Effect of 24,25(OH)2D3 on PTH levels and bone histology in dogs with chronic uremia.
Controversy exists as to whether 24,25(OH)2D3 has a direct inhibitory effect on parathyroid hormone (PTH) secretion. Therefore, the present investigation examined the effect of long-term administration of 24,25(OH)2D3 on immunoassayable PTH levels (iPTH) and bone histology in dogs with chronic renal failure. Chronic renal failure was produced in 16 dogs, half of which served as controls whereas the other half received 2.5 micrograms/day of 24,25(OH)2D3, orally. Serum iPTH, serum total, ionized calcium, serum phosphorus, and creatinine were followed at weekly or biweekly intervals in both groups. Also, creatinine clearances, serum levels of 25(OH)D3, 24,25(OH)2D3, and 1,25(OD)2D3 and the intestinal absorption of calcium were measured. After 1 year of chronic renal failure the dogs were sacrificed and rib biopsy specimens were obtained for histological examination and measurement of mineral content. Serum iPTH increased equally in the two dog groups with no effect at any time of 24,25(OH)2D3 treatment, despite a significant increase in the serum levels of 24,25(OH)2D3 and a concomitant decrease of the 1,25(OH)2D3 levels. There was no difference in the levels of serum calcium or in the calcium content of bone. Furthermore, after 8 months of uremia three control dogs were switched to the group treated with 24,25(OH)2D3 and followed for another 7 months. No suppressive effect of administering 24,25(OH)2D3 on the iPTH levels could be demonstrated in these three dogs.(ABSTRACT TRUNCATED AT 250 WORDS)


Solid phase synthesis of gastrin I. Comparison of methods utilizing strong acid for deprotection and cleavage.
A successful synthesis of human gastrin I in 60% overall yield based on the first residue attached to a benzhydrylamine-resin was achieved by the stepwise solidphase method. The synthesis was carried out on a 1% crosslinked polystyrene support, using conventional benzyl-based side chain protecting groups and final deprotection with different acidic protocols. Several improvements in this general approach were applied, including new scavengers, new resin attachment and especially a new technique that allows the strong acid reactions to occur by an SN2 mechanism.


Individual and mixtures of metal exposures in associations with biomarkers of oxidative stress and global DNA methylation among pregnant women.
Prenatal exposure to metals has been linked with adverse pregnancy outcomes. Oxidative stress and epigenetic changes are potential mechanisms of action. We aimed to examine the associations of individual and mixtures of metal exposures with oxidative stress and DNA methylation among pregnant women. We measured a panel of 16 metals and 3 oxidative stress biomarkers including 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) and 8-isoprostaglandin F2α (8-isoPGF2α) in urine from 113 pregnant women in a Chinese cohort. Biomarkers of global DNA methylation including Alu and long interspersed nucleotide element-1 (LINE-1) in cord blood were measured. Multivariable linear regression and Bayesian kernel machine regression (BKMR) models were separately applied to estimate the associations between individual and mixtures of metal exposures and biomarkers of oxidative stress and global DNA methylation. In single-metal analyses, we observed positive associations between 11 metals [arsenic (As), cadmium (Cd), thallium (Tl), barium (Ba), nickel (Ni), vanadium (V), cobalt (Co), zinc (Zn), copper (Cu), selenium (Se) and molybdenum (Mo)] and at least one of oxidative stress biomarkers (all FDR-adjusted P-values < 0.05). In mixture analyses, we found positive overall associations of metal mixtures with 8-OHdG and 8-isoPGF2α, and Se was the most important predictor. There was no evidence on associations of urinary metals as individual chemicals and mixtures with Alu and LINE-1 methylation. Urinary metals as individual chemicals and mixtures were associated with increased oxidative stress, especially Se.


Long-term survival of breast cancer patients with brain metastases: subanalysis of the BMBC registry.
Up to 30% of metastatic breast cancer (BC) patients develop brain metastases (BM). Prognosis of patients with BM is poor and long-term survival is rare. Identification of factors associated with long-term survival is important for improving treatment modalities. A total of 2889 patients of the national registry for BM in BC (BMBC) were available for this analysis. Long-term survival was defined as overall survival (OS) in the upper third of the failure curve resulting in a cut-off of 15 months. A total of 887 patients were categorized as long-term survivors. Long-term survivors compared to other patients were younger at BC and BM diagnosis (median 48 versus 54 years and 53 versus 59 years), more often had HER2-positive tumors (59.1% versus 36.3%), less frequently luminal-like (29.1% versus 35.7%) or triple-negative breast cancer (TNBC) (11.9% versus 28.1%), showed better Eastern Cooperative Oncology Group (ECOG) performance status (PS) at the time of BM diagnosis (ECOG 0-1, 76.9% versus 51.0%), higher pathological complete remission rates after neoadjuvant chemotherapy (21.6% versus 13.7%) and lower number of BM (n = 1, BM 40.9% versus 25.4%; n = 2-3, BM 26.5% versus 26.7%; n ≥4, BM 32.6% versus 47.9%) (P < 0.001). Long-term survivors had leptomeningeal metastases (10.4% versus 17.5%) and extracranial metastases (ECM, 73.6% versus 82.5%) less frequently, and asymptomatic BM more often at the time of BM diagnosis (26.5% versus 20.1%), (P < 0.001). Median OS in long-term survivors was about two times higher than the cut-off of 15 months: 30.9 months [interquartile range (IQR) 30.3] overall, 33.9 months (IQR 37.1) in HER2-positive, 26.9 months (IQR 22.0) in luminal-like and 26.5 months (IQR 18.2) in TNBC patients. In our analysis, long-term survival of BC patients with BM was associated with better ECOG PS, younger age, HER2-positive subtype, lower number of BM and less extended visceral metastases. Patients with these clinical features might be more eligible for extended local brain and systemic treatment.


Use of Digital Health Resources by Sexual and Gender Minority Caregivers of Older Adults: Findings From the 2020 Caregiving in the U.S. Survey.
We applied Andersen's Behavioral Model of Health Services Use to investigate the health needs and use of digital health resources among sexual and/or gender minority (SGM) caregivers. Data were from the Caregiving in the U.S. 2020 survey. Regression analyses were used to describe associations between predisposing, enabling, and need factors and usage of digital health resources. SGM caregivers provided more hours of care per week, reported higher levels of care intensity, and reported higher physical, emotional, and financial strain compared with non-SGM caregivers. Regression analyses indicated SGM status was a significant predictor of overall use of digital health resources. Younger caregivers, racial minority caregivers, those providing higher levels of care, and those reporting a poorer health status were more likely to use digital health resources. Digital health resources may be useful tools for SGM caregivers of older adults. More research is needed to investigate the reasons SGM caregivers use these resources.


[Origin of tissue basophils and basophilic granulocytes of the blood].
The paper deals with analysis of modern literature on origin of basophils and basophilic blood granulocytes. Data of radioimmunologic, electron-microscopic, cytochemical and morphological studies make it possible to conclude that these cells are of bonemarrow origin.


Determination of plutonium in feces and urine.
A method was developed for the determination of plutonium (239Pu, 238Pu, etc.) in feces and urine excreted by persons for 24 h. Plutonium is successively separated from inorganic macrocomponents present in samples and from other alpha emitters by the help of coprecipitation with BiPO4, LaF3 and extraction with TTA. After separation, the electrodeposition of plutonium on stainless-steel discs can be carried out. The chemical yields of separation of plutonium are about 80%.


Long-term Survival After Heart Transplantation: A Population-based Nested Case-Control Study.
Heart transplantation is the mainstay of treatment for patients in end-stage heart failure. This study sought to contrast survival after transplantation with that of the general population to quantify standardized mortality rates using a nested case-control study design. Control subjects were noninstitutionalized inhabitants of the United States identified through the National Longitudinal Mortality study. Case subjects were adults who underwent heart transplantation between 1990 and 2007 and identified through the Organ Procurement and Transplantation Network. Propensity-matching (5:1, nearest neighbor, caliper = 0.1) was utilized to identify suitable control subjects based on age, sex, race, and state of permanent residency. The primary study endpoint was 10-year survival. In all, 31,883 heart transplant recipients were matched to 159,415 noninstitutionalized residents of the United States. The 10-year survival of heart transplant recipients was 53%. The population expected mortality rate was 15.9 deaths per 100 person-years with an observed rate of 45.1 deaths per 100 person-years (standardized mortality rate [SMR] 2.84; 95% confidence interval, 2.82 to 2.87). The broadest gaps between observed and expected survival were evident in female (SMR 3.63), black (SMR 3.67), and Hispanic (SMR 4.12) recipients. Standardized mortality ratios declined over time (1990 to 1995, 3.09; 1996 to 2000, 2.90; 2001 to 2007, 2.58). The long-term standardized survival of older recipients was closest to that expected for their age. Heart transplant recipients have considerable long-term survival and have a threefold higher standardized long-term mortality rate than that of the noninstitutionalized population. Long-term mortality rates have consistently declined over time and will likely continue to decrease.


Buccofacial apraxia without aphasia due to a right parietal lesion.
Buccofacial praxis in right-handers is thought to be mediated by the left hemisphere. We present the case of a right-handed man without family history of sinistrality who exhibited a buccofacial apraxia following a unilateral right parietal infarction. Other findings such as intact language, visuospatial impairment, and hemi-inattention are more characteristic of right posterior lesions.


Pu-erh tea ameliorates obesity and modulates gut microbiota in high fat diet fed mice.
Obesity is regarded to be associated with fat accumulation, chronic inflammation, and gut microbiota dysbiosis. Raw and ripened pu-erh tea extract (PETe) have the effect of reducing body weight gain and fat accumulation, which are associated with gut microbiota. However, little is known about the difference of raw and ripened PETe on the regulation of gut microbiota. Here, our results suggested that supplementation of raw and ripened PETe displayed similar anti-obesogenic effect in high fat diet (HFD)-induced obesity mice, by attenuating the body weight gain, fat accumulation, oxidative injury, and low-grade inflammation, improving the glucose tolerance, alleviating the metabolic endotoxemia, and regulating the mRNA and protein expression levels of the lipid metabolism-related genes. 16S rRNA sequencing of fecal samples indicated that raw and ripened PETe intervention displayed different regulatory effect on the HFD-induced gut microbiota dysbiosis at different taxonomic levels. The microbial diversity, the relative abundance of Firmicutes and Bacteroidetes as well as F/B ratio were reversed more closer to normal by ripened PETe. Phylotypes of Bacteroidaceae, Ruminococcaceae, Lachnospiraceae, Muribaculaceae, and Rikenellaceae which are negatively correlated with obesity were enhanced notably by the intervention of ripened PETe, while Erysipelotrichaceae and Lactobacillaceae which have positive correlation with obesity were decreased dramatically. In addition, the treatment of ripened PETe had better effect on the increase of benefical Bacteroides, Alistipes, and Akkemansia and decrease of obesity associated Faecalibaculum and Erysipelatoclostridium (p < 0.05). These findings suggested that pu-erh tea especially ripened pu-erh tea could serve as a great candidate for alleviation of obesity in association with the modulation of gut microbiota.


