Primary breast lymphoma: a pooled analysis of prognostic factors and survival in 93 cases.
Primary breast lymphoma is a rare disease. The small number of patients and the paucity of data make large-series studies difficult. We conducted a pooled analysis to evaluate the treatment outcome and prognostic factors in patients with primary breast lymphoma. In a search of PUBMED and MEDLINE we found 7 observational studies with 93 patientsthatwere eligible for inclusion. Treatments included single therapy or combined surgery, chemotherapy and radiotherapy. We analyzed the correlation between treatment protocols, tumor relapse and survival. Histopathology and cancer stage were analyzed to evaluate their significance in treatment outcome. All 93 patients were female, with a mean age of 57 years. The histopathology of 63 patients (68%) was diffuse large cell lymphoma. According to Ann Arbor classification, 57% were stage I, 23% were stage II, 4% were stage III, and 16% were stage IV. Thirteen percent received surgery alone, 27% received chemotherapy alone, 7% received radiotherapy alone, 10% received surgery and chemotherapy, 10% received surgery and radiotherapy, 22% received chemotherapy and radiotherapy, and 11% received surgery combined with chemotherapy and radiotherapy. With a median follow-up duration of 34 months (mean, 53 months), 48% had relapse of disease, 50% had no relapse, while 2% had disease progression. The mean time to first tumor relapse after treatment was 20 months. The 3-year and 5-year overall survival rates were 70% and 56%, respectively. Radiotherapy was a significant prognostic factor predicting tumor relapse (P=0.044). Tumor stage was a significant prognostic factor affecting overall survival, disease-free survival and disease-specific survival (P=0.0231, 0.0015, 0.0124, respectively). With a 3-year overall survival rate of 70%, the high relapse rate of 48% is a cause for concern. Patients who received chemotherapy and radiotherapy had better survival outcome and a lower relapse rate. We suggestthat chemotherapy and radiotherapy be the initial treatment for patients with primary breast lymphoma.


Integrating stay-green and PIN-FORMED genes: PIN-FORMED genes as potential targets for designing climate-resilient cereal ideotypes.
Plant architecture modification (e.g. short-stature crops) is one of the key outcomes of modern crop breeding for high-yielding crop varieties. In cereals, delayed senescence, or stay-green, is an important trait that enables post-anthesis drought stress adaptation. Stay-green crops can prolong photosynthetic capacity during grain-filling period under post-anthesis drought stress, which is essential to ensure grain yield is not impacted under drought stress conditions. Although various stay-green quantitative trait loci have been identified in cereals, the underlying molecular mechanisms regulating stay-green remain elusive. Recent advances in various gene-editing technologies have provided avenues to fast-track crop improvement, such as the breeding of climate-resilient crops in the face of climate change. We present in this viewpoint the focus on using sorghum as the model cereal crop, to study PIN-FORMED (PIN) auxin efflux carriers as means to modulate plant architecture, and the potential to employ it as an adaptive strategy to address the environmental challenges posed by climate uncertainties.


Anaphora and branching direction in Japanese.
This paper constitutes a response to Lust & Mazuka's (1989) defence of the Principal Branching Direction parameter and their critique of O'Grady, Suzuki-Wei & Cho's (1986) experiment, which purported to show that even children learning left-branching languages exhibit a preference for forward patterns of anaphora. Results of new experimental work with children learning Japanese are reported and shown to support the claim that there is a universal preference for forward patterns of anaphora in the early stages of language acquisition.


