and reduces perioperative anaesthetic requirement.
Dexmedetomidine, an α-2 adrenoreceptor agonist, is gaining popularity for its sympatholytic, sedative, anaesthetic sparing and haemodynamic stabilising properties without significant respiratory depression. We assessed the efficacy of dexmedetomidine in attenuating sympathoadrenal response to tracheal intubation and analysed reduction in intraoperative anaesthetic requirement. Sixty patients scheduled for elective surgery of more than 3 hours were randomly selected. Control group received isoflurane-opioid and study group received isoflurane-opioid-dexmedetomidine anaesthesia. Dexmedetomidine infusion in a dose of 1 μg/kg was given over 10 min before the induction of anaesthesia and was continued in a dose of 0.2-0.7 μg/kg/Hr until skin closure. All patients were induced with thiopentone, fentanyl and vecuronium. Haemodynamic variables were continuously recorded. The need for thiopentone and isoflurane was decreased by 30% and 32%, respectively, in the dexmedetomidine group as compared to the control group. After tracheal intubation, maximal average increase was 8% in systolic and 11% in diastolic blood pressure in dexmedetomidine group, as compared to 40% and 25%, respectively, in the control group. Similarly, average increase in heart rate was 7% and 21% in the dexmedetomidine and control groups, respectively. Fentanyl requirement during the operation was 100±10 μg in the control group and 60±10 μg in the dexmedetomidine group. Perioperative infusion of dexmedetomidine is effective in attenuating sympathoadrenal response to tracheal intubation. It has significant anaesthetic and opioid sparing effect.


The road from discovery to clinical diagnostics: lessons learned from the first FDA-cleared in vitro diagnostic multivariate index assay of proteomic biomarkers.
After more than a decade of biomarker discovery research using advanced genomic and proteomic technologies, very few biomarkers have been translated into clinical diagnostics for patient care. This has become an urgent issue to be addressed because the continuing funding from both the public and private sources are called into question. We use as an example, OVA1, the first in vitro diagnostic multivariate index assay (IVDMIA) of proteomic biomarkers recently cleared by the US FDA (Food and Drug Administration) to describe our experience through the long road from biomarker discovery, to validation, and finally to multi-institutional trial for regulatory approval by the FDA. We discuss 3 issues that are key bridges in the path of biomarker development to actual clinical diagnostics: 1) to generate sufficient and "portable" evidence in preliminary validation studies to support investment for large-scale validation trials; 2) to carefully and clearly define clinical utility that balances desire for broad applicability and feasibility for completing clinical trials for regulatory approval; and 3) to select/develop assays with analytical performance suitable for clinical deployment. We learned that the road from biomarker discovery, validation, to clinical diagnostics could be long and winding, and often frustrating. However, we also know that, with the right approaches, at the end of the road, there is a rainbow waiting for us. Provide insights and recommendations for the translation of proteomic biomarkers into clinical diagnostics.


Ecological restoration success is higher for natural regeneration than for active restoration in tropical forests.
Is active restoration the best approach to achieve ecological restoration success (the return to a reference condition, that is, old-growth forest) when compared to natural regeneration in tropical forests? Our meta-analysis of 133 studies demonstrated that natural regeneration surpasses active restoration in achieving tropical forest restoration success for all three biodiversity groups (plants, birds, and invertebrates) and five measures of vegetation structure (cover, density, litter, biomass, and height) tested. Restoration success for biodiversity and vegetation structure was 34 to 56% and 19 to 56% higher in natural regeneration than in active restoration systems, respectively, after controlling for key biotic and abiotic factors (forest cover, precipitation, time elapsed since restoration started, and past disturbance). Biodiversity responses were based primarily on ecological metrics of abundance and species richness (74%), both of which take far less time to achieve restoration success than similarity and composition. This finding challenges the widely held notion that natural forest regeneration has limited conservation value and that active restoration should be the default ecological restoration strategy. The proposition that active restoration achieves greater restoration success than natural regeneration may have arisen because previous comparisons lacked controls for biotic and abiotic factors; we also did not find any difference between active restoration and natural regeneration outcomes for vegetation structure when we did not control for these factors. Future policy priorities should align the identified patterns of biophysical and ecological conditions where each or both restoration approaches are more successful, cost-effective, and compatible with socioeconomic incentives for tropical forest restoration.


Fate of clinical research studies after ethical approval--follow-up of study protocols until publication.
Many clinical studies are ultimately not fully published in peer-reviewed journals. Underreporting of clinical research is wasteful and can result in biased estimates of treatment effect or harm, leading to recommendations that are inappropriate or even dangerous. We assembled a cohort of clinical studies approved 2000-2002 by the Research Ethics Committee of the University of Freiburg, Germany. Published full articles were searched in electronic databases and investigators contacted. Data on study characteristics were extracted from protocols and corresponding publications. We characterized the cohort, quantified its publication outcome and compared protocols and publications for selected aspects. Of 917 approved studies, 807 were started and 110 were not, either locally or as a whole. Of the started studies, 576 (71%) were completed according to protocol, 128 (16%) discontinued and 42 (5%) are still ongoing; for 61 (8%) there was no information about their course. We identified 782 full publications corresponding to 419 of the 807 initiated studies; the publication proportion was 52% (95% CI: 0.48-0.55). Study design was not significantly associated with subsequent publication. Multicentre status, international collaboration, large sample size and commercial or non-commercial funding were positively associated with subsequent publication. Commercial funding was mentioned in 203 (48%) protocols and in 205 (49%) of the publications. In most published studies (339; 81%) this information corresponded between protocol and publication. Most studies were published in English (367; 88%); some in German (25; 6%) or both languages (27; 6%). The local investigators were listed as (co-)authors in the publications corresponding to 259 (62%) studies. Half of the clinical research conducted at a large German university medical centre remains unpublished; future research is built on an incomplete database. Research resources are likely wasted as neither health care professionals nor patients nor policy makers can use the results when making decisions.


Situation alignment and routinization in language acquisition.
Pickering & Garrod (P&G) describe a mechanism by which the situation models of dialog participants become progressively aligned via priming at different levels. This commentary attempts to characterize how alignment and routinization can be extended into the language acquisition domain by establishing links between alignment and joint attention, and between routinization and grammatical construction learning.


Epidemiological and clinical characteristics of acute gastroenteritis according to their etiology (rotavirus or other) in children younger than 5 years old at a private institution in the city of Buenos Aires.
Acute gastroenteritis is a common disease in children. Rotavirus is the major etiologic agent. To describe the epidemiological and clinical characteristics of acute gastroenteritis according to their etiology (rotavirus or other) in children younger than 5 years old in a private institution in the City of Buenos Aires. to analyze related costs. Cross sectional, descriptive, observational study conducted during one year in children younger than 5 years old with gastroenteritis. The presence of rotavirus was diagnosed with the VIKIA® Rota-Adeno test. Demographic, clinical and immunization data were collected. A univariate data analysis was performed. A total of 275 patients were included; 18.5% of them were R+. Rotavirus was more common in children younger than 2 years old and in the period between March and June. The cases of rotavirus gastroenteritis were more severe, required more hospitalizations (OR 2.07; 95% CI 1.17-7.13), and resulted in higher costs. In the sample studied, the immunization outcome measure reduced the risk of rotavirus infection. Acute gastroenteritis caused by rotavirus were different from other etiologies in that they had a seasonal peak and in relation to the median age of patients, the severity of the condition, the association with hospitalization and the increase in costs.


The First Samples from Almahata Sitta Showing Contacts Between Ureilitic and Chondritic Lithologies: Implications for the Structure and Composition of Asteroid 2008 TC3.
Almahata Sitta (AhS), an anomalous polymict ureilite, is the first meteorite observed to originate from a spectrally classified asteroid (2008 TC3). However, correlating properties of the meteorite with those of the asteroid is not straightforward because the AhS stones are diverse types. Of those studied prior to this work, 70-80% are ureilites (achondrites) and 20-30% are various types of chondrites. Asteroid 2008 TC3 was a heterogeneous breccia that disintegrated in the atmosphere, with its clasts landing on Earth as individual stones and most of its mass lost. We describe AhS 91A and AhS 671, which are the first AhS stones to show contacts between ureilitic and chondritic materials and provide direct information about the structure and composition of asteroid 2008 TC3. AhS 91A and AhS 671 are friable breccias, consisting of a C1 lithology that encloses rounded to angular clasts (<10 μm to 3 mm) of olivine, pyroxenes, plagioclase, graphite, and metal-sulfide, as well as chondrules (~130-600 μm) and chondrule fragments. The C1 material consists of fine-grained phyllosilicates (serpentine and saponite) and amorphous material, magnetite, breunnerite, dolomite, fayalitic olivine (Fo 28-42), an unidentified Ca-rich silicate phase, Fe,Ni sulfides, and minor Ca-phosphate and ilmenite. It has similarities to CI1 but shows evidence of heterogeneous thermal metamorphism. Its bulk oxygen isotope composition (δ18O = 13.53‰, δ17O = 8.93‰) is unlike that of any known chondrite, but similar to compositions of several CC-like clasts in typical polymict ureilites. Its Cr isotope composition is unlike that of any known meteorite. The enclosed clasts and chondrules do not belong to the C1 lithology. The olivine (Fo 75-88), pyroxenes (pigeonite of Wo ~10 and orthopyroxene of Wo ~4.6), plagioclase, graphite, and some metal-sulfide are ureilitic, based on mineral compositions, textures, and oxygen isotope compositions, and represent at least six distinct ureilitic lithologies. The chondrules are probably derived from type 3 OC and/or CC, based on mineral and oxygen isotope compositions. Some of the metal-sulfide clasts are derived from EC. AhS 91A and AhS 671 are plausible representatives of the bulk of the asteroid that was lost. Reflectance spectra of AhS 91A are dark (reflectance ~0.04-0.05) and relatively featureless in VNIR, and have an ~2.7 μm absorption band due to OH- in phyllosilicates. Spectral modeling, using mixtures of laboratory VNIR reflectance spectra of AhS stones to fit the F-type spectrum of the asteroid, suggests that 2008 TC3 consisted mainly of ureilitic and AhS 91A-like materials, with as much as 40-70% of the latter, and <10% of OC, EC and other meteorite types. The bulk density of AhS 91A (2.35 ± 0.05 g/cm3) is lower than bulk densities of other AhS stones, and closer to estimates for the asteroid (~1.7-2.2 g/cm3). Its porosity (36%) is near the low end of estimates for the asteroid (33-50%), suggesting significant macroporosity. The textures of AhS 91A and AhS 671 (finely comminuted clasts of disparate materials intimately mixed) support formation of 2008 TC3 in a regolith environment. AhS 91A and AhS 671 could represent a volume of regolith formed when a CC-like body impacted into already well-gardened ureilitic + impactor-derived debris. AhS 91A bulk samples do not show a solar wind (SW) component, so they represent sub-surface layers. AhS 91A has a lower cosmic ray exposure (CRE) age (~5-9 Ma) than previously studied AhS stones (11-22 Ma). The spread in CRE ages argues for irradiation in a regolith environment. AhS 91A and AhS 671 show that ureilitic asteroids could have detectable ~2.7 μm absorption bands.