Loss of Nexmif results in the expression of phenotypic variability and loss of genomic integrity.
We identified two NEXMIF variants in two unrelated individuals with non-autoimmune diabetes and autistic traits, and investigated the expression of Nexmif in mouse and human pancreas and its function in pancreatic beta cells in vitro and in vivo. In insulin-secreting INS-1E cells, Nexmif expression increased strongly in response to oxidative stress. CRISPR Cas9-generated Nexmif knockout mice exhibited a reduced number of proliferating beta cells in pancreatic islets. RNA sequencing of pancreatic islets showed that the downregulated genes in Nexmif mutant islets are involved in stress response and the deposition of epigenetic marks. They include H3f3b, encoding histone H3.3, which is associated with the regulation of beta-cell proliferation and maintains genomic integrity by silencing transposable elements, particularly LINE1 elements. LINE1 activity has been associated with autism and neurodevelopmental disorders in which patients share characteristics with NEXMIF patients, and can cause genomic instability and genetic variation through retrotransposition. Nexmif knockout mice exhibited various other phenotypes. Mortality and phenotypic abnormalities increased in each generation in both Nexmif mutant and non-mutant littermates. In Nexmif mutant mice, LINE1 element expression was upregulated in the pancreas, brain, and testis, possibly inducing genomic instability in Nexmif mutant mice and causing phenotypic variability in their progeny.


Utstein-style audit of Protocol C: a non-standard resuscitation protocol for healthcare professionals.
International guidelines for basic life support and defibrillation are identical for lay people and healthcare professionals. In 2002, a small meeting hosted by the Resuscitation Council (UK) debated recent advances in resuscitation science, along with the possibility of more demanding procedures for treating out of hospital cardiac arrest (OHCA) that could take advantage of the expertise available with professional use. The resulting algorithm known as Protocol C could not be tested in a randomized trial for reasons relating to consent, but was introduced by one ambulance service as an observational study. Results from a 2-year period from one city within the service area are presented, using the Utstein style of reporting to show the recommended 'comparator' group whilst also providing epidemiological data on the frequency of cardiac arrest within the community and the outcome of all resuscitation attempts. Manual methods were used to collect data from 2009 and 2010 for cases of cardiac arrest treated by crews from the two ambulance stations within the city of Brighton and Hove. All transported patients were tracked individually through the hospital because no official method of data linkage is available. Outcome data were obtained for survival to hospital discharge, or to 30 days for the few who remained in hospital care for that duration. In the epidemiological analysis, 454 patients with OHCA were treated over 2 years, of whom 151 (33%) had sustained return of spontaneous circulation (ROSC) at hospital handover and 59 (13%) survived to discharge or for 30 days. Within the 'comparator' group of 79 patients, 47 (59%) achieved sustained ROSC to hospital handover and 24 (30%) survived. The use of Protocol C has been associated with rates of sustained ROSC to hospital and of survival to discharge that have reached the range of international best practice. The improvement noted in this observational study cannot be ascribed to the new protocol alone; any wider use should await randomized trials to test the impact of this single variable. Meanwhile, wider adoption of the Utstein system to compare results for treatment of OHCA will provide a potent stimulus for emergency services to seek ways of improving outcome.


Effects of Weight Loss on Obstructive Sleep Apnea Severity. Ten-Year Results of the Sleep AHEAD Study.
Rationale: Weight loss is recommended to treat obstructive sleep apnea (OSA).Objectives: To determine whether the initial benefit of intensive lifestyle intervention (ILI) for weight loss on OSA severity is maintained at 10 years.Methods: Ten-year follow-up polysomnograms of 134 of 264 adults in Sleep AHEAD (Action for Health in Diabetes) with overweight/obesity, type 2 diabetes mellitus, and OSA were randomized to ILI for weight loss or diabetes support and education (DSE).Measurements and Main Results: Change in apnea-hypopnea index (AHI) was measured. Mean ± SE weight losses of ILI participants of 10.7 ± 0.7, 7.4 ± 0.7, 5.1 ± 0.7, and 7.1 ± 0.8 kg at 1, 2, 4, and 10 years, respectively, were significantly greater than the 1-kg weight loss at 1, 2, and 4 years and 3.5 ± 0.8 kg weight loss at 10 years for the DSE group (P values ≤ 0.0001). AHI was lower with ILI than DSE by 9.7, 8.0, and 7.9 events/h at 1, 2, and 4 years, respectively (P values ≤ 0.0004), and 4.0 events/h at 10 years (P = 0.109). Change in AHI over time was related to amount of weight loss, baseline AHI, visit year (P values < 0.0001), and intervention independent of weight change (P = 0.01). OSA remission at 10 years was more common with ILI (34.4%) than DSE (22.2%).Conclusions: Participants with OSA and type 2 diabetes mellitus receiving ILI for weight loss had reduced OSA severity at 10 years. No difference in OSA severity was present between ILI and DSE groups at 10 years. Improvement in OSA severity over the 10-year period with ILI was related to change in body weight, baseline AHI, and intervention independent of weight change.


Global prevalence of congenital hypothyroidism among neonates from 1969 to 2020: a systematic review and meta-analysis.
Little is known about the global prevalence of congenital hypothyroidism (CH), though it is known to vary across countries and time periods. This meta-analysis aims to estimate the global and regional prevalence of CH among births between 1969 and 2020. PubMed, Web of Sciences, and Embase databases were searched for relevant studies between January 1, 1975, and March 2, 2020. Pooled prevalence was calculated using a generalized linear mixed model, and expressed as a rate per 10,000 neonates. The meta-analysis involved 116 studies, which analyzed 330,210,785 neonates, among whom 174,543 were diagnosed with CH. The pooled global prevalence of CH from 1969 to 2020 was 4.25 (95% confidence interval (CI) 3.96-4.57). The geographic region with highest prevalence was the Eastern Mediterranean (7.91, 95% CI 6.09-10.26), where the prevalence was 2.48-fold (95% CI 2.04-3.01) that in Europe. The national income level with the highest prevalence was upper-middle (6.76, 95% CI 5.66-8.06), which was 1.91-fold (95% CI 1.65-2.22) that in high-income countries. Global prevalence of CH was 52% (95% CI 4-122%) higher in 2011-2020 than in 1969-1980, after adjusting for geographic region, national income level, and screening strategy. Conclusion: The global prevalence of CH increased from 1969 to 2020, which may reflect the implementation of national neonatal screening, neonatal testing for thyroid-stimulating hormone, and a lowering of the diagnostic level of this hormone. Additional factors are likely to be driving the increase, which should be identified in future research. What is Known: • Cumulated evidence had suggested that the occurrences of congenital hypothyroidism (CH) among newborns were varied in different countries.. • Up-trends of the birth prevalence of CH were observed in many European and American countries. What is New: • This is the first meta-analysis to estimate global and regional prevalence of CH among newborns. • The global prevalence of CH has increased by 127% since 1969. The Eastern Mediterranean has the highest prevalence and stands out with the most pronounced escalation in the prevalence of CH.


Epigenetic Dysregulations in Arsenic-Induced Carcinogenesis.
Arsenic is a crucial environmental metalloid whose high toxicity levels negatively impact human health. It poses significant health concerns to millions of people in developed and developing countries such as the USA, Canada, Bangladesh, India, China, and Mexico by enhancing sensitivity to various types of diseases, including cancers. However, how arsenic causes changes in gene expression that results in heinous conditions remains elusive. One of the proposed essential mechanisms that still has seen limited research with regard to causing disease upon arsenic exposure is the dysregulation of epigenetic components. In this review, we have extensively summarized current discoveries in arsenic-induced epigenetic modifications in carcinogenesis and angiogenesis. Importantly, we highlight the possible mechanisms underlying epigenetic reprogramming through arsenic exposure that cause changes in cell signaling and dysfunctions of different epigenetic elements.


The spectrophotometric study of the binding of vitamin E to water + dimethyl sulfoxide and water + diethyl sulfoxide containing reversed micelles.
The effect of dimethyl sulfoxide (DMSO) and its nearest homologue diethyl sulfoxide (DESO) as a polar cosolvents on the binding of vitamin E to water + DMSO (DESO) containing reversed micelles of sodium bis(2-ethylhexyl) sulfosuccinate (AOT) has been investigated by a spectrophotometric method. The results suggest that compare with water without organic cosolvent-containing reversed micelles in this case an increase of binding constant of vitamin E in reversed micelles takes place. The results obtained shown that with the addition of DMSO and DESO it will be possible to monitoring a penetration of vitamin E into micellar core.


Ethnopharmacologic investigation on tropane-containing drugs in Chinese solanaceous plants.
The role of tropane-containing drugs derived from Solanaceae has long been recognized. This report deals with Chinese solanaceous plants, including historic, botanical, phytochemical, pharmacological and clinical aspects. Our investigation revealed that this kind of drug is constantly being confirmed to be of true therapeutic value; however, further studies are in order.


Use of activated carbons for detoxification of a lignocellulosic hydrolysate: Statistical optimisation.
In order to improve bioethanol production from hydrolysates from olive tree pruning residues the present study assessed a detoxification method using the same waste material. The objective was to develop optimal removal without diminishing fermentable sugars. A statistical optimisation study was performed for the production of activated carbons using the same olive tree pruning residue as raw material. The effect of the impregnation ratio, activation temperature and the time needed for maximum removal of the phenolic compounds was assayed. The conditions for maximum adsorption were as follows: 799.18 °C, IR 4.88 and 101.38 min of activation, removing 55%, 64% and 41% of total phenolic compounds, HMF and furfural, respectively. The activated carbon obtained under optimum conditions (Aop) was submitted to adsorption kinetics and equilibrium assays. Experimental kinetic data were well represented by a pseudo-first order kinetic and intraparticle diffusion model, which helped explain the adsorption mechanism. Experimental isotherms were analysed with Langmuir, Freundlich and Temkin models, and Langmuir best fitted the experimental data. Hydrolysate from olive tree pruning residues, detoxified with the optimum activated carbon, was fermented with a commercial Saccharomyces cerevisiae yeast, obtaining a 100% theoretical maximum ethanol yield and a 56% bioconversion of fermentable sugars.