Atrial Fibrillation in Hypertrophic Cardiomyopathy: Is the Extent of Septal Hypertrophy Important?
Hypertrophic cardiomyopathy (HCM) is a cardiac disease associated with a high incidence of atrial fibrillation (AF). Recent studies have suggested that interventricular septum thickness may influence the risk stratification of patients with AF. We evaluated the effects of septal hypertrophy on morbidity and mortality in patients with HCM. Patients were followed for a median of 6.1 years and were divided into two groups according to the extent of septal hypertrophy. A total of 1,360 HCM patients were enrolled: 482 (33%) apical or apicoseptal, 415 (28%) asymmetric septal, 388 (27%) basal septal, 38 (2.6%) concentric, and 37 (2.5%) diffuse and mixed type. Ninety-two all-cause deaths and 21 cardiac deaths occurred. The total event rates were significantly higher for patients with HCM with more extensive septal hypertrophy (group A) compared to those with HCM ± focal septal hypertrophy (group B), regardless of type (p<0.001). Arrhythmias occurred in 502 patients, with a significantly higher incidence in group A than in group B (p<0.001). Among patients with arrhythmias, the incidence of AF was significantly higher in group A than group B (p<0.001). In univariate Cox analysis, a greater extent of septal hypertrophy (p<0.001), E/E´ ratio (p = 0.011), and mitral regurgitation grade (p = 0.003) were significantly associated with developing AF. In multivariate Cox analyses, a greater extent of septal hypertrophy [odds ratio (OR) 5.44 (2.29-12.92), p<0.001] in patients with HCM was significantly associated with developing AF. In conclusion, a greater extent of septal hypertrophy is an independent predictor of progression to AF in patients with HCM.


Epidemics of squirrelpox virus disease in red squirrels ( Sciurus vulgaris): temporal and serological findings.
Squirrelpox virus (SQPV) causes a fatal disease in free-living red squirrels (Sciurus vulgaris) which has contributed to their decline in the United Kingdom. Given the difficulty of carrying out and funding experimental investigations on free-living wild mammals, data collected from closely monitored natural outbreaks of disease is crucial to our understanding of disease epidemiology. A conservation programme was initiated in the 1990s to bolster the population of red squirrels in the coniferous woodland of Thetford Chase, East Anglia. In 1996, 24 red squirrels were reintroduced to Thetford from Northumberland and Cumbria, while in 1999 a captive breeding and release programme commenced, but in both years the success of the projects was hampered by an outbreak of SQPV disease in which seven and four red squirrels died respectively. Valuable information on the host-pathogen dynamics of SQPV disease was gathered by telemetric and mark-recapture monitoring of the red squirrels. SQPV disease characteristics were comparable to other virulent poxviral infections: the incubation period was <15 days; the course of the disease an average of 10 days and younger animals were significantly more susceptible to disease. SQPV disease places the conservation of the red squirrel in jeopardy in the United Kingdom unless practical disease control methods can be identified.


Evidence of the effectiveness of flour fortification programs on iron status and anemia: a systematic review.
More than 80 countries fortify flour, yet the public health impact of this intervention on iron and anemia outcomes has not been reviewed. The objective of this systematic review was to review published and gray literature pertaining to the impact of flour fortification on iron and anemia. A systematic review was conducted by searching 17 databases and appealing for unpublished reports, yielding 1881 documents. Only studies of government-supported, widely implemented fortification programs in which anemia or iron status was measured prior to and ≥12 months after initiation of fortification were included. Details about the design, coverage, compliance with national standards, and evaluation (e.g., anemia prevalence before and after fortification) of flour fortification programs were extracted from the reports. Thirteen studies describing 26 subgroups (n = 14 for children ≤15 y, n = 12 for women of reproductive age) were included. During the period from pre- to postfortification (and as difference-in-difference for those studies that included a control group), there were statistically significant decreases in the prevalence of anemia in 4 of 13 subgroups of children and in 4 of 12 subgroups of women of reproductive age as well as significant decreases in the prevalence of low ferritin in 1 of 6 subgroups of children and in 3 of 3 subgroups of women of reproductive age. . Evidence of the effectiveness of flour fortification for reducing the prevalence of anemia is limited; however, evidence of effectiveness for reducing the prevalence of low ferritin in women is more consistent.