Female control of mate plugging in a female-cannibalistic spider (Micaria sociabilis).
Sperm competition imposes a strong selective pressure on males, leading to the evolution of various physiological, morphological and behavioral traits. Sperm competition can be prevented by blocking or impeding the access to female genitalia by means of a mating plug. We investigated the factors responsible for plug production and function in the promiscuous female-cannibalistic spider Micaria sociabilis (Gnaphosidae). We performed mating trials using females with and without a plug that consists of an amorphous mass. The mating trials demonstrated that the probability of male plugging increased non-linearly with the duration of copulation. Copulation duration and plug production seem to be controlled by the female. We found that females terminated matings later if males were fast at genital coupling. Whereas incomplete plugs had disappeared on the day following copulation, complete plugs persisted (40%). In matings with females with complete plugs, only a small proportion of males (7%) were able to remove the plug, indicating the high effectiveness of plugging. Moreover, males ceased attempts to copulate with plugged females with higher probability. 3D X-ray microscopy of the female and male genitalia showed that the plug material can extend far into the female genital tract and that the plug material is produced by a massive gland inside the palpal organ of the modified male pedipalps. Our study demonstrates that the mating plug in M. sociabilis constitutes an effective male strategy to avoid sperm competition that seems to be under female control.


In vitro and in vivo studies of the anticancer action of terbinafine in human cancer cell lines: G0/G1 p53-associated cell cycle arrest.
Terbinafine (TB) (Lamisil), a promising oral antifungal agent used worldwide, has been used in the treatment of superficial mycosis. In our study, we demonstrated that TB dose-dependently decreased cell number in various cultured human malignant cells. Flow cytometry analysis revealed that TB interrupts the cell cycle at the G0/G1 transition. The TB-induced cell cycle arrest in colon cancer cell line (COLO 205) occurred when the cyclin-dependent kinase (cdk) system was inhibited just as the levels of p53, p21/Cip1 and p27/Kip1 proteins were augmented. In the TB-treated COLO 205, the binding between p53 protein and p53 consensus binding site in p21/Cip1 promoter DNA probe was increased. Pretreatment of COLO 205 with p53-specific antisense oligodeoxynucleotide decreased the TB-induced elevations of p53 and p21/Cip1 proteins, which in turn led to arrest in the cell cycle at the G0/G1 phase. Moreover, in the p53 null cells, HL60, TB treatment did not induce cell cycle arrest. Taken together, these results suggest an involvement of the p53-associated signaling pathway in the TB-induced antiproliferation in COLO 205. We further examined whether administration of TB could affect the growth of tumors derived from human colon cancer cells in an in vivo setting. COLO 205 cells implanted subcutaneously in nude mice formed solid tumor; subsequent intraperitoneal injections of TB (50 mg/kg) led to obvious decline in tumor size, up to 50-60%. In these tumors, increases in the p21/Cip1, p27/Kip1 and p53 proteins and the occurrence of apoptosis were observed. Combined treatment with TB and nocodazole (ND), a clinically used anticancer agent, potentiated the apoptotic effect in COLO 205. These findings demonstrate for the first time that TB can inhibit the proliferation of tumor cells in vitro and in vivo.


Language profiles and mental health problems in children with specific language impairment and children with ADHD.
This study aimed to explore whether children with specific language impairment (SLI) and children with ADHD can be differentiated from each other in terms of their language profiles, and also to investigate whether these two clinical groups differ regarding mental health problems. A total of 59 children in the age range 6 to 12 years participated in the study. The parents completed the Children's Communication Checklist-Second Edition and the Strengths and Difficulties Questionnaire. Communication impairments were as prominent in the ADHD group as in the SLI group; however, the groups were separable from each other in terms of their language profiles. Furthermore, the ADHD group experienced significantly more mental health problems compared with the SLI group. Language should be assessed in children with ADHD and instruments sensitive to ADHD should be included when assessing children with SLI. Mental health should be an area of concern to be addressed in both groups.


The Pathological Buying Screener: Development and Psychometric Properties of a New Screening Instrument for the Assessment of Pathological Buying Symptoms.
The study was designed to develop a new screening instrument for pathological buying (PB), and to examine its psychometric properties in a large-scale sample. By using a facet theoretical approach and based on literature as well as on clinical experience, a 20-item Pathological Buying Screener (PBS) was developed and administered to a representative German sample (n = 2,539). Valid data were available from 2,403 participants who were subjects for three subsequent empirical studies. The first study explored the factor structure using exploratory factor analyses in a subsample of 498 participants. Based on factor loadings, a 13-item version with the two factors loss of control / consequences and excessive buying behavior was revealed. This two-factor model was confirmed in study 2 by confirmatory factor analysis performed on another subsample (n = 1,905). Study 3 investigated age and gender effects and convergent validity of the PBS using the Compulsive Buying Scale (CBS) in the full sample (N = 2,403). The total PBS score was adequately correlated with the CBS score. Hierarchical regression analyses with the CBS score as the dependent variable and the two PBS factors as the predictors indicated an own incremental validity of the two factors in participants ≤ 65 years. The reliability of the total score as well as of the two subscales was good to excellent. Overall, the PBS represents a useful measure for PB. Future studies are needed to replicate the two-factor structure in clinical samples and to define a valid cutoff for PB.


A Hand-Held Device to Apply Instrument-Assisted Soft Tissue Mobilization at Targeted Compression Forces and Stroke Frequencies.
Instrument-assisted soft tissue mobilization (IASTM) is a manual therapy technique that is commonly used to treat dysfunctions in ligaments and other musculoskeletal tissues. The objective of this study was to develop a simple hand-held device that helps users accurately apply targeted compressive forces and stroke frequencies during IASTM treatments. This portable device uses a force sensor, tablet computer, and custom software to guide the application of user-specified loading parameters. To measure performance, the device was used to apply a combination of targeted forces and stroke frequencies to foam blocks and silicone pads. Three operators using the device applied targeted forces between 0.3 and 125 N with less than 10% error and applied targeted stroke frequencies between 0.25 and 1.0 Hz with less than 3% error. The mean error in applying targeted forces increased significantly at compressive forces less than 0.2 N and greater than 125 N. For experimental validation, the device was used to apply a series of IASTM treatments over three-weeks to rodents with a ligament injury, and the targeted compressive force and stroke frequency were repeatedly applied with an average error less than 5%. This validated device can be used to investigate the effect of IASTM loading parameters on tissue healing in animal and human studies, and therefore can support the optimization and adoption of IASTM protocols that improve patient outcomes.


Comparison by meta-analysis of percutaneous coronary intervention versus coronary artery bypass grafting in patients with a mean age of ≥70 years.
A paucity of published data evaluating the outcomes of older patients (age ≥70 years) undergoing revascularization for unprotected left main coronary artery disease is available. We performed aggregate data meta-analyses of the clinical outcomes (all-cause mortality, nonfatal myocardial infarction, stroke, repeat revascularization, and major adverse cardiac and cerebrovascular events at 30 days and 12 and 22 months) in studies comparing percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with a mean age of ≥70 years and unprotected left main coronary artery disease. A comprehensive, time-unlimited literature search to January 31, 2013 identified 10 studies with a total of 2,386 patients (PCI, n = 909; CABG, n = 1,477). Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using the random-effects model. The patients in the PCI group were more likely than those in the CABG group to present with acute coronary syndrome (59.6% vs 44.8%, p <0.001). PCI was associated with a shorter hospital stay (4.2 ± 0.8 vs 8.3 ± 0.01 days, p <0.001). No significant differences were found between PCI and CABG for all cause-mortality, nonfatal myocardial infarction, and major adverse cardiac and cerebrovascular events at 30 days and 12 and 22 months. However, PCI was associated with lower rates of stroke at 30 days (OR 0.14, 95% CI 0.02 to 0.76) and 12 months (OR 0.14, 95% CI 0.03 to 0.60) and higher rates of repeat revascularization at 22 months (OR 4.34, 95% CI 2.69 to 7.01). These findings were consistent with the findings from a subgroup analysis of patients aged ≥75 years. In conclusion, older patients (age ≥70 years) with unprotected left main coronary artery disease had comparable rates of all-cause mortality, nonfatal myocardial infarction, and major adverse cardiac and cerebrovascular events after PCI or CABG. The patients undergoing PCI had a shorter hospital stay and lower rates of early stroke; however, they experienced higher repeat revascularization rates at longer term follow-up.