BCG vaccine: an investigation of colony morphology from four different strains after their introduction as seed for vaccine preparation in four production laboratories.
Four collaborating BCG production laboratories had each prepared vaccine from four different BCG strains. In this laboratory the morphology of colonies cultured from samples of the 16 vaccine lots thus available was examined, and it was found that changes monitored in earlier small-scale experimental reconstructions had also occurred during some of the full-scale production procedures, in accordance with prediction. In particular, a minority population carried by the Danish BCG strain had replaced the original majority when this strain had been employed as seed for the production of vaccine by the British procedure. Similarly, a minority carried by the Japanese strain had replaced the original majority when this strain was introduced as seed into the production procedures in the United Kingdom and France. Serial subcultures made in this laboratory showed, in accordance with previous experience, that the changes that had occurred in the Japanese strain could be completely reversed by serial subculture as a surface pellicle on Sauton medium.


Radiofrequency thermoablation of the peripheral branches of trigeminal nerve versus the Gasserian ganglion for treating idiopathic trigeminal neuralgia: A systematic review and meta-analysis.
Trigeminal neuralgia is characterized by pain at the distribution of one or more of the trigeminal nerve branches and is usually treated with anti-epileptic medication. When first line treatment fails, patients receive other treatment modalities including radiofrequency thermoablation (RFT) of the Gasserian ganglion and peripheral branches of the trigeminal nerve. The aim of this study is to compare RFT of the Gasserian ganglion and peripheral branches of trigeminal nerve in terms of efficacy and rate of complications. This was a systematic review and meta-analysis that searched Medline, Cochrane Central Register of Controlled Trials, and Embase using Medical Subject Headings and the references of the enrolled studies with no restriction on date. We included only RCTs that compared the RFT of the Gasserian ganglion and peripheral branches of trigeminal nerve with one of the following outcomes: pain scales, immediate effective rate, recurrence rate, and complications. Five articles were eligible for our review and showed that there was no difference between RFT of the peripheral nerves and the Gasserian ganglion in terms of pain scores. There was a non-significant trend for RFT of the peripheral nerve to have higher immediate effect rates and higher recurrence rates. RFT of the Gasserian ganglion group was associated with masticatory weakness, while the other group was associated with facial swelling and numbness of V2. RFT of the peripheral branches is a safe and effective method to treat idiopathic trigeminal neuralgia but leads to a higher recurrence rate when compared with RFT of the Gasserian ganglion.


Mechanisms underlying the diabetes-induced hyporeactivity of the rabbit carotid artery to atrial natriuretic peptide.
Atrial natriuretic peptide (ANP) plays an important role in the pathophysiology of the vascular complications in diabetes. The working hypothesis was that diabetes might modify the vascular actions of ANP in isolated rabbit carotid arteries and the mechanisms involved in these actions. ANP (10(-12)-10(-7)M) induced a relaxation of precontracted carotid arteries, which was lower in diabetic than in control rabbits. In arteries from both groups of animals, endothelium removal increased the ANP-induced relaxation. Isatin inhibited the relaxation to ANP both in arteries with and without endothelium. Carotid arteries from diabetic rabbits showed a decreased natriuretic peptide receptor (NPR)-A expression and an enhanced NPR-C expression. Inhibition of NO-synthesis did not modify ANP-induced relaxation in control rabbits but inhibited it in diabetic rabbits. In arteries with endothelium indomethacin enhanced the relaxation to ANP in control rabbits but did not modify it in diabetic rabbits. In endothelium-denuded arteries indomethacin inhibited the relaxation to ANP in both groups of animals. In KCl-depolarised arteries, relaxation to ANP was almost abolished both in control and diabetic rabbits. Tetraethylammonium inhibited the relaxation to ANP, and this inhibition was higher in diabetic than in control rabbits. These results suggest that diabetes produces hyporeactivity of the rabbit carotid artery to ANP by a mechanism that at least includes a reduced expression of NPR-A, an enhanced expression of NPR-C and a reduced participation of K(+)-channels. Furthermore, diabetes enhances endothelial NO release and diminishes the ratio thromboxane A(2)/prostacyclin. This increase of vasodilators could result from compensatory mechanisms counteracting the arterial hyporeactivity to ANP.


[Possible surgical approaches to the orbit].
For removal of tumors and foreign bodies from the orbit, for treatment of severe inflammatory diseases, and for repositioning of bone fragments following fractures or during reconstruction of the bony orbit, several different surgical approaches are available. During the past decade, improved understanding of the pathology and pathophysiology of particular orbital diseases, advancements in clinical endoscopy and microscopy, the introduction of modern imaging techniques for preoperative visualization of pathologic findings, modern approaches to orbital reconstruction, as well as developments in adjuvant therapy have led to a reduction in invasiveness and development of the modern minimally invasive surgical approaches to the orbit usually used today. This review article aims to describe several surgical approaches to the orbit that are nowadays commonly applied-frequently in the context of interdisciplinary therapy-as well as their indications and potential complications. Particular attention is paid to minimally invasive approaches. These different surgical approaches allow a 360-degree exposure of the internal orbital structures with the optic nerve at the center ("round the clock access to the orbit"). The review is complemented by hints and tricks for particular approaches, as well as by a review of the latest literature in the field.


Nursing and medical students' experiences of interprofessional education during clinical training in psychiatry.
The aim of the study was to describe nursing and medical students' experiences of participation in an interprofessional education (IPE) activity, "round school," during their clinical rotations in psychiatric care. Data were collected in six focus groups with 32 students from nursing and medical programs, focusing on their experiences of the IPE activity and their reflections on interprofessional collaboration. The students considered the round school to be meaningful and true-to-life. Important conditions for learning were well-informed staff, sufficient time for preparation and feedback, clear routines, instructions, and an open climate. Non-explicit instructions and limited preunderstanding of psychiatric care left the students feeling uncertain. Students' reflections regarding interprofessional competences encompassed both similarities and differences in roles, responsibilities, and collaboration. Evidence of hierarchical and stereotypical images of the nurse-physician relationship was identified. Round school is an example of how IPE can be integrated into the units' regular ward rounds. However, if the clinical everyday work is not based on collaboration between different professions, it can be arduous to implement IPE. Well-planned preparations are necessary, both in the clinic and at the faculty.


Cognitive dysfunction and its clinical and radiological determinants in patients with symptomatic arterial disease and diabetes.
Both vascular disease and diabetes type 2 (DM2) decrease cognitive functioning in elderly people. It is uncertain if DM2 affects cognition independent of vascular disease. In patients with symptomatic arterial disease, we studied the effect of DM2 on cognition and identified clinical and radiological determinants for impaired cognition in patients with DM2. 766 patients (mean age 58.8+/-9.5 years; 108 DM2) with symptomatic arterial disease underwent neuropsychological testing. In 542 patients (77 DM2), volumes of brain tissue, ventricles and white matter lesions were obtained by segmentation of brain MR images. Infarcts were distinguished into small (lacunar) or large (cortical or subcortical). Patients with arterial disease and DM2 performed worse on neuropsychological tests compared to similar patients without DM2 (adjusted composite z-score: beta -0.14 [-0.25 to -0.02]). Insulin treatment, systolic and diastolic blood pressures were significantly associated with cognition in patients with DM2. Large infarcts, global and cortical atrophy on MRI were independently associated with cognition in patients with DM2. The presence of DM2 in patients with symptomatic arterial disease is associated with decreased cognitive functioning. Insulin treatment, high blood pressure, brain atrophy and large infarcts were determinants for cognitive dysfunction in patients with DM2 and arterial disease.


Capillary electrochromatography: theories on electroosmotic flow in porous media.
In view of the present interest in capillary electrochromatography (CEC), theories dealing with electroosmotic flow (EOF) in porous media are reviewed with particular regard to the use of packed capillaries in CEC. Two of the models found in the pertinent literature are applicable to CEC and give simple analytical solutions. The first of the two models is based on von Smoluchowski's work as adapted and extended by Overbeek. It deals with EOF through packed capillaries under conditions of low electric field strength where the EOF varies linearly with the field strength because there is no polarization of the double layer. Overbeek's model originally developed for porous media of infinite dimensions was modified in an attempt to account for the wall effect that assumes importance in the packed capillary columns used in CEC. The second model proposed by Dukhin and his coworkers predicts EOF of at least an order of magnitude higher than that expected by classical theories. This "electroosmosis of the second kind" is believed to occur in columns packed with conductive particles like ion exchangers at high electric field strengths when the double layer is polarized and the EOF becomes a non-linear function of the applied voltage. Conditions necessary for electroosmosis of the the second kind are likely to arise upon the further development of CEC when further enhancement of the speed of analysis is brought about at electric field strength higher than that employed at present.


Cloning and differential expression during the sexual cycle of a meiotic endonuclease-encoding gene from the basidiomycete Coprinus cinereus.
The naturally synchronous meiosis of the fungus, Coprinus cinereus, provides an ideal system for the investigation of differential gene expression in relation to meiosis and fruiting body development. We have cloned a cDNA from the fruiting body of C. cinereus encoding the 12-kDa subunit of a meiotic endonuclease (mENase). The identification of the 12-kDa subunit cDNA clone was achieved by the mENase antiserum against a lambda gt11 cDNA expression library. It was confirmed by a direct match of the amino acid (aa) sequence obtained from purified 12-kDa polypeptide with the nucleotide sequence. Northern blot analysis using the cDNA clone as a probe showed that the mENase-encoding gene (MenA) for the 12-kDa subunit was expressed mainly in fruiting bodies and at a very low level in the asexual vegetative mycelium. In addition, it was differentially expressed in the early meiotic stages. The MenA transcript was most abundant in fruiting body primordia prior to the premeiotic S-phase; it remained high from karyogamy to early pachytene, declined drastically by late pachytene and diplotene, and was undetectable by sterigma stage. Western blot analysis showed that the mENase protein was produced at a very low level in mycelium; it was produced in great quantity during the early meiotic stages and decreased to a low level at the end of meiosis.