Effects of 25 hydroxy vitamin D levels on the severity and asthma control in school age asthma patients.
The objective was to determine vitamin D levels in patients between the ages 6 and 18 years, followed for asthma, and the relation between vitamin D levels and asthma control and severity. Patients with asthma and healthy volunteers between the ages 6 and 18 years were enrolled into the study as patient and control groups, respectively. Patient demographic information and clinical findings were recorded; a respiratory function test was performed. Body mass index (BMI), 25(OH) D,calcium, phosphorus, alkaline phosphatase, total IgE and eosinophil levels were determined for all patients. Asthma severity and control conditions were established based on GINA (Global Initiative for Asthma) criteria. Seventy two patients with asthma and 66 healthy children were included. Compared to the control group, decreased serum vitamin D levels were detected in patient group. Thirty eight (52.8%) patients in asthma patient group had vitamin D defficiency; in this group, asthma control was poor and asthma severity was significantly higher. No significant correlation was found between vitamin D levels and gender, obesity, respiratory functions, skin test, serum eosinophil and total IgE levels. The frequency of vitamin D deficiency and insufficiency was higher in children with asthma, compared to the controls. Lower levels of vitamin D are associated with poor asthma control and increased asthma severity.


Nonparametric bounds in two-sample summary-data Mendelian randomization: Some cautionary tales for practice.
Recently, in genetic epidemiology, Mendelian randomization (MR) has become a popular approach to estimate causal exposure effects by using single nucleotide polymorphisms from genome-wide association studies (GWAS) as instruments. The most popular type of MR study, a two-sample summary-data MR study, relies on having summary statistics from two independent GWAS and using parametric methods for estimation. However, little is understood about using a nonparametric bound-based analysis, a popular approach in traditional instrumental variables frameworks, to study causal effects in two-sample MR. In this article, we explore using a nonparametric, bound-based analysis in two-sample MR studies, focusing primarily on implications for practice. We also propose a framework to assess how likely one can obtain more informative bounds if we used a different MR design, notably a one-sample MR design. We conclude by demonstrating our findings through two real data analyses concerning the causal effect of smoking on lung cancer and the causal effect of high cholesterol on heart attacks. Overall, our results suggest that while a bound-based analysis may be appealing due to its nonparametric nature, it is far more conservative in two-sample settings than in one-sample settings to get informative bounds on the causal exposure effect.


Sun exposure behavior and protection: recommendations for travelers.
Although there have been recent advances in the development of photoprotective clothing and broad-spectrum sunscreens, few peer-reviewed publications have focused on photoprotection recommendations for travelers. In order to describe the adverse health effects of excessive ultraviolet (UV) radiation exposures; review recent studies of public perceptions regarding photoprotection and sun exposure behaviors; identify special populations at increased risks of drug-induced photosensitivity reactions and UV-induced skin cancers; and recommend several effective photoprotection strategies for travelers, Internet search engines were queried with the key words as search terms to examine the latest references on photoprotection and the epidemiology of UV-associated skin cancers. Observational studies have demonstrated that the public knows little about proper sunscreen protection, selection, and use, and often abuses sunscreens for intentional UV overexposures. Cohort studies have identified special populations at increased risks of UV-associated skin cancers without the proper use of sunscreens and photoprotective clothing including children, fair-skinned persons, patients taking photosensitizing drugs, and organ transplant recipients (OTRs). Clinical investigations support the regular use of broad-spectrum sunscreens to prevent the development of premalignant actinic keratoses (AK) in all sun-exposed subjects, especially OTRs; to prevent the development of squamous cell carcinomas from new AK in sun-exposed subjects, especially OTRs; to possibly prevent the development of cutaneous malignant melanomas in children and adults; and to possibly prevent the development of basal cell carcinomas in OTRs. Recommended photoprotection strategies for travelers should include avoiding intense sunlight, wearing photoprotective clothing, wearing sunglasses, and selecting the right sunscreen for their skin type. Travel medicine practitioners should counsel travelers about photoprotection and encourage travelers to take advantage of recent advances in the development of more effective broad-spectrum sunscreens and photoprotective clothing for themselves and their children.