Regulation of interneuron excitability by gap junction coupling with principal cells.
Electrical coupling of inhibitory interneurons can synchronize activity across multiple neurons, thereby enhancing the reliability of inhibition onto principal cell targets. It is unclear whether downstream activity in principal cells controls the excitability of such inhibitory networks. Using paired patch-clamp recordings, we show that excitatory projection neurons (fusiform cells) and inhibitory stellate interneurons of the dorsal cochlear nucleus form an electrically coupled network through gap junctions containing connexin36 (Cxc36, also called Gjd2). Remarkably, stellate cells were more strongly coupled to fusiform cells than to other stellate cells. This heterologous coupling was functionally asymmetric, biasing electrical transmission from the principal cell to the interneuron. Optogenetically activated populations of fusiform cells reliably enhanced interneuron excitability and generated GABAergic inhibition onto the postsynaptic targets of stellate cells, whereas deep afterhyperpolarizations following fusiform cell spike trains potently inhibited stellate cells over several hundred milliseconds. Thus, the excitability of an interneuron network is bidirectionally controlled by distinct epochs of activity in principal cells.


Sarcopenia in COPD: relationship with COPD severity and prognosis.
To evaluate the prevalence of sarcopenia in COPD patients, as well as to determine whether sarcopenia correlates with the severity and prognosis of COPD. A cross-sectional study with COPD patients followed at the pulmonary outpatient clinic of our institution. The patients underwent dual-energy X-ray absorptiometry. The diagnosis of sarcopenia was made on the basis of the skeletal muscle index, defined as appendicular lean mass/height2 only for low-weight subjects and adjusted for fat mass in normal/overweight subjects. Disease severity (COPD stage) was evaluated with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. The degree of obstruction and prognosis were determined by the Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index. We recruited 91 patients (50 females), with a mean age of 67.4 ± 8.7 years and a mean BMI of 25.8 ± 6.1 kg/m2. Sarcopenia was observed in 36 (39.6%) of the patients, with no differences related to gender, age, or smoking status. Sarcopenia was not associated with the GOLD stage or with FEV1 (used as an indicator of the degree of obstruction). The BMI, percentage of body fat, and total lean mass were lower in the patients with sarcopenia than in those without (p < 0.001). Sarcopenia was more prevalent among the patients in BODE quartile 3 or 4 than among those in BODE quartile 1 or 2 (p = 0.009). The multivariate analysis showed that the BODE quartile was significantly associated with sarcopenia, regardless of age, gender, smoking status, and GOLD stage. In COPD patients, sarcopenia appears to be associated with unfavorable changes in body composition and with a poor prognosis.


Population pharmacokinetics of piperaquine after two different treatment regimens with dihydroartemisinin-piperaquine in patients with Plasmodium falciparum malaria in Thailand.
The population pharmacokinetics of piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interindividual random variability on all parameters and were similar with the three- and four-dose regimens. Children had a lower body weight-normalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to piperaquine (area under the concentration-time curve from 0 to 63 days [AUC day 0-63]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUC day 3-20) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted piperaquine doses in children may need to be higher than in adults.


Professional attitudes to patient participation groups: an exploratory study.
An exploratory study of the development of patient participation groups in general practice and general practitioners' attitudes towards them suggests that many general practitioners may not yet be aware of this innovation and may at first react negatively to the idea. This response stems in part from misconceptions about the origins and functions of these groups, a failure to see their relevance to professional objectives, and a fear that they will threaten general practitioners' autonomy and status. In contrast, general practitioners who have formed groups believe they have an important contribution to make to their developing role and have been encouraged by their experience so far. Therefore, at present, patient participation groups should neither be rejected out of hand, nor welcomed as a panacea.


Correction for vascular artifacts in cerebral blood flow values measured by using arterial spin tagging techniques.
"Vascular" artifacts can have substantial effects on human cerebral blood flow values calculated by using arterial spin tagging approaches. One vascular artifact arises from the contribution of "tagged" arterial water spins to the observed change in brain water MR signal. This artifact can be reduced if large bipolar gradients are used to "crush" the MR signal from moving arterial water spins. A second vascular artifact arises from relaxation of "tagged" arterial blood during transit from the tagging plane to the capillary exchange site in the imaging slice. This artifact can be corrected if the arterial transit times are measured by using "dynamic" spin tagging approaches. The mean transit time from the tagging plane to capillary exchange sites in a gray matter region of interest was calculated to be approximately 0.94 s. Cerebral blood flow values calculated for seven normal volunteers agree reasonably well with values calculated by using radioactive tracer approaches.


What causes eyelid bags? Analysis of 114 consecutive patients.
The purpose of this study was to identify the anatomical basis for perception of lower eyelid bags in patients seeking aesthetic surgery and to evaluate the cumulative contribution of different anatomic characteristics before surgery. The histories and photographs of patients whose motivation for aesthetic consultation was lower eyelid bags were analyzed. Six categories of anatomic basis for the lower eyelid bags were identified. For each patient, a score from 0 to 4 was given in each category. The cumulative contribution score for each category was calculated as total points for that category for all patients, divided by the 456 total available points. The authors also developed a "uniqueness score" to reflect the percentage contribution of the worst identified anatomic problem compared with the other problems. This was calculated for each patient as the maximum score in one category, divided by total points for that patient. A total of 114 consecutive cases were evaluated (67 men and 47 women; mean age, 52 +/- 11 years; age range, 23 to 76 years). The cumulative contribution score for each anatomic variable was as follows: cheek descent and hollow tear trough, 52 percent; prolapse of orbital fat, 48; skin laxity and sun damage, 35; eyelid fluid, 32; orbicularis hyperactivity, 20; and triangular cheek festoon, 13. Prolapsed orbital fat and tear trough deformity both received the higher score and were more common in men as compared with women. The average uniqueness score was 38 percent, with a range of 20 to 75 percent. No one category played a dominant role for most patients. Tear trough depression, skin laxity, and triangular malar mound were significantly more common in patients older than 50 years. Linear regression analysis showed that recommendation for surgery is based on the extent of fat prolapse, skin elasticity, and midface descent. Significant positive correlations were found in all six categories and in uniqueness scores calculated by different observers (r values ranged from 0.31 to 0.73; p < 0.001, Pearson correlation), with the highest score in agreement with the contribution of eyelids fat (r = 0.73) and skin laxity (r = 0.66); the uniqueness score correlation was r = 0.45 (p < 0.001). Eyelid bags do not have a single anatomic basis. For different anatomic problems, different treatments are recommended.


CLINICAL AND MAGNETIC RESONANCE IMAGING FEATURES OF INFLAMMATORY VERSUS NEOPLASTIC MEDIAL RETROPHARYNGEAL LYMPH NODE MASS LESIONS IN DOGS AND CATS.
Medial retropharyngeal lymph node (MRLN) mass lesions are a common cause of cranial cervical masses in dogs and cats, and are predominantly due to metastatic neoplasia, primary neoplasia, or inflammatory lymphadenitis. The purpose of this retrospective cross-sectional study was to test the hypothesis that clinical and magnetic resonance imaging (MRI) characteristics for dogs and cats with MRLN mass lesions would differ for inflammatory vs. neoplastic etiologies. Dogs and cats with MRLN mass lesions that had undergone MRI and had a confirmed cytological or histopathological diagnosis were recruited from medical record archives. Clinical findings were recorded by one observer and MRI characteristics were recorded by two other observers who were unaware of clinical findings. A total of 31 patients were sampled, with 15 in the inflammatory lymphadenitis group and 16 in the neoplasia group. Patients with inflammatory lymphadenitis were more likely to be younger and present with lethargy (P = 0.001), pyrexia (P = 0.000), and neck pain (P = 0.006). Patients with inflammatory lymphadenitis were also more likely to have a leukocystosis (P = 0.02) and segmental neutrophilia (P = 0.001). Inflammatory masses were more likely to have moderate or marked MRI perinodal contrast enhancement (P = 0.021) and local muscle contrast enhancement (P = 0.03) whereas the neoplastic masses were more likely to have greater MRI width (P = 0.002) and height (P = 0.009). In conclusion, findings indicated that some clinical and MRI characteristics differed for dogs and cats with inflammatory vs. neoplastic medial retropharyngeal lymph node masses. Although histopathological or cytological diagnosis remains necessary for confirmation, these findings may help with the ranking of differential diagnoses of future cases.