Providing Oxygen during Intubation in the NICU Trial (POINT): study protocol for a randomised controlled trial in the neonatal intensive care unit in the USA.
Nearly half of neonatal intubations are complicated by severe desaturation (≥20% decline in pulse oximetry saturation (SpO2)). Apnoeic oxygenation prevents or delays desaturation during intubation in adults and older children. Emerging data show mixed results for apnoeic oxygenation using high-flow nasal cannula (NC) during neonatal intubation. The study objective is to determine among infants ≥28 weeks' corrected gestational age (cGA) who undergo intubation in the neonatal intensive care unit (NICU) whether apnoeic oxygenation with a regular low-flow NC, compared with standard of care (no additional respiratory support), reduces the magnitude of SpO2 decline during intubation. This is a multicentre, prospective, unblinded, pilot randomised controlled trial in infants ≥28 weeks' cGA who undergo premedicated (including paralytic) intubation in the NICU. The trial will recruit 120 infants, 10 in the run-in phase and 110 in the randomisation phase, at two tertiary care hospitals. Parental consent will be obtained for eligible patients prior to intubation. Patients will be randomised to 6 L NC 100% oxygen versus standard of care (no respiratory support) at time of intubation. The primary outcome is magnitude of oxygen desaturation during intubation. Secondary outcomes include additional efficacy, safety and feasibility outcomes. Ascertainment of the primary outcome is performed blinded to intervention arm. Intention-to-treat analyses will be conducted to compare outcomes between treatment arms. Two planned subgroup analyses will explore the influence of first provider intubation competence and patients' baseline lung disease using pre-intubation respiratory support as a proxy. The Institutional Review Boards at the Children's Hospital of Philadelphia and the University of Pennsylvania have approved the study. Upon completion of the trial, we intend to submit our primary results to a peer review forum after which we plan to publish our results in a peer-reviewed paediatric journal. ClinicalTrials.gov Registry (NCT05451953).


Acetate production by a coupled syntrophic acetogenesis with homoacetogenesis process: effect of sludge inoculum concentration.
The effect of sludge inoculum concentration on acetate (Ac) production by a novel coupled system was investigated. The coupled system consisted ofa syntrophic acetogenesis phase and a homoacetogenesis phase. The results showed that the inoculum concentration not only affected the acetate production at the syntrophic acetogenesis phase but also that produced at the homoacetogenesis phase. When the inoculum concentration in the syntrophic acetogenesis phase was 4 g l(-1), the acetate yield of the coupled system was found to be about 0.36 g Ac g(-1) glucose. In addition, when the inoculum concentration in the homoacetogenesis phase was 4 g l(-1), a maximum acetate production of 11.2 g l(-1) was obtained in the syntrophic acetogenesis phase and the yield of acetate was 0.39 g Ac g(-1) glucose. Analysis shows that the variation in acetate yield might be attributed to different metabolic pathways and the imbalance between hydrogen production and hydrogen consumption in the coupled system with different inoculum concentrations.


Functional analysis of the cDNA encoding human tyrosinase precursor.
The DNA segment harboring the promoter region and the exon 1 of the human tyrosinase gene has been cloned and characterized. Sequence analysis reveals the amino-terminal half of tyrosinase molecule including a signal peptide, of which six amino acid residues are not represented in the tyrosinase cDNA, pHT gamma 1 [Shibahara et al. (1988) Tohoku J. Exp. Med. 156, 403-414]. We therefore constructed the expression plasmid containing the human tyrosinase precursor cDNA, and introduced it into mouse amelanotic melanoma cells. Both tyrosine hydroxylase and dopa oxidase activities were expressed only in the cells transfected with such a full-length cDNA, providing direct evidence that tyrosinase actually possesses a dual catalytic activity.


Use of the Leeds-Keio prosthetic ligament for repair of patellar tendon rupture after total knee arthroplasty.
We describe a technique for repair of the patellar tendon rupture after total knee arthroplasty (TKA), using the Leeds-Keio (L-K) prosthetic ligament. Two patients were followed for a mean of 38 months. Knee extension power and improved function were obtained in both cases. Use of the L-K ligament is a treatment option for repair of patellar tendon rupture following TKA.


[Schistosomiasis and its prognostic significance in patients with colorectal cancer. National Cooperative Group on Pathology and Prognosis of Colorectal Cancer].
This paper analyses 430 cases of colorectal cancer complicated with schistosomiasis. The 5 year survival rate was 45.6%, lower than that without schistosomiasis. The lowered 5 year survival rate may have been associated with higher percentage of negative immune response in the regional lymph nodes and higher percentage of infiltrating growth pattern of the tumor. The infection of schistosome should be considered as one of the important factors in prognosis.


Relations Between Moso Bamboo Surface Properties Pretreated by Kraft Cooking and Dilute Acid with Enzymatic Digestibility.
Lignocellulosics pretreatment is intended to dismantle biomass' natural recalcitrance. Chemical and morphological changes of lignocellulosic materials would occur through varying pretreatment processes. In order to figure out why the acid-pretreated and Kraft-cooked bamboo residues showed very different enzymatic digestibility, the surface properties of pretreated bamboo residues were characterized in this work. It was found that analyzed surface properties were considered to be associating with each corresponding enzymatic digestibility of the pretreated samples. The zeta potentials of pretreated bamboo residues have a negative correlation with enzymatic efficiency. Kraft-cooked substrates were found to posse a less hydrophobic nature and demonstrated higher enzymatic conversion than substrates that were dilute sulfuric acid pretreated. The surface accessibility analysis (BET and Direct Red staining) revealed that the higher enzymatic efficiency of Kraft-cooked materials was mostly due to the larger cellulosic surface area than that in acid-pretreated materials. The results re-affirm that different pretreatments create a variety of surface characteristics, leading to the idea that pretreatment and enzymatic hydrolysis can be favorably turned to maximize carbohydrate recovery from bamboo residues.


Modulation of FLT3 signal transduction through cytoplasmic cysteine residues indicates the potential for redox regulation.
Oxidative modification of cysteine residues has been shown to regulate the activity of several protein-tyrosine kinases. We explored the possibility that Fms-like tyrosine kinase 3 (FLT3), a hematopoietic receptor-tyrosine kinase, is subject to this type of regulation. An underlying rationale was that the FLT3 gene is frequently mutated in Acute Myeloid Leukemia patients, and resulting oncogenic variants of FLT3 with 'internal tandem duplications (FLT3ITD)' drive production of reactive oxygen in leukemic cells. FLT3 was moderately activated by treatment of intact cells with hydrogen peroxide. Conversely, FLT3ITD signaling was attenuated by cell treatments with agents inhibiting formation of reactive oxygen species. FLT3 and FLT3ITD incorporated DCP-Bio1, a reagent specifically reacting with sulfenic acid residues. Mutation of FLT3ITD cysteines 695 and 790 reduced DCP-Bio1 incorporation, suggesting that these sites are subject to oxidative modification. Functional characterization of individual FLT3ITD cysteine-to-serine mutants of all 8 cytoplasmic cysteines revealed phenotypes in kinase activity, signal transduction and cell transformation. Replacement of cysteines 681, 694, 695, 807, 925, and 945 attenuated signaling and blocked FLT3ITD-mediated cell transformation, whereas mutation of cysteine 790 enhanced activity of both FLT3ITD and wild-type FLT3. These effects were not related to altered FLT3ITD dimerization, but likely caused by changed intramolecular interactions. The findings identify the functional relevance of all cytoplasmic FLT3ITD cysteines, and indicate the potential for redox regulation of this clinically important oncoprotein.


Characterization of proteins from the calcified matrix of atherosclerotic human aorta.
The nature of proteins occluded in the mineralized matrix of calcified areas of atherosclerotic human aortic tissue has been investigated. In spite of their reported presence in atherosclerotic lesions, neither plasma lipoproteins, immunoglobulin G or fibrinogen could be detected among the proteins specifically trapped in the mineralized matrix and released by decalcification. However, human serum albumin was present in the decalcifying extract in a persistent complex with a more acidic protein component. Also present in the decalcifying extract was an acidic protein component with a molecular weight between 6000 and 10000 which contained both serine phosphate and gamma-carboxyglutamic acid. This component closely resembled in amino acid composition the non-albumin moiety of the serum albumin complex, suggesting that this low molecular weight, gamma-carboxyglutamic acid-containing protein component was present in the calcified matrix both in the free form and in association with human serum albumin.


The association between spondylolisthesis and decreased muscle health throughout the lumbar spine for patients with operative lumbar spinal stenosis.
There are data underlining the relationship between muscle health and spine related pathology, but little data regarding changes in paralumbar muscle associated with lumbar spondylolisthesis. We aimed to define changes in paralumbar muscle health associated with spondylolisthesis. A retrospective review was performed on consecutive patients with lumbar spine pathology requiring an operation. A pre-operative lumbar MRI was analysed for muscle health measurements including lumbar indentation value (LIV), paralumbar cross-sectional area divided by body mass index (PL-CSA/BMI), and Goutallier classification of fatty atrophy. All measurements were taken from an axial slice of a T2-weighted image at lumbar disc spaces. Baseline health-related quality of life scores (HRQOLs), narcotic use and areas of stenosis were tracked. We performed Chi-square analyses and student's t test to determine statistically significant differences between cohorts. There were 307 patients (average age 56.1 ± 16.7 years, 141 females) included within our analysis. 112 patients had spondylolisthesis. There were no differences in baseline HRQOLs between the spondylolisthesis cohort (SC) and non-spondylolisthesis cohort (non-SC). There were significantly worse PL-CSA/BMI at L2-L3 (p = 0.03), L3-L4 (p = 0.04) and L4-L5 (p = 0.02) for the SC. Goutallier classification of paralumbar muscle was worse for SC at L1-L2 (p = 0.04) and at L4-L5 (p < 0.001). Increased grade of spondylolisthesis was associated with worse PL-CSA at L1-L2 (p = 0.02), L2-L3 (p = 0.03) and L3-L4 (p = 0.05). Similarly, there were worse Goutallier classification scores associated with higher-grade spondylolisthesis at all levels (p < 0.05). There are significant detrimental changes to paralumbar muscle health throughout the lumbar spine associated with spondylolisthesis.


[Experiences with an isolation method for retinal S-antigen and interphotoreceptor retinoid-binding protein].
S-antigen (AgS) and interphotoreceptor retinoid-binding protein (IRBP) are two highly potent uveitopathogenic autoantigens of the retina frequently used to trigger autoimmune uveitis in animal trials. The aim of this study was the simultaneous isolation of both proteins from bovine retina, additionally avoiding time-consuming dialysis and employing prepacked, commercially available cartridges. Retina extract, obtained in the usual manner, was precipitated with ammonium sulfate. Both the desalting and the buffer exchange of dissolved precipitate were carried out using a Bio-Gel P6 column. Subsequent separation with Econo-Pac Q gave prepurified AgS and IRBP fractions. Further purification was realized predominantly with Econo-Pac Q, -HTP and -HIC (5-ml cartridges). AgS and IRBP were isolated in high purity (sodium dodecylsulfate polyacrylamide gel electrophoresis, silver stain) from bovine retina using prepacked cartridges with yields of approximately 0.25 (for AgS) and 0.15 (for IRBP) mg/g retina, respectively. The application of ready-to-use cartridges allows simultaneous isolation of AgS and IRBP in milligram amounts under simplified conditions. This approach might be of particular interest for small samples of retina.


Comparison of esophageal screen findings on videofluoroscopy with full esophagram results.
Videofluoroscopic swallowing studies do not routinely obtain images of the esophagus. We incorporated a single esophageal screening swallow into our videofluoroscopic swallowing study protocol. The purpose of this study was to compare findings from "esophageal screening" with the results of full esophagram. Patients undergoing videofluoroscopic swallowing studies with an esophageal screen followed by full esophagram between January 1, 2009, and October 1, 2009, were retrospectively reviewed. Comparison of esophageal screening and esophagram results were undertaken, with esophagram used as the gold standard. Seventy-four patients underwent esophageal screening and esophagram. Sensitivity of esophageal screening is 63% (CI 50%-73%); specificity is 100% (CI 39%-100%). Positive and negative predictive values of esophageal screening were 100% and 13%, respectively. Esophageal screening identified 44/70 (63%) patients with esophageal disease. Esophageal screening is a simple tool that may guide further esophageal investigation. The sensitivity of esophageal screening is limited (63%). If clinical suspicion is high, formal esophagram should be considered.


Coordination properties of Cu(II) ions towards the peptides based on the His-Xaa-His motif from Fusobacterium nucleatum P1 protein.
The coordination capacity of the copper(II) ions with peptides (fragments of the P1 protein - one of the outer membrane protein from Fusobacterium nucleatum) based on the His-Xaa-His motif was carried out using potentiometric measurements, mass spectrometry and spectroscopic techniques: UV-Vis, CD and EPR. The selected tetrapeptides (Ac-HGHE-NH2, Ac-GHEH-NH2, Ac-HEHQ-NH2 and Ac-EHEH-NH2) form both mononuclear and bis-complexes with copper(II) ions. In the case of mononuclear complexes the CuL and CuLH-2 species dominate in the solution, where the coordination sphere is create by {2 × NIm} and {2 × NIm,2 × N-amide}, respectively. The Ac-HGHE-NH2 peptide form more stable the CuLH-2 complex with the 4 N{2 × NIm,2 × N-amide} binding site compared to the other ligands. The presence of glutamic acid residue in sequence Ac-HEHQ-NH2 produced the destabilization of the CuLH-2 complex in comparison to that of the Ac-HGHE-NH2 sequence. For the CuLH-3 complex the coordination process for complexes containing a histidyl residue in the first positions (H1) proceed towards C-terminal sequence of the peptide. The bis-complexes are formed in the solution, where the metal ion is bounded by four imidazole nitrogen atoms {4 × NIm}.


Particulate Matter-Induced Cardiovascular Dysfunction: A Mechanistic Insight.
Air pollution and particulate matter (PM) are significant factors for adverse health effects most prominently cardiovascular disease (CVD). PM is produced from various sources, which include both natural and anthropogenic. It is composed of biological components, organic compounds, minerals, and metals, which are responsible for inducing inflammation and adverse health effects. However, the adverse effects are related to PM size distribution. Finer particles are a significant cause of cardiovascular events. This review discusses the direct and indirect mechanisms of PM-induced CVD like myocardial infarction, the elevation of blood pressure, cardiac arrhythmias, atherosclerosis, and thrombosis. The two potential mechanisms are oxidative stress and systemic inflammation. Prenatal exposure has also been linked with cardiovascular outcomes later in life. Moreover, we also mentioned the epidemiological studies that strongly associate PM with CVD.


An evolutionarily conserved TNF-alpha-responsive enhancer in the far upstream region of human CCL2 locus influences its gene expression.
Comparative cross-species genomic analysis has served as a powerful tool to discover novel noncoding regulatory regions that influence gene expression in several cytokine loci. In this study, we have identified several evolutionarily conserved regions (ECRs) that are shared between human, rhesus monkey, dog, and horse and that are upstream of the promoter regions that have been previously shown to play a role in regulating CCL2 gene expression. Of these, an ECR that was ~16.5 kb (-16.5 ECR) upstream of its coding sequence contained a highly conserved NF-κB site. The region encompassing the -16.5 ECR conferred TNF-α responsiveness to homologous and heterologous promoters. In vivo footprinting demonstrated that specific nucleotide residues in the -16.5 ECR were protected or became hypersensitive after TNF-α treatment. The footprinted regions were found to bind NF-κB subunits in vitro and in vivo. Mutation/deletion of the conserved NF-κB binding site in the -16.5 ECR led to loss of TNF-α responsiveness. After TNF-α stimulation, the -16.5 ECR showed increased sensitivity to nuclease digestion and loss of histone signatures that are characteristic of a repressive chromatin. Chromosome conformation capture assays indicated that -16.5 ECR physically interacts with the CCL2 proximal promoter after TNF-α stimulation. Taken together, these results suggest that the -16.5 ECR may play a critical role in the regulation of CCL2.


Long-term cost-effectiveness of matrix-associated chondrocyte implantation in the German health care system: a discrete event simulation.
Cartilage defects in the knee can be caused by injury, various types of arthritis, or degeneration. As a long-term consequence of cartilage defects, osteoarthritis can develop over time, often leading to the need for a total knee replacement (TKR). The treatment alternatives of chondral defects include, among others, microfracture, and matrix-associated autologous chondrocyte implantation (M-ACI). The purpose of this study was to determine cost-effectiveness of M-ACI in Germany with available mid- and long-term outcome data, with special focus on the avoidance of TKR. We developed a discrete-event simulation (DES) that follows up individuals with cartilage defects of the knee over their lifetimes. The DES was conducted with a status-quo scenario in which M-ACI is available and a comparison scenario with no M-ACI available. The model included 10,000 patients with articular cartilage defects. We assumed Weibull distributions for short- and long-term effects for implant failures. Model outcomes were costs, number of TKRs, and quality-adjusted life years (QALYs). All analyses were performed from the perspective of the German statutory health insurance. The majority of patients was under 45 years old, with defect sizes between 2 and 7 cm2 (mean: 4.5 cm2); average modeled lifetime was 48 years. In the scenario without M-ACI, 26.4% of patients required a TKR over their lifetime. In the M-ACI scenario, this was the case in only 5.5% of cases. Thus, in the modeled cohort of 10,000 patients, 2700 TKRs, including revisions, could be avoided. Patients treated with M-ACI experienced improved quality of life (22.53 vs. 21.21 QALYs) at higher treatment-related costs (18,589 vs. 14,134 € /patient) compared to those treated without M-ACI, yielding an incremental cost-effectiveness ratio (ICER) of 3376 € /QALY. M-ACI is projected to be a highly cost-effective treatment for chondral defects of the knee in the German healthcare setting.


Simultaneous determination of mycophenolic acid and its metabolites by HPLC and pharmacokinetic studies in rat plasma and bile.
In this study, we determined the pharmacokinetics of mycophenolic acid (MPA) and its metabolites mycophenolic acid glucuronide (MPAG) and acyl glucuronide (AcMPAG) in rat plasma and bile, using a newly developed HPLC method. Protein precipitation and liquid-liquid extraction were employed in sample preparation of plasma and bile, respectively. The HPLC methods included a gradient elution consisting of acetonitrile and phosphate buffer at a flow rate of 1.2 mL/min, with UV detection at 254 nm. The HPLC method was found to be sensitive and linear (r(2) ≥ 0.9991, 1.0-128.0 and 0.25-32.0 mg/L for MPA; 1.0-128.0 and 0.5-64.0 mg/L for MPAG; 0.25-32.0 and 1.0-128.0 mg/L for AcMPAG in rat plasma and bile, respectively), precise (both the intra- and inter-day variability were ≤ 6.8%), and accurate (both the intra- and inter-day accuracy were between 92.2% and 105.4%). The average extraction efficiencies for MPA, MPAG and AcMPAG were 85.3%, 100.1%, and 94.7% in plasma, and 88.0%, 67.3%, and 68.3% in bile, respectively. The method was successfully employed for pharmacokinetic studies in plasma and bile after oral administration of mycophenolate mofetil (prodrug of MPA) in rats.


Radioiodination of glycoprotein-conjugated liposomes by using the Bolton-Hunter reagent and biodistribution in tumor-bearing mice.
We have developed a suitable radiolabeling method for our new type of glycoprotein-liposome conjugate (GCL), in order to investigate its potential utility as a drug carrier that can target the cellular functions of carbohydrate-binding proteins. In order to obtain radiolabeled GCL with high labeling efficiency, we introduced p-hydroxyphenylpropyl groups into the liposome membrane through the amine moiety of a constitutive phospholipid, dipalmitoylphosphatidylethanolamine (DPPE) by using Bolton-Hunter reagent (BHR). Radioiodination of the introduced tyrosyl groups was performed by the Chloramine-T method. The labeling efficiency of the BHR-treated liposome conjugate was high in comparison with that of the BHR-untreated liposome conjugate. An in vitro inhibition study showed that the binding affinity of 125I-labeled BHR-treated GCL (125I-F3S-BH) with lectin was twice as high as that of untreated conjugate (125I-F3S). The biodistribution of 125I-F3S-BH in mice was considerably different from that of 125I-F3S. 125I-F3S-BH was more rapidly taken up by the liver and was more rapidly excreted from the liver than 125I-F3S. Moreover, 125I-F3S-BH accumulated more rapidly into the kidneys, which resulted a lower radioactivity in the blood circulation at an earlier time point than in the case of 125I-F3S. The characteristics of tumor accumulation of 125I-F3S-BH and 125I-F3S were similar to those in blood. If F3S is to be employed as an in vivo targeting ligand in biodistribution studies, BHR would be a suitable tool for radiolabeling because it allows GCL to retain the biological activity and characteristics of the unmodified conjugate.


Safety, Efficacy, and Patient Satisfaction With OnabotulinumtoxinA for the Treatment of Upper Facial Lines in Japanese Subjects.
OnabotulinumtoxinA treatment for glabellar lines (GL) or crow's-feet lines (CFL) was previously studied in Japanese subjects. To assess safety and efficacy of repeated onabotulinumtoxinA for moderate to severe GL and CFL in Japanese subjects. This 13-month, double-blind, Phase 3 study randomized subjects to onabotulinumtoxinA 44 U (n = 48) or 32 U (n = 53) for CFL and GL for up to 5 treatments (CFL: 24 U or 12 U; GL: 20 U). Outcomes included proportion of subjects achieving none/mild severity at maximum smile (CFL) and maximum frown (GL), using the Facial Wrinkle Scale with Asian Photonumeric Guide (FWS-A); proportion of ≥1-grade improvement responders at maximum smile and at rest (CFL), at maximum frown and at rest (GL); subject-reported outcomes; and safety. Most subjects were responders (none/mild on FWS-A; CFL: 89.6% [44 U], 84.9% [32 U]; GL: 93.8% [44 U], 98.1% [32 U]) on Day 30. Across treatment groups, responder rates were consistent over time and treatments. Most subjects were satisfied with improved CFL appearance and with treatment. Incidence of treatment-emergent adverse events (TEAEs) and treatment-related TEAEs across groups was similar. All TEAEs but one (peritonitis) were mild or moderate. Repeated onabotulinumtoxinA was effective and well tolerated.