The effect of combined supplementation of carbohydrates and creatine on anaerobic performance.
The purpose of the study was to examine the effect of creatine (Cr) supplementation on anaerobic performance when ingesting creatine and carbohydrates (CHO) together. Twenty male physical education students comprised the two experimental (CR and CRCHO) and one control (CON) groups of the study. All groups performed three 30 s anaerobic Wingate tests (AWTs) interspersed with 6 minutes of recovery. The CR group (n = 7) ingested 5 g of Cr 5 times per day for 4 days. Subjects in the CRCHO group (n = 6) ingested the same quantity but additionally after each 5 g dose of Cr consumed 500 ml of a commercially available energy drink containing 100 g of simple sugars. Over all three AWTs average mean power improved significantly compared to baseline for the CR group (5.51%) but not for the CRCHO group (3.06%). Mean power for the second AWT was improved following the acute loading for the CR group only (4.54%) and for the third AWT for both CR (8.49%) and CRCHO (5.75%) groups. Over all three AWTs a significant change was recorded in average peak power following the acute loading for the CR group (8.26%) but not for the CRCHO group (4.11%). Peak power was significantly improved following the loading only for the CR group during the third AWT (19.79%). No changes in AWT performance were recorded for the CON group after intervention. The findings of the present study suggest that ingesting creatine together with carbohydrates will not further improve performance compared to the ingestion of creatine only.


A hierarchical spectral clustering and nonlinear dimensionality reduction scheme for detection of prostate cancer from magnetic resonance spectroscopy (MRS).
Magnetic resonance spectroscopy (MRS) has been shown to have great clinical potential as a supplement to magnetic resonance imaging in the detection of prostate cancer (CaP). MRS provides functional information in the form of changes in the relative concentration of specific metabolites including choline, creatine, and citrate which can be used to identify potential areas of CaP. With a view to assisting radiologists in interpretation and analysis of MRS data, some researchers have begun to develop computer-aided detection (CAD) schemes for CaP identification from spectroscopy. Most of these schemes have been centered on identifying and integrating the area under metabolite peaks which is then used to compute relative metabolite ratios. However, manual identification of metabolite peaks on the MR spectra, and especially via CAD, is a challenging problem due to low signal-to-noise ratio, baseline irregularity, peak overlap, and peak distortion. In this article the authors present a novel CAD scheme that integrates nonlinear dimensionality reduction (NLDR) with an unsupervised hierarchical clustering algorithm to automatically identify suspicious regions on the prostate using MRS and hence avoids the need to explicitly identify metabolite peaks. The methodology comprises two stages. In stage 1, a hierarchical spectral clustering algorithm is used to distinguish between extracapsular and prostatic spectra in order to localize the region of interest (ROI) corresponding to the prostate. Once the prostate ROI is localized, in stage 2, a NLDR scheme, in conjunction with a replicated clustering algorithm, is used to automatically discriminate between three classes of spectra (normal appearing, suspicious appearing, and indeterminate). The methodology was quantitatively and qualitatively evaluated on a total of 18 1.5 T in vivo prostate T2-weighted (w) and MRS studies obtained from the multisite, multi-institutional American College of Radiology (ACRIN) trial. In the absence of the precise ground truth for CaP extent on the MR imaging for most of the ACRIN studies, probabilistic quantitative metrics were defined based on partial knowledge on the quadrant location and size of the tumor. The scheme, when evaluated against this partial ground truth, was found to have a CaP detection sensitivity of 89.33% and specificity of 79.79%. The results obtained from randomized threefold and fivefold cross validation suggest that the NLDR based clustering scheme has a higher CaP detection accuracy compared to such commonly used MRS analysis schemes as z score and PCA. In addition, the scheme was found to be robust to changes in system parameters. For 6 of the 18 studies an expert radiologist laboriously labeled each of the individual spectra according to a five point scale, with 1/2 representing spectra that the expert considered normal and 3/4/5 being spectra the expert deemed suspicious. When evaluated on these expert annotated datasets, the CAD system yielded an average sensitivity (cluster corresponding to suspicious spectra being identified as the CaP class) and specificity of 81.39% and 64.71%, respectively.


Second allogeneic marrow transplantation for patients with recurrent leukemia after initial transplant with total-body irradiation-containing regimens.
The impact of a second marrow transplant on long-term disease-free survival (DFS) was evaluated for 77 consecutive patients aged 2 to 51 years who relapsed subsequent to allogeneic marrow transplantation after high-dose chemotherapy and total-body irradiation (TBI). Patients received a second transplant for recurrent chronic myelogenous leukemia (CML) (n = 28), acute myelogenous leukemia (AML) (n = 32), and acute lymphoblastic leukemia (ALL) (n = 15) or lymphoma (n = 2) that used the same marrow donor as the initial transplant. High-dose chemotherapy of busulfan (BU) and cyclophosphamide (CY), or CY, carmustine (BCNU), and etoposide (VP-16), was used as a preparative regimen for the second transplant. Graft-versus-host disease (GVHD) prophylaxis consisted of the following: no prophylaxis (n = 8), T-cell depletion (n = 36), methotrexate (MTX) only (n = 21), cyclosporine (CSP) only (n = 1), MTX and CSP (n = 9), or anti-thymocyte globulin (ATG) and prednisone (n = 2). Engraftment occurred in the 74 assessable patients. Severe veno-occlusive disease (VOD) was the most frequent cause of grades 3 and 4 regimen-related toxicity (RRT); it occurred in 20 patients. The probability of death before day 100 from nonleukemic causes was 36%. The probability of relapse after second transplant was 70%, and the DFS rate was 14% (median DFS, 36 months; range, 22 to 87). The DFS rates for ALL, AML, and CML were 8%, 10%, and 25%, respectively. Multivariate analysis showed that the risk of relapse was inversely associated with acute GVHD (relative risk [RR] of relapse = 0.2; P = .0009). No other factor was associated with relapse. DFS was associated with the presence of acute GVHD (RR of treatment failure = 0.5; P = .0085), and a reduction of DFS was associated with severe VOD (RR = 10.6; P = .0001) and those patients older than 10 years (RR = 2.5; P = .0337). These data show that some patients may benefit from a second marrow transplant for recurrent leukemia after an initial marrow transplant. Younger patients and patients with CML especially should be considered as potential candidates for a second transplant.


Pituitary volumes of the patients with borderline personality disorder are not changed.
Although it has important relationships with psychiatric symptoms via the hypothalamic-pituitary-adrenal axis, there have been limited investigations of pituitary neuroimaging in psychiatric disorder. Moreover, there have been no studies of borderline personality disorder. In the present investigation, we examined pituitary gland volumes in patients with borderline personality disorder. Seventeen right-handed female patients with borderline personality disorder, selected among the patients who had presented to Firat University School of Medicine Department of Psychiatry outpatient and inpatient clinics, and the same number of healthy control subjects were included in the present investigation. Pituitary gland volumes were manually detected. The results demonstrated that the mean volumes of the gland of the patients with borderline personality disorder were not significantly different than those of healthy control subjects (mean volume of 0.79 cm3 in the patient group, with a value of SD±0.11 and 0.81 cm3 in the healthy control group, with a value of SD±0.23; t=-0.21; p>0.05).


The calcium activation of gelsolin: insights from the 3A structure of the G4-G6/actin complex.
Gelsolin participates in the reorganization of the actin cytoskeleton that is required during such phenomena as cell movement, cytokinesis, and apoptosis. It consists of six structurally similar domains, G1-G6, which are arranged at resting intracellular levels of calcium ion so as to obscure the three actin-binding surfaces. Elevation of Ca(2+) concentrations releases latches within the constrained structure and produces large shifts in the relative positioning of the domains, permitting gelsolin to bind to and sever actin filaments. How Ca(2+) is able to activate gelsolin has been a major question concerning the function of this protein. We present the improved structure of the C-terminal half of gelsolin bound to monomeric actin at 3.0 A resolution. Two classes of Ca(2+)-binding site are evident on gelsolin: type 1 sites share coordination of Ca(2+) with actin, while type 2 sites are wholly contained within gelsolin. This structure of the complex reveals the locations of two novel metal ion-binding sites in domains G5 and G6, respectively. We identify both as type 2 sites. The absolute conservation of the type 2 calcium-ligating residues across the six domains of gelsolin suggests that this site exists in each of the domains. In total, gelsolin has the potential to bind eight calcium ions, two type 1 and six type 2. The function of the type 2 sites is to facilitate structural rearrangements within gelsolin as part of the activation and actin-binding and severing processes. We propose the novel type 2 site in G6 to be the critical site that initiates overall activation of gelsolin by releasing the tail latch that locks calcium-free gelsolin in a conformation unable to bind actin.


Peri-implant bone length changes and survival rates of implants penetrating the sinus membrane at the posterior maxilla in patients with limited vertical bone height.
The aim of this study was to measure the peri-implant bone length surrounding implants that penetrate the sinus membrane at the posterior maxilla and to evaluate the survival rate of these implants. Treatment records and orthopantomographs of 39 patients were reviewed and analyzed. The patients had partial edentulism at the posterior maxilla and limited vertical bone height below the maxillary sinus. Implants were inserted into the posterior maxilla, penetrating the sinus membrane. Four months after implant insertion, provisional resin restorations were temporarily cemented to the abutments and used for one month. Then, a final impression was taken at the abutment level, and final cement-retained restorations were delivered with mutually protected occlusion. The complications from the implant surgery were examined, the number of failed implants was counted, and the survival rate was calculated. The peri-implant bone lengths were measured using radiographs. The changes in initial and final peri-implant bone lengths were statistically analyzed. Nasal bleeding occurred after implant surgery in three patients. No other complications were found. There were no failures of the investigated implants, resulting in a survival rate of 100%. Significantly more bone gain around the implants (estimated difference=-0.6 mm, P=0.025) occurred when the initial residual bone height was less than 5 mm compared to the >5 mm groups. No significant change in peri-implant bone length was detected when the initial residual bone height was 5 mm or larger. This study suggests that implants penetrating the sinus membrane at the posterior maxilla in patients with limited vertical bone height may be safe and functional.