Clinical decision-making in older adults following emergency admission to hospital. Derivation and validation of a risk stratification score: OPERA.
Demographic changes alongside medical advances have resulted in older adults accounting for an increasing proportion of emergency hospital admissions. Current measures of illness severity, limited to physiological parameters, have shortcomings in this cohort, partly due to patient complexity. This study aimed to derive and validate a risk score for acutely unwell older adults which may enhance risk stratification and support clinical decision-making. Data was collected from emergency admissions in patients ≥65 years from two UK general hospitals (April 2017- April 2018). Variables underwent regression analysis for in-hospital mortality and independent predictors were used to create a risk score. Performance was assessed on external validation. Secondary outcomes included seven-day mortality and extended hospital stay. Derivation (n = 8,974) and validation (n = 8,391) cohorts were analysed. The model included the National Early Warning Score 2 (NEWS2), clinical frailty scale (CFS), acute kidney injury, age, sex, and Malnutrition Universal Screening Tool. For mortality, area under the curve for the model was 0.79 (95% CI 0.78-0.80), superior to NEWS2 0.65 (0.62-0.67) and CFS 0.76 (0.74-0.77) (P<0.0001). Risk groups predicted prolonged hospital stay: the highest risk group had an odds ratio of 9.7 (5.8-16.1) to stay >30 days. Our simple validated model (Older Persons' Emergency Risk Assessment [OPERA] score) predicts in-hospital mortality and prolonged length of stay and could be easily integrated into electronic hospital systems, enabling automatic digital generation of risk stratification within hours of admission. Future studies may validate the OPERA score in external populations and consider an impact analysis.


Asymmetric replication of an oriC plasmid in Escherichia coli.
Plasmid pTSO118 containing the Escherichia coli origin of replication, oriC, initiated replication simultaneously with the chromosome when temperature-sensitive host cells were synchronized by temperature shifts. Replicating intermediates of the plasmid as well as of the chromosome were isolated from the outer membrane fraction of the cell. Plasmid DNA with eye structures was enriched when cytosine-1-beta-arabinofuranoside was introduced into the culture during replication. Electron microscopy of the replicating molecules, after digestion with restriction endonucleases, showed that the replication fork proceeds exclusively counter-clockwise towards the unc operon. We conclude that the replication of the oriC plasmid is unidirectional or, if bidirectional, is highly asymmetric.


Postoperative complications after local resection of the stomach.
Local resection of the stomach for early gastric cancer is being performed more frequently, despite which no report focusing on the postoperative complications has been published. The purpose of this study was to investigate the incidence and factors affecting postoperative complications after local resection of the stomach. Local resection of the stomach was performed in 37 patients with gastric cancers, submucosal tumors (SMT), or bleeding gastric ulcers, 24 of whom underwent gastroscopy at least once after their operation. We retrospectively examined the complications and background relating to the operations performed in those 24 patients. Postoperative hemorrhage occurred in 2 patients, an open ulcer developed on the suture line in 2 and leakage developed in 1. The hemorrhage and open ulcer were observed only when wide resection with regional lymph node dissection was performed for early gastric cancers in the middle third of the stomach. These findings show that the possibility of postoperative hemorrhage and open ulcers on the suture line should be borne in mind, especially when wide local resection with lymph node dissection is performed for cancers in the middle part of the stomach.


Repairable and unrepairable DNA strand breaks induced by decay of 3H and 125I incorporated into DNA of mammalian cells.
Chinese hamster cells (Cl: 1) were labelled with 3H-thymidine or 125Iododeoxyuridine for 18 h and after 3 h in non-radioactive medium they were stored at 0 degrees C up to 6 h. The number of DNA strand breaks observed after the labelling period (37 degrees C) or after treatment at 0 degrees C was determined using the DNA-unwinding technique. 125I-decays in DNA were significantly more efficient than 3H-decays in introducing unrepairable DNA strand breaks during the labelling period. 32% of 125I-induced and 3% of 3H-induced DNA strand breaks were unrepaired after 21 h at 37 degrees C. Comparison between the effects of 125I- or 3H-disintegrations in DNA in three different ways shows 7--12 times more pronounced effects for 125I-decays. For 125I-labelled cells 3--4 DNA strand breaks were found per decay and the corresponding value for 3H- labelled cells was 2.


Metabolite G-protein coupled receptor signaling: Potential regulation of eicosanoids.
Eicosanoids are a family of bioactive compounds derived from arachidonic acid (AA) that play pivotal roles in physiology and disease, including inflammatory conditions of multiple organ systems. The biosynthesis of eicosanoids requires a series of catalytic steps that are controlled by designated enzymes, which can be regulated by inflammatory and stress signals via transcriptional and translational mechanisms. In the past decades, evidence have emerged indicating that G-protein coupled receptors (GPCRs) can sense extracellular metabolites, and regulate inflammatory responses including eicosanoid production. This review focuses on the recent advances of metabolite GPCRs research, their role in regulation of eicosanoid biosynthesis, and the link to pathophysiological conditions.


Terbium-based metal-organic frameworks through energy transfer modulation for visual logical sensing zinc and fluorine ions.
Zinc is the second most abundant trace element in the human central nervous system, which is closely related to various physiological activities in the human body. Fluoride ion is one of the most harmful elements in drinking water. Excessive intake of F- may cause dental fluorosis, renal failure, or DNA damage. Therefore, it is urgent to develop sensors with high sensitivity and selectivity for the detection of Zn2+ and F- ions at the same time. In this work, a series of mixed lanthanide metal-organic frameworks (Ln-MOFs) probes are synthesized using a simple method of in situ doping. The luminous color can be finely modulated by changing the molar ratio of Tb3+ and Eu3+ during synthesis. Benefiting from the unique energy transfer modulation mechanism, the probe has the continuous detection capability of zinc ions and fluoride ions. The detection of Zn2+ and F- in a real environment shows that the probe has a good practical application prospect. The as-designed sensor at 262 nm excitation can sequentially detect Zn2+ concentrations ranging from 10-8 to 10-3 M (LOD = 4.2 nM) and F- levels ranging from 10-5 to 10-3 M (LOD = 3.6 μM) with high selectivity. Based on different output signals, a simple Boolean logic gate device is constructed to realize intelligent visualization of Zn2+ and F- monitoring.


Synthesis of thiazole-4-carboxamide-adenine difluoromethylenediphosphonates substituted with fluorine at C-2' of the adenosine.
Synthesis of an analogue 3 of thiazole-4-carboxamide adenine-dinucleotide (TAD) in which the beta-oxygen atom of the pyrophosphate bridge is replaced by a difluoromethylene group has been achieved. Likewise, 2'-deoxy-2'-fluoroadenosine containing analogues of TAD (4) and its difluoromethylenediphosphonate congener (5) have been synthesized. Adenosine 5'-difluoromethylenediphosphonate (8) was prepared from 5'-O-tosyladenosine (6) and tris(tetra-n-butylammonium)difluoromethylenediphosphonate (7) by a modified procedure of Poulter's. Compound 8 was converted into the 2',3'-cyclic carbonate 9 by treatment with triethyl orthoformate. Treatment of 9 with 2',3'-O-isopropylidenetiazofurin (10) in pyridine in the presence of DCC gave a mixture of dinucleotide 11 and the isopropylidene-protected diadenosine tetraphosphonate 12. After deprotection of 11, the desired beta-difluoromethylene TAD (3) was separated by HPLC as the minor product. The diadenosine tetraphosphonate 12, an analogue of Ap4A, was obtained as the major component. Alternatively, 2',3'-O-isopropylidenetiazofurin (10) was tosylated, and the product 13 was further converted into the corresponding difluoromethylenediphosphonate 14 by coupling with 7. DCC-catalyzed coupling of 14 with 2'-deoxy-2'-fluoroadenosine (15) followed by deisopropylidenation afforded the analogue 5. Again the corresponding tetraphosphonate analogue of tiazofurin 17 was the predominant product. Dinucleotide 4 was obtained by coupling of the carbonyldiimidazole-activated tiazofurin 5'-monophosphate with 2'-deoxy-2'-fluoroadenosine 5'-monophosphate. 2'-Deoxy-2'-fluoroadenosine (15) was prepared efficiently from the known N6-benzoyl-3'-O-tetrahydropyranyladenosine (18), which was converted into 3'-O-tetrahydropyranyl-2'-O-triflyl-5'-O-trityladenosine (20) by tritylation and triflation. Treatment of 20 with sodium acetate in hexamethylphosphoric triamide, followed by deacetylation afforded 9-(3-O-tetrahydropyranyl-5-O-trityl-beta-D- arabinofuranosyl)-N6-benzoyladenine (22), which was then treated with DAST. After deprotection of the product, 15 was obtained in good yield.


Identification of astigmatid mites using ITS2 and COI regions.
Identification of astigmatid mites based on their morphological characteristics is difficult because of the similarity of their organs, especially in immature mites. The ribosomal second internal transcribed spacer (ITS2) and the mitochondrial cytochrome oxidase subunit I (COI) regions are highly conserved in the eukaryotes and are usually used as barcodes. The ITS2 and COI regions of six species of astigmatid mites (Aleuroglyphus ovatus, Blomia tropicalis, Dermatophagoides farinae, Dermatophagoides pteronyssinus, Euroglyphus maynei, Tyrophagus putrescentiae) were obtained by polymerase chain reaction and sequenced. The lengths of the ITS2 sequences varied from 316 to 488 bp, while the COI regions were 377 or 378 bp long. Considering the ITS2 genes, the intraspecific genetic distance was in the range of 0.00-0.077844, whereas the interspecific genetic distance was 0.202426-0.912959. The values were 0.000-0.029748 and 0.138403-0.279304 for intra- and interspecific genetic distances when COI genes were used. The phylogenetic trees inferred from the ITS2 and the COI regions, by using maximum parsimony and neighbor-joining methods, were identical to those based on their morphological classification. Thus, the ITS2 and COI regions can be applied as barcodes to identify different species of astigmatid mites.