Analysis of a novel VHS107 haplotype in CLA-2 and WSA mice. Evidence for gene conversion among IgVH genes in outbred populations.
Gene conversion has been suggested as the basis for many VH allelic differences, particularly in the murine VHS107 family. Whether conversion among IgVH genes is likely to have occurred in outbred populations has not been directly addressed. The CLA-2/Cn and WSA strains, which were recently and independently derived from a feral population exhibiting low responsiveness to PC, provide the opportunity to approach this question. In previous studies, the heavy chain cDNA sequence of a PC-specific hybridoma derived from CLA-2/Cn suggested gene conversion events within the VHS107 family. Accordingly, we have examined the germline VHS107 genes of CLA-2/Cn and WSA. The results indicate that: (a) The CLA-2 and WSA strains bear an identical but novel VHS107 family haplotype, which lacks a V3 element and contains a V1, a V13, and two V11 genes; (b) low PC responsiveness in these populations is unlikely due to an inability to express the V1 member of the VHS107 gene family; and (c) when compared with the other known VHS107 haplotypes, the proportion of differences consistent with gene conversion greatly exceeds that expected by random base substitution. Thus, gene conversion events appear to have occurred with considerable frequency in the evolution of the murine VHS107 family, especially among the V3, V13, and V11 members.


Use of echocardiographic pulmonary acceleration time and estimated vascular resistance for the evaluation of possible pulmonary hypertension.
During ultrasound examination, tricuspid regurgitation may be absent or gives a signal that is not reliable for the estimation of systolic pulmonary pressure. The aim of this study was to evaluate the usefulness of acceleration time (AT) from the right ventricular outflow tract (RVOT) as an estimation of the trans-tricuspid valve gradient (TTVG) and to investigate the correlation between estimated and invasive pulmonary vascular resistance (PVR). The AT was correlated to the TTVG measured with routine standard echocardiography in 121 patients. In a subgroup of 29 patients, systolic pulmonary pressure (SPAP) and mean pulmonary arterial pressure (MPAP) were obtained from recent right heart catheterization (RHC). We found no significant correlation between the estimation of right atrial pressure (RAP) by echocardiography and the RAP obtained by RHC. Estimated SPAP (TTGV + RAP mean from RHC) showed a good linear relation to invasively measured SPAP. TTVG and AT showed a non-linear relation, similar to SPAP and MPAP measured by catheterization and AT. For detection of SPAP above 38 mmHg a cut-off for AT of 100 ms resulted in a sensitivity of 89% and a specificity of 84%. For detection of MPAP above 25 mmHg a cut-off for AT of 100 ms resulted in similar sensitivity and specificity. Invasive PVR and the ratio of TTVG and the time velocity integral of the RVOT (TVI (RVOT) ) had a strong linear relation. Our study confirms that AT appears to be useful for the evaluation of pulmonary hypertension. In high risk patients, an AT of less than 100 ms indicates a high probability of pulmonary hypertension. Furthermore, PVR estimation by ultrasound seems preferably be done by using the ratio of TTVG and TVI RVOT.


Intended and unintended consequences of abortion law reform: perspectives of abortion experts in Victoria, Australia.
In Victoria, Australia, abortion was decriminalised in October 2008, bringing the law in line with clinical practice and community attitudes. We describe how experts in abortion service provision perceived the intent and subsequent impact of the 2008 Victorian abortion law reform. Experts in abortion provision in Victoria were recruited for a qualitative semi-structured interview about the 2008 law reform and its perceived impact, until saturation was reached. Nineteen experts from a range of health care settings and geographic locations were interviewed in 2014/2015. Thematic analysis was conducted to summarise participants' views. Abortion law reform, while a positive event, was perceived to have changed little about the provision of abortion. The views of participants can be categorised into: (1) goals that law reform was intended to address and that have been achieved; (2) intent or hopes of law reform that have not been achieved; (3) unintended consequences; (4) coincidences; and (5) unfinished business. All agreed that law reform had repositioned abortion as a health rather than legal issue, had shifted the power in decision making from doctors to women, and had increased clarity and safety for doctors. However, all described outstanding concerns; limited public provision of surgical abortion; reduced access to abortion after 20 weeks; ongoing stigma; lack of a state-wide strategy for equitable abortion provision; and an unsustainable workforce. Law reform, while positive, has failed to address a number of significant issues in abortion service provision, and may have even resulted in a 'lull' in action.


Impact of the European paediatric legislation in paediatric rheumatology: past, present and future.
Conducting clinical trials in paediatric rheumatology has been difficult mainly because of the lack of funding for academic studies and the lack of interest by pharmaceutical companies in the small and non-rewarding paediatric market. The situation changed dramatically a few years ago with the introduction of the Best Pharmaceuticals for Children Act in the USA and of specific legislation for the development of paediatric medicines (Paediatric Regulation) in the European Union (EU). The EU Paediatric Regulation had a positive impact in paediatric rheumatology-in particular, on the development of new treatments for children with juvenile idiopathic arthritis (JIA). Some problems remain, however, such as greater harmonisation of the regulatory aspects of medicines, how to handle me-too agents, how to conduct adequate pharmacokinetic studies and develop age-appropriate formulations, ethical problems in study review and implementation, and a change in the current JIA classification. The introduction of specific legislation, coupled with the existence of large international networks such as the Pediatric Rheumatology Collaborative Study Group (PRCSG at http://www.prcsg.org), covering North America, and the Paediatric Rheumatology International Trials Organisation (PRINTO at http://www.printo.it), covering more than 50 countries, has led to great advances in paediatric rheumatology. Future changes might increase the possibility of conducting trials with similar approaches in other paediatric rheumatological conditions and provide evidence-based treatments for children affected by rheumatic diseases.


Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy.
Hepatitis C virus (HCV) is a major global health burden accounting for around 170 million chronic infections worldwide. Since its discovery, which dates back to about 30 years ago, many details of the viral genome organization and the astonishing genetic diversity have been unveiled but, owing to the difficulty of culturing HCV in vitro and obtaining fully susceptible yet immunocompetent in vivo models, we are still a long way from the full comprehension of viral life cycle, host cell pathways facilitating or counteracting infection, pathogenetic mechanisms in vivo, and host defences. Here, we illustrate the viral life cycle into cells, describe the interplay between immune and genetic host factors shaping the course of infection, and provide details of the molecular approaches currently used to genotype, monitor replication in vivo, and study the emergence of drug-resistant viral variants.


Vertically Oriented and Interpenetrating CuSe Nanosheet Films with Open Channels for Flexible All-Solid-State Supercapacitors.
As a p-type multifunctional semiconductor, CuSe nanostructures show great promise in optoelectronic, sensing, and photocatalytic fields. Although great progress has been achieved, controllable synthesis of CuSe nanosheets (NSs) with a desirable spacial orientation and open frameworks remains a challenge, and their use in supercapacitors (SCs) has not been explored. Herein, a highly vertically oriented and interpenetrating CuSe NS film with open channels is deposited on an Au-coated polyethylene terephthalate substrate. Such CuSe NS films exhibit high specific capacitance (209 F g-1) and can be used as a carbon black- and binder-free electrode to construct flexible, symmetric all-solid-state SCs, using polyvinyl alcohol-LiCl gel as the solid electrolyte. A device fabricated with such CuSe NS films exhibits high volumetric specific capacitance (30.17 mF cm-3), good cycling stability, excellent flexibility, and desirable mechanical stability. The excellent performance of such devices results from the vertically oriented and interpenetrating configuration of CuSe NS building blocks, which can increase the available surface and facilitate the diffusion of electrolyte ions. Moreover, as a prototype for application, three such solid devices in series can be used to light up a red light-emitting diode.


Requirement of the 5'-end genomic sequence as an upstream cis-acting element for coronavirus subgenomic mRNA transcription.
We have developed a defective interfering (DI) RNA containing a chloramphenicol acetyltransferase reporter gene, placed behind an intergenic sequence, for studying subgenomic mRNA transcription of mouse hepatitis virus (MHV), a prototype coronavirus. Using this system, we have identified the sequence requirement for MHV subgenomic mRNA transcription. We show that this sequence requirement differs from that for RNA replication. In addition to the previously identified requirement for an intergenic (promoter) sequence, additional sequences from the 5' end of genomic RNA are required for subgenomic mRNA transcription. These upstream sequences include the leader RNA and a spacer sequence between the leader and intergenic sequence, which is derived from the 5' untranslated region and part of gene 1. The spacer sequence requirement is specific, since only the sequence derived from the 5' end of RNA genome, but not from other MHV genomic regions or heterologous sequences, could initiate subgenomic transcription from the intergenic sequence. These results strongly suggest that the wild-type viral subgenomic mRNAs (mRNA2 to mRNA7) and probably their counterpart subgenomic negative-sense RNAs cannot be utilized for mRNA amplification. Furthermore, we have demonstrated that a partial leader sequence present at the 5' end of genome, which lacks the leader-mRNA fusion sequence, could still support subgenomic mRNA transcription. In this case, the leader sequences of the subgenomic transcripts were derived exclusively from the wild-type helper virus, indicating that the MHV leader RNA initiates in trans subgenomic mRNA transcription. Thus, the leader sequence can enhance subgenomic transcription even when it cannot serve as a primer for mRNA synthesis. These results taken together suggest that the 5'-end leader sequence of MHV not only provides a trans-acting primer for mRNA initiation but also serves as a cis-acting element required for the transcription of subgenomic mRNAs. The identification of an upstream cis-acting element for MHV subgenomic mRNA synthesis defines a novel sequence requirement for regulating mRNA synthesis in RNA viruses.