Historical and projected hysterectomy rates in the USA: Implications for future observed cervical cancer rates and evaluating prevention interventions.
SEER-reported cervical cancer incidence rates reflect the total female population including women no longer at risk due to hysterectomy. Hysterectomy rates have been declining in the United States as alternative treatments have become available, which could result in an apparent increase in SEER-reported cervical cancer rates. We aimed to obtain nationally representative historical data on hysterectomy rates in USA, use trends analysis to project rates back to 1935 and forward to 2035, and then predict the impact of changing hysterectomy rates on SEER-reported cervical cancer rates. We performed a systematic search of Medline, Embase, Premedline, Cochrane Central databases and extracted nationally-representative hysterectomy incidence data from 1965 to 2009, including data on the number of cervix-preserving (subtotal) procedures. We then projected rates back to 1935, and forward to 2035 based on trends from joinpoint regression. These rates were then used to estimate hysterectomy prevalence out to 2035, and then to predict the impact of changing hysterectomy rates on SEER-reported cervical cancer rates to 2035. We examined alternative assumptions regarding projected hysterectomy incidence rates out to 2035, including a scenario in which rates decline no further from 2009 rates, and a scenario where rates decline at twice the baseline rate. Estimated age-standardized hysterectomy incidence increased from 2.4 to 10.6 per 1000 women between 1935 and 1975. Thereafter, rates are predicted to fall to 3.9 per 1000 by 2035. Subtotal hysterectomy procedures declined from being the predominant method in 1935 to less than 12% of procedures from 1970 onwards. Consequently, holding all else constant, an increase in SEER-reported age-standardized cervical cancer incidence rates (ages 0-85+) of 9% is expected from 2009 to 2035. The predictions were minimally impacted by alternative scenarios for future hysterectomy rates. Declining hysterectomy rates have implications for the interpretation of SEER-reported cervical cancer rates. A background increase in cervical cancer rates due to decreasing population hysterectomy exposure may partially offset expected decreases from recent cervical screening changes recommended by the US Preventive Services Task Force. Evaluations of new cervical cancer prevention opportunities should consider the background impact of historical and projected hysterectomy rates.


Pharmacologic inducers of the uric acid exporter ABCG2 as potential drugs for treatment of gouty arthritis.
Uric acid is the end product of purine catabolism and its plasma levels are maintained below its maximum solubility in water (6-7 mg/dl). The plasma levels are tightly regulated as the balance between the rate of production and the rate of excretion, the latter occurring in urine (kidney), bile (liver) and feces (intestinal tract). Reabsorption in kidney is also an important component of this process. Both excretion and reabsorption are mediated by specific transporters. Disruption of the balance between production and excretion leads to hyperuricemia, which increases the risk of uric acid crystallization as monosodium urate with subsequent deposition of the crystals in joints causing gouty arthritis. Loss-of-function mutations in the transporters that mediate uric acid excretion are associated with gout. The ATP-Binding Cassette exporter ABCG2 is important in uric acid excretion at all three sites: kidney (urine), liver (bile), and intestine (feces). Mutations in this transporter cause gout and these mutations occur at significant prevalence in general population. However, mutations that are most prevalent result only in partial loss of transport function. Therefore, if the expression of these partially defective transporters could be induced, the increased number of the transporter molecules would compensate for the mutation-associated decrease in transport function and hence increase uric acid excretion. As such, pharmacologic agents with ability to induce the expression of ABCG2 represent potentially a novel class of drugs for treatment of gouty arthritis.


Role of S100B protein in urine and serum as an early predictor of mortality after severe traumatic brain injury in adults.
S100B is a calcium-binding protein released into the blood from astroglial cells due to brain injury. Some authors have described a correlation between S100B serum concentration and severity of brain damage. There is not much information about the accuracy of urinary S100B for predicting outcome after severe traumatic brain injury (TBI). 55 patients with severe TBI were included in the study. Blood and urine samples were drawn to determine S100B levels on admission and on the subsequent 24, 48, 72 and 96 h. S100B concentrations (serum and urine) were significantly higher in patients who were dead a month after the accident compared to survivors. ROC-analysis showed that S100B at 24h post-severe TBI is a useful tool for predicting mortality (serum: AUC 0.958, urine: AUC 0.778). The best cut-offs for S100B were 0.461 μg/L and 0.025 μg/L (serum and urine respectively), with a sensitivity of 90% for both measurements and a specificity of 88.4% (serum) and 62.8% (urine). We can state that the determination of S100B levels both in urine and serum acts as a sensitive and an effective biomarker for the early prediction of mortality after severe TBI.


Development of an efficient remediation system with a low cost after identification of water pollutants including phenolic compounds in a tannery built-up area in Bangladesh.
Water pollution caused by tannery wastewater is an important issue in developing countries. Most studies have focused on inorganic chemicals represented by chromium as a tannery-related main pollutant. This is the first study in which pollution of water by tannery-related organic chemicals was assessed by a combination of qualitative and quantitative analyses. Our quantitative analysis showed that the maximum concentration of total phenolic compounds (phenols), consisting of phenol, bisphenol F, p-cresol and chlorocresol, in canal water in a tannery built-up area in Bangladesh was >67-fold higher than the Environmental, Health and Safety (EHS) guideline value. Mapping of our results indicated tanneries as the sources of phenols pollution. Our original depurative, a hydrotalcite-like compound consisting of magnesium and iron (MF-HT), could adsorb all kinds of phenols and exhibited the highest phenol adsorption ability (115.8 mg/g) among reported hydrotalcite-like compounds. The levels of phenols in canal water samples were reduced to levels below the guideline value by using MF-HT with assistance of a photocatalytic reaction. Moreover, the mean level of chromium (112.2 mg/L) in canal water samples was decreased by 99.7% by using the depurative. Thus, the depurative has the potential for solving the problem of tannery-related water pollution by phenols and chromium.


Analysis of secondary plant metabolites by indirect desorption electrospray ionization imaging mass spectrometry.
Secondary metabolites in plant material can be imaged in a simple and robust way by creating an imprint of the plant material on a porous Teflon surface. The Teflon surface serves to extract compounds from the plant material for enhanced desorption electrospray ionization imaging analysis, while maintaining the spatial information of the sample. The method, which remedies for limitations in mass spectrometry imaging of compounds embedded in plant material, was demonstrated on leaves and petals of Hypericum perforatum and leaves of Datura stramonium.


Clinical and Genotype Characteristics and Symptom Migration in Patients With Mixed Phenotype Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey.
Transthyretin amyloidosis (ATTR amyloidosis) is primarily associated with a cardiac or neurologic phenotype, but a mixed phenotype is increasingly described. This study describes the mixed phenotype cohort in the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, longitudinal, observational survey of patients with ATTR amyloidosis, including both hereditary (ATTRv) and wild-type disease, and asymptomatic carriers of pathogenic transthyretin variants. Baseline characteristics of patients with a mixed phenotype (at enrollment or reclassified during follow-up) are described (data cutoff: January 4, 2022). Approximately one-third of symptomatic patients (n = 1185/3542; 33.5%) were classified at enrollment or follow-up as mixed phenotype (median age, 66.5 years). Of those, 344 (29.0%) were reclassified to mixed phenotype within a median 1-2 years of follow-up. Most patients with mixed phenotype had ATTRv amyloidosis (75.7%). The most frequent genotypes were V30M (38.9%) and wild type (24.3%). These THAOS data represent the largest analysis of a real-world mixed phenotype ATTR amyloidosis population to date and suggest that a mixed phenotype may be more prevalent than previously thought. Patients may also migrate from a primarily neurologic or cardiologic presentation to a mixed phenotype over time. These data reinforce the need for multidisciplinary evaluation at initial assessment and follow-up of all patients with ATTR amyloidosis. ClinicalTrials.gov: NCT00628745.


Identification of T and B lymphocytes in pigs by combined E-rosette test and surface Ig labelling.
A procedure for combining labelling of B lymphocytes with [125I]anti-Ig-antibodies and E-rosetting is described which permits simultaneous detection of B lymphocytes and T lymphocytes. Pig lymphocytes were incubated with iodinated anti-Ig antibodies and the E-rosette test with SRBC was performed. E-rosettes appeared stable after methanol fixation of cell smears on agarose-coated slides and treatment for autoradiography on stripping films. The percentage of cells classified as B or T lymphocytes in pig peripheral blood closely resembles that in man. No doubly marked cells were demonstrated provided cells were classified as E-rosettes only when 5 or more red cells were attached.


[Temperature and reaction heat of elastomer casting materials].
Cross linking of the elastomer cast material is an exothermic process. The heat of reaction may produce temperature increases of several degrees centigrade in the thermically insolated samples. The heat of reaction per volume was measured; polysulfide and polyether values are approximately 10 times higher than those for silicone.


PIF4 enhances DNA binding of CDF2 to co-regulate target gene expression and promote Arabidopsis hypocotyl cell elongation.
How specificity is conferred within gene regulatory networks is an important problem in biology. The basic helix-loop-helix PHYTOCHROME-INTERACTING FACTORs (PIFs) and single zinc-finger CYCLING DOF FACTORs (CDFs) mediate growth responses of Arabidopsis to light and temperature. We show that these two classes of transcription factor (TF) act cooperatively. CDF2 and PIF4 are temporally and spatially co-expressed, they interact to form a protein complex and act in the same genetic pathway to promote hypocotyl cell elongation. Furthermore, PIF4 substantially strengthens genome-wide occupancy of CDF2 at a subset of its target genes. One of these, YUCCA8, encodes an auxin biosynthesis enzyme whose transcription is increased by PIF4 and CDF2 to contribute to hypocotyl elongation. The binding sites of PIF4 and CDF2 in YUCCA8 are closely spaced, and in vitro PIF4 enhances binding of CDF2. We propose that this occurs by direct protein interaction and because PIF4 binding alters DNA conformation. Thus, we define mechanisms by which PIF and CDF TFs cooperate to achieve regulatory specificity and promote cell elongation in response to light.


Intimate Partner Violence Around the Time of Pregnancy and Utilization of WIC Services.
Intimate partner violence (IPV) around the time of pregnancy is a risk factor for adverse pregnancy and birth outcomes. The supplemental nutrition program for women, infants, and children (WIC), available to low income pregnant women, may provide an opportunity to identify victims of IPV and refer them to services. This cross-sectional study aims to determine whether WIC participants are more likely than non-WIC participants to have reported IPV before or during pregnancy in the United States. The 2004-2011 National Pregnancy Risk Assessment Monitoring System (PRAMS) survey (n = 319,689) was analyzed in 2015. Self-reported WIC participation, pre-pregnancy IPV, and IPV during pregnancy were examined. The associations between IPV and WIC participation were analyzed using multiple logistic regression and adjusted odds ratios with corresponding 95% confidence intervals were calculated. Subpopulation analysis was conducted, stratified by race/ethnicity. Nearly half of the study sample received WIC (48.1%), approximately 4% of women reported physical abuse 12 months before their most recent pregnancy, and 3% reported abuse during pregnancy. After adjusting for confounders, women who reported IPV before and during pregnancy had significantly higher odds of WIC utilization compared to women who did not report IPV. However, when stratified by race, the association was only significant for non-Hispanic White women (pre-pregnancy AOR 1.47, 95% CI [1.17, 1.85]; during pregnancy AOR 1.47, 95% CI [1.14, 1.88]). There is an association between IPV before and during pregnancy and utilization of WIC. Public health professionals and policy makers should be aware of this association and use this opportunity to screen and address the needs of WIC recipients.