Expressed emotion of families and the course of mood disorders: a cohort study in Japan.
Findings on expressed emotion (EE) of the family and the course of mood disorders have not been consistent. There has also been no report on these problems from Asia. The subjects were 32 patients diagnosed to have mood disorders on the basis of DSM-IV and ICD-10 and 36 principal members of their families. EE was evaluated using Camberwell Family Interview (CFI). A cohort study was conducted for 9 months after discharge of the patients. The patients were divided into a high-EE group and a low-EE group using a few cut-off points concerning the number of critical comments (CCs) and emotional over-involvement (EOI), the 9-month relapse risks were compared, and the relapse risk ratio and its 95% confidence interval were calculated. Also, the sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and the optimal cut-off point was evaluated. Multiple logistic regression analysis was performed to control the effects of potential confounding factors. When the subjects with three or more CCs, or an EOI score of three or higher were regarded as a high-EE group, and the others as a low-EE group, the nine-month relapse risks were 83.3% (5/6) and 19.2% (5/26), respectively, and the relapse risk ratio (95% confidence interval) was 4.3 (1.8-12.2). The values of the validity parameters were the highest with these cut-off points. The effect of EE was also significant on multiple logistic regression analysis. Small sample size and severity of the patients. Families' EE based on CFI correlated with relapse also in Japan.


Confirmation the optimal aeration parameters for nitrogen removal and nitrous oxide emission in wastewater ecological soil infiltration systems with brown earth.
Nitrogen removal is an obstacle for the wide application of wastewater ecological soil infiltration (WESI) system in domestic wastewater treatment. In this study, matrix dissolved oxygen (DO), nitrogen removal and nitrous oxide (N2O) emission in aerated pilot WESI systems were investigated under different aeration times (1, 2, 3, 4 and 6 h/d) and aeration rates (1, 2, 3 and 4 L/min). The results showed that aerobic conditions in upper matrix and anoxic or anaerobic conditions in the subsequent matrix were developed in an aerated/non-aerated cycle at the optimal aeration condition of aeration time of 4 h/d and aeration rate of 3 L/min. Simultaneously, high removal efficiency of chemical oxygen demand (COD) (97.9%), NH4 +-N (98.2%), total nitrogen (TN) (90.7%) and low N2O emission rate (13.2 mg/(m2 d)) were obtained. The results would provide optimal aeration parameters for application of intermittent aerated WESI systems.


Effectiveness of acupoint pressure on older people with constipation in nursing homes: a double-blind quasi-experimental study.
Aims: To compare the differences between acupoint pressure, abdominal massage and laxatives in treatment of constipation for residents in two nursing homes.Background: There is lack of evidence on the utility of complementary therapies in the management of constipation among older adults.Design: Quasi-experimental.Methods: A total of 90 participants from two nursing homes in Taiwan were assigned to three groups: the control group (with laxatives only), group I (with laxatives and abdominal massage) and group II (with laxatives, acupoint pressure therapy [APT] and abdominal massage). The intervention was performed over 10 days. A double-blind technique was applied in both participants and the outcome assessors. Constipation as main outcome was evaluated and recorded for 10 days. Observation of the frequency of defecation and the consistency, particularly firmness of faeces over each 24 h' period was recorded. The Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) checklist was utilised in reporting methods and findings.Results: Three variations were revealed as interface factors and showed significant differences in each group. The results showed a statistically significant decrease in constipation in the experimental groups I and II. The scores of defecation frequency, difficulty degree and time of defecation, stool quality and awareness of defecation were obviously improved after treatment.Conclusions: We concluded APT could be used in conjunction with laxatives and must be considered as a long-term intervention. The combination of APT, abdominal massage and laxatives is superior to both abdominal massage with laxatives and laxatives alone.Relevance to clinical practice: Acupoint pressure as an effective complementary therapy of constipation among older adults living in nursing home provides a non-pharmacological, independent nursing intervention that nurses could use. This is relevant to nursing home settings where nurses make autonomous decision on important clinical assessments and interventions.


Late Fusion Incomplete Multi-View Clustering.
Incomplete multi-view clustering optimally integrates a group of pre-specified incomplete views to improve clustering performance. Among various excellent solutions, multiple kernel $k$k-means with incomplete kernels forms a benchmark, which redefines the incomplete multi-view clustering as a joint optimization problem where the imputation and clustering are alternatively performed until convergence. However, the comparatively intensive computational and storage complexities preclude it from practical applications. To address these issues, we propose Late Fusion Incomplete Multi-view Clustering (LF-IMVC) which effectively and efficiently integrates the incomplete clustering matrices generated by incomplete views. Specifically, our algorithm jointly learns a consensus clustering matrix, imputes each incomplete base matrix, and optimizes the corresponding permutation matrices. We develop a three-step iterative algorithm to solve the resultant optimization problem with linear computational complexity and theoretically prove its convergence. Further, we conduct comprehensive experiments to study the proposed LF-IMVC in terms of clustering accuracy, running time, advantages of late fusion multi-view clustering, evolution of the learned consensus clustering matrix, parameter sensitivity and convergence. As indicated, our algorithm significantly and consistently outperforms some state-of-the-art algorithms with much less running time and memory.


The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors.
The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) seems almost inevitable, even in patients with lung cancer that initially respond well to EGFR-TKIs. MET amplification was recently found to be a mechanism of escape from the anticancer effect of EGFR inhibitors. In the present study, we investigated the means whereby MET affects sensitivity to EGFR-TKIs in PC-9 cells. Gefitinib- or erlotinib-resistant sublines were established by exposing the parental PC-9 cell line to chronic, repeated treatments with these drugs. These resistant sublines showed more than 100-fold more resistance to gefitinib and erlotinib and acquired cross-resistance to other EGFR-TKIs. The T790M EGFR mutation was found by pyrosequencing, and this seemed to be the cause of drug resistance. Resistant cells also showed MET activation, although gene amplification was not detected. Furthermore, the induction of MET activity was not found to be associated with sensitivity to EGFR-TKIs. Interestingly, increased passage number without exposure to gefitinib or erlotinib caused MET activation, but this did not affect sensitivity to EGFR-TKIs. In addition, hepatocyte growth factor was found to block the ability of EGFR-TKIs to inhibit MET activation. However, sustained MET activation by hepatocyte growth factor did not modulate the cellular effects of gefitinib or erlotinib. Rather, activated MET enhanced migration and invasion abilities. Summarizing, MET activation may be acquired during cancer cell proliferation and enhances migratory and invasive abilities without affecting cellular sensitivity to EGFR-TKIs. Accordingly, the present study suggests that MET activation caused by factors other than MET gene amplification is not a suitable surrogate marker of resistance to EGFR-TKIs.


Engineered Living Materials Based on Adhesin-Mediated Trapping of Programmable Cells.
Engineered living materials have the potential for wide-ranging applications such as biosensing and treatment of diseases. Programmable cells provide the functional basis for living materials; however, their release into the environment raises numerous biosafety concerns. Current designs that limit the release of genetically engineered cells typically involve the fabrication of multilayer hybrid materials with submicrometer porous matrices. Nevertheless the stringent physical barriers limit the diffusion of macromolecules and therefore the repertoire of molecules available for actuation in response to communication signals between cells and their environment. Here, we engineer a novel living material entitled "Platform for Adhesin-mediated Trapping of Cells in Hydrogels" (PATCH). This technology is based on engineered E. coli that displays an adhesion protein derived from an Antarctic bacterium with a high affinity for glucose. The adhesin stably anchors E. coli in dextran-based hydrogels with large pore diameters (10-100 μm) and reduces the leakage of bacteria into the environment by up to 100-fold. As an application of PATCH, we engineered E. coli to secrete the bacteriocin lysostaphin which specifically kills Staphyloccocus aureus with low probability of raising antibiotic resistance. We demonstrated that living materials containing this lysostaphin-secreting E. coli inhibit the growth of S. aureus, including the strain resistant to methicillin (MRSA). Our tunable platform allows stable integration of programmable cells in dextran-based hydrogels without compromising free diffusion of macromolecules and could have potential applications in biotechnology and biomedicine.


Aspirin, nonsteroidal anti-inflammatory drugs, acetaminophen, and pancreatic cancer risk: a clinic-based case-control study.
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) show indisputable promise as cancer chemoprevention agents. However, studies have been inconsistent as to whether aspirin has a protective effect in development of pancreatic cancer. To further evaluate the association between aspirin, NSAID, and acetaminophen use with pancreatic cancer risk, we used a clinic-based case-control study of 904 rapidly ascertained histologically or clinically documented pancreatic ductal adenocarcinoma cases, and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from April 2004 to September 2010. Overall, there is no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreatic cancer. Aspirin use for 1 d/mo or greater was associated with a significantly decreased risk of pancreatic cancer (OR = 0.74, 95% CI: 0.60-0.91, P = 0.005) compared with never or less than 1 d/mo. Analysis by frequency and frequency-dosage of use categories showed reduced risk (P = 0.007 and 0.022, respectively). This inverse association was also found for those who took low-dose aspirin for heart disease prevention (OR = 0.67, 95% CI: 0.49-0.92, P = 0.013). In subgroup analyses, the association between aspirin use and pancreatic cancer was not significantly affected by pancreatic cancer stage, smoking status, or body mass index. Our data suggest that aspirin use, but not non-aspirin NSAID use, is associated with lowered risk of developing pancreatic cancer.