Targeting the 5-HT(3) receptor in the treatment of irritable bowel syndrome.
Irritable bowel syndrome, which affects 5-10% of the population includes around 25% with predominantly diarrhoea (IBS-D). Several lines of evidence suggest an increase in mucosal 5-HT availability in IBS-D including a decrease in the serotonin transporter (SERT) which is also seen following acute diverticulitis. 5-HT(3) receptor antagonists have proved effective in suppressing urgency, prolonging small and large bowel transit and relieving symptoms in IBS-D. Alosetron continues to be used under restricted availability without any serious morbidity despite ischemic colitis which occurs at a rate of <1/1000 patient year. Other agents such as ramosetron and ondansetron are still in use and have not been associated with ischemic colitis. 5-HT(3) receptor agonists stimulate intestinal motility, shorten transit times and in a pilot trial accelerated transit in patients with IBS-C.


Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3- and viral-induced expression of type I interferons.
Toll-like receptors (TLRs) sense pathogen-associated molecules and respond by inducing cytokines and type I interferon. Here we show that genetic ablation of the E3 ubiquitin ligase Pellino3 augmented the expression of type I interferon but not of proinflammatory cytokines in response to TLR3 activation. Pellino3-deficient mice had greater resistance against the pathogenic and lethal effects of encephalomyocarditis virus (EMCV). TLR3 signaling induced Pellino3, which in turn interacted with and ubiquitinated TRAF6. This modification suppressed the ability of TRAF6 to interact with and activate IRF7, resulting in downregulation of type I interferon expression. Our findings highlight a new physiological role for Pellino3 and define a new autoregulatory network for controlling type I interferon expression.


Effect of medicines management versus standard care on readmissions in multimorbid patients: a randomised controlled trial.
To investigate the effect of pharmacist-led medicines management in multimorbid, hospitalised patients on long-term hospital readmissions and survival. Parallel-group, randomised controlled trial. Recruitment from an internal medicine hospital ward in Oslo, Norway. Patients were enrolled consecutively from August 2014 to the predetermined target number of 400 patients. The last participant was enrolled March 2016. Follow-up until 31 December 2017, that is, 21-40 months. Acutely admitted multimorbid patients ≥18 years, using minimum four regular drugs from minimum two therapeutic classes. 399 patients were randomly assigned, 1:1, to the intervention or control group. After excluding 11 patients dying in-hospital and 2 erroneously included, the primary analysis comprised 386 patients (193 in each group) with median age 79 years (range 23-96) and number of diseases 7 (range 2-17). Intervention patients received pharmacist-led medicines management comprising medicines reconciliation at admission, repeated medicines reviews throughout the stay and medicines reconciliation and tailored information at discharge, according to the integrated medicines management model. Control patients received standard care. The primary endpoint was difference in time to readmission or death within 12 months. Overall survival was a priori the clinically most important secondary endpoint. Pharmacist-led medicines management had no significant effect on the primary endpoint time to readmission or death within 12 months (median 116 vs 184 days, HR 0.82, 95% CI 0.64 to 1.04, p=0.106). A statistically significantly increased overall survival was observed during 21-40 months follow-up (HR 0.66, 95% CI 0.48 to 0.90, p=0.008). Pharmacist-led medicines management had no statistically significant effect on time until readmission or death. A statistically significant increased overall survival was seen. Further studies should be conducted to investigate the effect of such an intervention on a larger scale. NCT02336113.


Transoral surgery using the Flex Robotic System: Initial experience in the United States.
This multicenter, retrospective review documents the initial experience using the Flex system for transoral surgery in 2 United States academic centers. All patients who underwent transoral robotic surgery using the Medrobotics Flex Robotic System (Raynham, MA) between September 2015 and May 2017 were reviewed. Rates of successful surgery and complications were evaluated. Thirty-six men and 32 women were enrolled in the study. The average age was 55.6 years (range 17-82 years). The Flex system was used successfully in surgery of the tongue base, the palatine tonsils, the supraglottis, the glottis, the hypopharynx, the oral tongue, and the soft palate. Only 6 cases (7.6%) required readmission after discharge. There were no intraoperative or immediate postoperative complications, with no cases of intraoperative hemorrhage. To the best of our knowledge, this is the first study in the United States evaluating the use of the Flex system to safely resect lesions in the oral cavity, larynx, and pharynx.


[Comparison of the residual hearing on the profound hearing-impaired children with the hearing aids and cochlear implants].
To compare the hearing test data of the profound hearing-impaired children with the hearing aids and with cochlear implants; to find out the useful method to measure the residual hearing. Twenty-two profound hearing-impaired children participated in the study with complete set of hearing test and verbal rehabilitation file. Ten children fitted hearing aids and underwent verbal rehabilitation more than 3 months. Among the other 12 children with cochlear implants, 10 children fell in the same year range with the hearing aid patients. The children with hearing aids were divided into two groups according to the achievement of the verbal rehabilitation. ASSR threshold and pure- tone threshold were compared between the groups. (1) ASSR test: 7 children (14 ears) with hearing aids achieved good verbal representation, in which ASSR threshold can be recorded on 2.71 frequency on average [(110.92 +/- 7.43) dB HL]. Among 3 children with hearing aids representing poor verbal achievement and 5 children with additional cochlear implant because of the poor verbal achievement with hearing aids, only 1.06 frequency had response of ASSR test [(110.88 +/- 48.52 ) dB HL]. (2) Pure tone audiometry: the average threshold of the 7 children with good representation was (96.11 +/- 7.81) dB HL, and the threshold on 3 frequency were less than 100 dB HL on average. The average threshold of the other 3 children with poor verbal achievement was (112.19 +/- 5.15) dB HL, and none of the frequency threshold was 100 dB HL. The number of the frequency with the response of ASSR and the threshold < or =100 dB HL of pure tone audiometry is an effective indication of the useful residual hearing.


trans-Selective Insertional Dihydroboration of a cis-Diborene: Synthesis of Linear sp3 -sp2 -sp3 -Triboranes and Subsequent Cationization.
The reaction of aryl- and amino(dihydro)boranes with dibora[2]ferrocenophane 1 leads to the formation 1,3-trans-dihydrotriboranes by formal hydrogenation and insertion of a borylene unit into the B=B bond. The aryltriborane derivatives undergo reversible photoisomerization to the cis-1,2-μ-H-3-hydrotriboranes, while hydride abstraction affords cationic triboranes, which represent the first doubly base-stabilized B3 H4 + analogues.


Correlation of transforming growth factor β-1 vitreous levels with clinical severity of proliferative vitreoretinopathy in patients with rhegmatogenous retinal detachment.
To correlate the vitreous concentration of transforming growth factor β-1 (TGF β-1) with the degree of clinical severity of proliferative vitreoretinopathy (PVR). A prospective, observational, cross-sectional study carried out on cases and controls. The study included 40 patients with a diagnosis of PVR secondary to rhegmatogenous retinal detachment. Vitreous was obtained in patients undergoing pars plana vitrectomy by rhegmatogenous retinal detachment, who were treated during the period from August 2015 to June 2016, in a national reference centre for ophthalmological care in Mexico City, Mexico. The levels of TGFβ-1 were quantified by ELISA technique. An ANOVA test was performed for the comparison of the different groups, together with a post-hoc Dunns test. A statistically significant difference was considered when obtaining P <.05. The levels of TGFβ-1 were quantified, and the following means were found for each group: In the group with PVR grade A, 1150.6 ± 452.08 pg / ml, PVR grade B: 1129.6 ± 365.54 pg / ml, and PVR grade C: 1146.4 ± 330.21 pg / ml. The statistical analysis did not find significant differences when comparing the different PVR groups. (P=.53). However, when performing the differential analysis for each level of severity, a statistically significant increase in the expression of TGFβ-1 was observed in the group of patients with PVR-A at a greater number of days of evolution of the detachment. (P=.03). There were no statistically significant differences for PVR-B and PVR-C (P=.16 and P=.16, respectively). Although the levels of TGFβ-1 are not directly related to the clinical severity grade, suggesting that there must be other factors involved in the advanced stages of PVR, TGFβ-1 may have greater relevance during the initial stages of the clinical course by promoting the epithelial-mesenchymal transition due to its greater expression in PVR-A. Thus, it can be concluded that each isoform plays a very particular role in the complex process of PVR.


Clinical applications of arterial stiffness: therapeutics and pharmacology.
This short review describes the effects of drugs and nonpharmacologic treatments on large artery stiffness in clinical trials. Arterial stiffness is generally accepted as a predictive factor for cardiovascular morbidity and mortality. The drug-induced reduction in arterial stiffness may parallel the reduction in cardiovascular work. This review summarizes the discussion of a task force that worked on the therapeutic aspects during a Consensus Conference on the 'Clinical applications of arterial stiffness," held in Paris on June 17, 2000. The effects of drugs on arterial stiffness are detailed in patients with hypertension, heart failure, and other arterial diseases. Other issues are raised, including the reversibility of arterial changes following pharmacologic treatment, and the possibility for nonpharmacologic treatment to be effective on arterial stiffness. Directions for future therapeutic trials are suggested.


Primitive neuroectodermal tumor incidence, treatment patterns, and outcome: An analysis of the National Cancer Database.
Primitive neuroectodermal tumors (PNETs) comprise less than 1% of all sarcomas. The rarity of this disease has resulted in a paucity of information about disease process and management. This study sought to evaluate the incidence, treatment patterns, and outcomes among patients with PNET. The National Cancer Database was queried for diagnoses of PNET between 2004 and 2014. Patients were dichotomized based on tumor type (central [cPNET] vs peripheral [pPNET]). Demographic, tumor, treatment, and outcome variables were analyzed for the entire patient cohort and by type of PNET. White (86.4%) males (56.6%) represented the majority of patients. The incidence of PNET remained stable over the study period (r2 = 0.0821). A total of 70.7% underwent surgical resection of the primary site, 50.3% received radiation, and 74.7% received systemic chemotherapy. Compared to those with pPNET, patients with cPNET more often received radiation treatment (P < .001), primary tumor resection (P < .001), and experienced increased 90-day mortality (P < .014). cPNET and pPNET are rare and aggressive malignancies that tend to arise in White males. Multimodal treatment including surgery, chemotherapy, and radiation is conventional. Patients with cPNET more often receive radiation and primary tumor resection with increased 90-day mortality.