Functionally distinct isoforms of the CRE-BP DNA-binding protein mediate activity of a T-cell-specific enhancer.
Expression of the CD3 delta gene of the T-cell receptor (TCR) complex is regulated by a T-cell-specific enhancer. A highly conserved 40-bp motif (element delta A) within the CD3 delta enhancer is responsible for mediating its activity and specificity. Element delta A exhibits sequence similarities to the cyclic AMP response element (CRE) but does not respond to changes in the level of cyclic AMP. Using the delta A element as a probe, we have isolated three cDNA clones encoding three distinct protein isoforms, products of differential splicing and alternate promoter usage of the CRE-BP gene. These isoforms share the DNA binding and dimerization domains at the C terminus of the protein but differ at their N termini. In transfection assays, their activities as transcription regulators differ: CRE-BP2 is a potent activator, CRE-BP3 is a weak activator, and CRE-BP1 is transcriptionally inert. Mutations in the basic region of the CRE-BP1 protein which abrogate its ability to bind DNA render this protein a dominant repressor of the delta A enhancer. Antibodies to the CRE-BP protein interact specifically with the ubiquitous and predominantly T-cell-restricted nuclear complexes that bind to the delta A element and suggest the presence of this protein in homo- and heterodimeric complexes. Since the delta A motif is also present in the enhancer and promoter of the TCR alpha and beta genes, the CRE-BP isoforms may mediate expression of other members of the CD3/TCR complex during T-cell development.


The difference in autonomic denervation and its effect on atrial fibrillation recurrence between the standard segmental and circumferential pulmonary vein isolation techniques.
This study examined the difference in autonomic modification (AM) and its effect on paroxysmal atrial fibrillation (PAF) recurrence between segmental pulmonary vein isolation (S-PVI) and circumferential PVI (C-PVI). Successful S-PVI or C-PVI with a basket catheter was achieved in 120 consecutive PAF patients. Serial 24 Holter-recordings were obtained before, immediately, and 1, 3, 6, 12 months after the PVI to analyse the heart rate variability (HRV). Nineteen patients were excluded from analysis because of additional ablation for recurrent PAF after successful PVI. Among the residual 101 patients, 33 had PAF recurrences (S-PVI = 44.0%, C-PVI = 21.6%) at 1 year of follow-up. The root mean square of successive differences and high-frequency power reflecting parasympathetic nervous activity were significantly lower in patients with and without PAF recurrences after C-PVI and patients without PAF recurrences after S-PVI than patients with PAF recurrences after S-PVI (P < 0.005-0.0001). However, there were no significant differences in any HRV parameters in the immediate aftermath of PVI among the patients without PAF recurrences after S-PVI and those with and without PAF recurrences after C-PVI. Although additional radiofrequency ablation for AM may be recommended after S-PVI to reduce PAF recurrences, it should be carefully determined after C-PVI.


Cooperation, virulence and siderophore production in bacterial parasites.
Kin selection theory predicts that the damage to a host resulting from parasite infection (parasite virulence) will be negatively correlated to the relatedness between parasites within the host. This occurs because a lower relatedness leads to greater competition for host resources, which favours rapid growth to achieve greater relative success within the host, and that higher parasite growth rate leads to higher virulence. We show that a biological feature of bacterial infections can lead to the opposite prediction: a positive correlation between relatedness and virulence. This occurs because a high relatedness can favour greater (cooperative) production of molecules that scavenge iron (siderophores), which results in higher growth rates and virulence. More generally, the same underlying idea can predict a positive relationship between relatedness and virulence in any case where parasites can cooperate to increase their growth rate; other examples include immune suppression and the production of biofilms to aid colonization.


Clinical outcomes of 201 neonates born to mothers with COVID-19: a systematic review.
To evaluate the clinical manifestations and outcomes of neonates born to women who had Coronavirus Disease 2019 (COVID-19) during pregnancy. A systematic literature search was conducted on PubMed and Embase till April 15, 2020, by combining the terms (COVID-19, Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2, Novel Coronavirus, 2019-nCov, Wuhan pneumonia) and (pregnancy, pregnant women, mother, fetus, neonate, newborn, infant). We included 16 case series and 12 case reports describing a total of 223 pregnant women and 201 infants. Four newborns born to mothers affected by COVID-19 were reported to have laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection within 48 hours after birth. However, Reverse Transcription-Polymerase Chain Reaction tests of the breast milk, placenta, amniotic fluids, and cord blood and maternal vaginal secretions were all negative for SARS-CoV-2 in the reported cases. Fetal death was reported in two cases, and 48 of 185 newborns (25.9%) were born prematurely. Infants born small for gestational age and low birth weight (< 2,500 g) accounted for 8.3% and 15.6% of reported cases, respectively. Birth asphyxia and respiratory distress syndrome were observed in 1.8% and 6.4% of neonates, respectively. There was one neonatal death due to intractable gastric bleeding among the SARS-CoV-2-negative infants. Current evidence suggests that COVID-19 during pregnancy rarely affects fetal and neonatal mortality, but can be associated with adverse neonatal morbidities. Vertical transmission has not been observed in the majority of the reported cases. The infants born to mothers with COVID-19 are carefully monitored for accompanying complication, and quarantine of infected mothers is warranted.


Hemodialysis facility-based quality-of-care indicators and facility-specific patient outcomes.
We evaluated whether incremental achievement of up to 8 facility quality goals was associated with improvement in facility-specific mortality and hospitalization rates. Prospective observational study. 1,085 Fresenius Medical Care, North America facilities providing hemodialysis (HD) for 25 or more patients during January 2006. The facility average for the period up to December 31, 2006, was used to determine achievement of each goal for equilibrated Kt/V, missed HD treatments, hemoglobin level, bicarbonate level, albumin level, phosphorus level, fistulae, and HD catheters. Linear regression models were used to relate facility-wide achievement of goals with facility-specific hospital days and standardized mortality ratios. Most facilities (64%) achieved 2 to 4 of 8 goals, with only 8% meeting more than 5 quality goals. Achieving more than 5 goals averaged 3.5 fewer hospital days/patient-year and 20% lower standardized mortality ratios (all P < 0.001). The incremental number of goals met also was associated with improvement in facility mortality (P < 0.001) and hospital days (P < 0.001). Catheter and albumin level goals were achieved least (6% and 9% of facilities, respectively), but they had the best outcomes. Facilities achieving more than 5 goals had older patients (64.0 versus 61.5 years; P < 0.001), fewer African American patients (16% versus 38%; P < 0.001), and fewer women (44% versus 46%; P = 0.003) compared with the average. Observational design with residual confounding from unmeasured patient-, facility-, and treatment-related factors. Achieving more facility quality goals was significantly associated with better facility-based measurements of patient outcomes. Although these results do not establish a causal relationship, findings agree with the present practice of monitoring facility performance for continuous quality improvement.


Scientific Evidence in Health Technology Assessment Reports: An In-Depth Analysis of European Assessments on High-Risk Medical Devices.
The aim of this study was to examine the scientific evidence on clinical effectiveness and safety used in health technology assessments (HTAs) of high-risk medical devices (MDs) in Europe. We applied a systematic approach to identify European institutions involved in HTA and to select reports assessing MDs considered high-risk according to the definition in the new German health care regulation §137h. Reports published between 2010 and 2015 were considered in our subsequent analysis. We used a structured tool based on widely accepted methodologic principles from Drummond's framework to extract key information on the clinical evidence considered in the reports. Out of 1376 identified reports, 93 were eligible for analysis. All reports based their assessment primarily on direct evidence, in most cases (68%) identified through an independent systematic literature search. In more than half the identified studies considered in the reports, clinical evidence for demonstration of effectiveness and safety was of moderate or low quality. Even when systematic reviews and randomized controlled trials were available for assessment, most studies showed an unclear or high risk of bias. This study confirms that the quality of scientific evidence used in HTA of high-risk MDs is low and therefore the use of evidence needs improvement. The European Commission recently updated the regulation on MDs but mainly focused on the safety of materials and the CE (Conformité Européene [European Conformity]) mark. Our results show that additional changes are necessary, specifically with regard to the marketing authorization process of MDs, with stricter quality requirements based on methodologically robust trials, possibly in combination with other evidence sources.


Targeted and shotgun metagenomic approaches provide different descriptions of dryland soil microbial communities in a manipulated field study.
The extent to which different sequence-based approaches describe environmental microbial communities in comparative studies is an important consideration when deriving inferences from ecological studies. The ability of a targeted metagenomic approach [small subunit (SSU) rRNA pyrosequencing] and shotgun metagenome approaches were compared to identify distinguishing features in dryland soil microbial communities from two different habitats: biological soil crusts (biocrusts) and creosote bush root zones. A parallel comparison was conducted to determine the ability of each approach to detect community differences potentially arising from a more subtle experimental treatment, long-term elevated atmospheric carbon dioxide. As expected, the biocrust datasets were clearly differentiated from root zone datasets using either of the sequencing approaches. However, the composition described by each approach was significantly different. The magnitude of comparative differences due to habitat or elevated CO2 treatment was larger with pyrosequenced SSU datasets or SSU reads recruited from shotgun metagenomes, than from SEED-classified shotgun metagenome reads. Finally, based on prior knowledge of the biocrust communities, the SSU-based datasets more accurately identified the dominant biocrust cyanobacteria sequences compared to the shotgun metagenome datasets.


[Strategies for measuring medication adherence in patients with schizophrenia].
Long-term therapy should be administrated for patients with schizophrenia and the medication adherence is very important for the prognosis and outcome in these patients. In this study, we screened the literatures from various databases in accordance with our search criteria. A total of 11 literatures with the results of reliability and validity regarding the measurement of schizophrenia medication adherence were enrolled in our analysis. Based on the measurements, they were classified into subjective methods and objective ones. The objective methods include blood plasma and urine concentrations, pharmacy records, pill counts and Medication Event Monitoring System. The subjective methods include Drug Attitude Inventory, Rating of Medication Influences Scale, Brief Evaluation of Medication Influences and Beliefs, the Brief Adherence Rating Scale, Medication Adherence Rating Scale, and Morisky scales. In general, single method for measuring medication adherence in patients with schizophrenia is limited. We recommend researchers to use 2 or more methods when measuring the medication adherence in patients with schizophrenia.


The rare and the common: scale and the genetic imaginary in Alzheimer's disease drug development.
In this paper I examine how the promissory value of genetics is constituted through processes of scale and scaling, focussing on the relationship between "rare" and "common" forms of disease. I highlight the bodies and spaces involved in the production of post-genomic knowledge and technologies of Alzheimer's disease and the development of new disease-modifying drugs. I focus on the example of the development of a monoclonal antibody therapy for Alzheimer's disease. I argue that the process of therapeutic innovation, from genetic studies and animal models to phase III clinical trials, reflects the persistent importance of a genetic imaginary and a mutually constitutive relationship between the rare and the common in in shaping visions of Alzheimer's disease medicine. Approaching this relationship as a question of scale, I suggest the importance of attending to how and where genomic knowledge is "scaled" or proves resistant to scaling.


Existence of early-onset NIDDM Japanese demonstrating severe diabetic complications.
To identify the clinical characteristics of early-onset NIDDM patients with severe diabetic complications. The clinical cases of a large number of diabetic patients who visited a diabetes center within the period 1970-1990 were reviewed. Of a total of 16,842 diabetic patients, 1,065 (6.3%) had early-onset NIDDM (diabetes diagnosed before 30 years of age). These 1,065 patients were divided into two groups, those who developed proliferative retinopathy before the age of 35 (n = 135) and those who did not (n = 930). Development of proliferative retinopathy, nephropathy, renal failure, blindness, and atherosclerotic vascular disease were compared between the two groups. The subgroup of 135 patients was characterized by poor glycemic control, often requiring insulin therapy and a higher familial prevalence of diabetes, and contained a greater proportion of women than the subgroup of 930 patients. Of the 135 patients, 99 (67%) developed proliferative retinopathy before the first visit. The 135 patients developed severe progressive complications in contrast to the 930 patients. A total of 81 patients (60%) developed diabetic nephropathy at a mean age of 31 years, 31 (23%) developed renal failure requiring dialysis at a mean age of 35 years, 32 (24%) became blind at a mean age of 32 years, and 14 (10%) developed atherosclerotic vascular disease at a mean age of 36 years. Some Japanese early-onset NIDDM patients develop severe diabetic complications in their youth. Most of them had no symptoms nor regular treatment regarding diabetes until they were noticed to have developed severe diabetic complications. Although the relevant prevalence and the pathogenetic mechanism underlying the rapid onset of the complications remain to be determined, prolonged inadequate treatment of and familial predisposition to diabetes may be contributing factors. Careful diabetes care in the twenties, not only for IDDM but also for NIDDM patients, is warranted.


Intercellular adhesion molecule 1 is critical for activation of CD28-deficient T cells.
Presentation of Ag to T lymphocytes in the absence of the requisite costimulatory signals leads to an Ag-specific unresponsiveness termed anergy, whereas Ag presentation in conjunction with costimulation leads to clonal expansion. B7/CD28 signaling has been shown to provide this critical costimulatory signal and blockade of this pathway may inhibit in vitro and in vivo immune responses. Although T cells from CD28-deficient mice are lacking in a variety of responses, they nonetheless are capable of various primary and secondary responses without the induction of anergy expected in the absence of costimulation. This suggests that there may be alternative costimulatory pathways that can replace CD28 signaling under certain circumstances. In this paper, we show that ICAM-1becomes a dominant costimulatory molecule for CD28-deficient T cells. ICAM-1 costimulates anti-CD3-mediated T cell proliferation and IL-2 secretion in CD28-deficient murine T cells. Furthermore, splenocytes from ICAM-1-deficient mice could not activate CD28-deficient T cells and splenocytes lacking both ICAM and CD28 fail to proliferate in response to anti-CD3-induced T cell signals. This confirms that not only can ICAM-1 act as a CD28-independent costimulator, but it is the dominant, requisite costimulatory molecule for the activation of T cells in the absence of B7/CD28 costimulation.


Total hip replacement for coxarthrosis secondary to congenital dysplasia and dislocation of the hip. Long-term results.
Between 1970 and 1982, sixty-six total hip replacements were performed with cement, without bone-grafting, in fifty-three patients who had congenital dysplasia and dislocation of the hip. Preoperatively, the patients had had Crowe type-II, III, or IV subluxation. Current information was available for fifty-nine hips in forty-six patients after an average duration of follow-up of sixteen years (range, ten to twenty-one years). The average age of the patients at the time of the operation was fifty-three years (range, twenty-three to seventy-three years). The average Harris hip score at the most recent examination was 92 points (range, 61 to 100 points). Eight hips were revised. The reason for the revision was infection in two hips, fracture of the femoral stem in two, and loosening of the acetabular component in four. The rate of revision for aseptic loosening, therefore, was 10 per cent (six hips). In the unrevised hips for which radiographs were available, the rate of radiographic loosening of the femoral component was 5 per cent (two hips) and that of the acetabular component was 32 per cent (twelve hips). We did not find a relationship between the amount of horizontal or vertical displacement of the center of the femoral head and the rate of loosening. Kaplan-Meier survivorship analysis with revision as the end point predicted a rate of survival of 85 per cent (95 per cent confidence interval, 75 to 95 per cent) at fifteen years. With radiographic loosening as the end point, the predicted rate of survival was 68 per cent (95 per cent confidence interval, 54 to 81 per cent) at fifteen years. We concluded that, for patients who have Crowe type-II, III, or IV congenital dysplasia of the hip, good long-term results can be obtained with insertion of a femoral stem with cement. The high rate of loosening of cemented acetabular components is a concern.


Application of temporarily functional antibiotic-containing bone cement prosthesis in revision hip arthroplasty.
To investigate the clinical outcome of two-stage revision total hip arthroplasty for infected hip arthroplasty using antibiotic-impregnated cement prosthesis. Forty-one patients, who suffered from an infection after hip replacement or internal fixation of femoral neck and trochanteric fractures, were treated with a two-stage revision hip arthroplasty and followed up for an average of 37 months. All the patients were implanted with antibiotic-impregnated cement prosthesis as one-stage treatment and were then managed with two-stage revision hip arthroplasty after 12-24 weeks. During the follow-up, Merle d'Aubigné hip score and Harris score were employed for assessment of hip function, and infection recurrence was observed. According to Merle d'Aubigné hip score, 16 patients (39.2 %) were excellent, 19 (46.3 %) were good, 6 (14.6 %) were moderate, and no bad result and the average score was 15.42. Mean Harris score of preoperation, interval period, and postoperation was 46.7, 66.5, and 92.3, respectively. There was no infection recurrence. Two-stage revision total hip arthroplasty for infected hip arthroplasty using antibiotic-impregnated cement prosthesis has a satisfying clinical outcome.


The protease-activated receptor 2 regulates pigmentation via keratinocyte-melanocyte interactions.
Close association exists between melanocytes, the pigment melanin-producing cells in the body, and their neighboring keratinocytes. Keratinocytes are the pigment recipients and skin pigmentation is the result of this interaction. While the chemical basis of melanin production (melanogenesis) is well documented, the molecular mechanism of melanosome transfer needs to be elucidated. We are now providing first evidence that the protease-activated receptor 2 (PAR-2) expressed on keratinocytes, but not on melanocytes, is involved in melanosome transfer and therefore may regulate pigmentation. Activation of PAR-2 with trypsin or with the peptide agonist SLIGRL induced pigmentation in both two- and three-dimensional cocultures of keratinocytes and melanocytes, but not in cocultures that were spatially separated, indicating the need for intimate cell-cell contact. Topical application of SLIGRL on human skin transplanted on SCID mice resulted in a visible skin darkening. Histological examination revealed increased deposits of melanin in the keratinocytes. Inhibition of PAR-2 activation by RWJ-50353, a serine protease inhibitor, resulted in depigmentation and changes in expression of melanogenic-specific genes. Keratinocyte-melanocyte contact was essential for this depigmenting effect. Topical application of this inhibitor induced lightening of the dark skin Yucatan swine, which was confirmed by histochemical analysis. The results presented here suggest a novel mechanism for the regulation of pigmentation, mediated by the activation or inhibition of the keratinocyte receptor PAR-2.