Optical trapping and control of a dielectric nanowire by a nanoaperture.
We demonstrate that a single sub-wavelength nanoaperture in a metallic thin film can be used to achieve dynamic optical trapping and control of a single dielectric nanowire. A nanoaperture can trap a nanowire, control its orientation when illuminated by a linearly polarized incident field, and rotate the nanowire when illuminated by a circularly polarized incident field. Compared to other designs, this approach has the advantage of a low-power driving field entailing low heating and photodamage.


Distal Corporal Anchoring Stitch: A Technique to Address Distal Corporal Crossovers and Impending Lateral Extrusions of a Penile Prosthesis.
Unidentified distal crossovers, delayed distal crossovers, and impending lateral extrusion are complications of penile prosthesis implant insertion but are not as common as prosthesis infection or mechanical failure. To evaluate results of a surgical technique, the distal corporal anchoring stitch, that addresses fixation of the penile prosthesis in patients with these complications. A lateral sub-coronal incision is used on the side where the crossover or laterally extruding cylinder should be positioned. Dissection is carried through the Buck fascia, followed by a transverse incision of the tunica albuginea, where the distal aspect of the affected cylinder is delivered. A 4-0 PDS suture is threaded through the distal cylinder ring of the implant. A new, properly positioned intracorporal channel is created and the suture is passed through the distal end of the channel. Once the suture is through the glans and the cylinder is in the correct position, a small cruciate incision is made on the glans at the location of the anchor stitch. The suture is tied with the knot buried in the glans tissue. Fifty-three patients underwent treatment of their distal penile implant crossover with a distal corporoplasty using this method and their anatomic and functional outcomes and overall satisfaction were evaluated. This technique ensured that the cylinder remained in the newly created, appropriately positioned channel. No patients developed infections, wound-healing defect, glandular hypoesthesia, anesthesia, or altered sensation or pain in the glans related to the suture and only two reported recurrence of a lateral herniation that did not require further treatment. Distal fixation of the penile prosthesis is a useful surgical adjunct to treating patients with prosthetic lateral extrusions or crossovers that can be applied in almost all cases. Considering these rare complications, our experience is based on a relatively large number of patients and showed a low incidence of complications and a high satisfaction rate. The main limitation of this study is the retrospective nature of the data and the series included patients from two high-volume surgeons that might not be generalizable to all practices. The distal corporal anchoring stitch is safe and effective in securing distal fixation of the extruding inflatable penile prosthesis. Antonini G, Busetto GM, Del Giudice F, et al. Distal Corporal Anchoring Stitch: A Technique to Address Distal Corporal Crossovers and Impending Lateral Extrusions of a Penile Prosthesis. J Sex Med 2017;14:767-773.


[A boy with a painful lump in the right inguinal region].
A 6-year-old male, with no history of importance, was seen in the Emergency Department, presenting with a painful lump in the right inguinal region since four days. An ultrasound revealed a torsion of an ectopical testis. Surgery showed a necrotic right testicle and a right orchiectomy was performed.


EuroSCORE Performance in Minimally Invasive Cardiac Surgery: Discrimination Ability and External Calibration.
Prediction of operative risk in adults undergoing cardiac surgery remains a challenge. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) is one of the most commonly used in clinical settings. Recently, the new EuroSCORE II was published attempting to improve the accuracy of risk prediction. We sought to assess the predictive value of EuroSCORE or EuroSCORE II in selected field of minimally invasive cardiac surgery. Patients who underwent cardiac surgery operation with minimally invasive approach from 2007 to 2013 identified from prospective cardiac surgical database. Additional variables included in EuroSCORE II, but not in original EuroSCORE, were retrospectively collected via electronic health records reviewing. The C-statistic was calculated for the EuroSCORE (additive and logistic) and EuroSCORE II. The Hosmer-Lemeshow test was used to assess model calibration by comparing observed and expected morality in number of risk strata. There were 39 hospitals deaths (1.6%). A total of 2472 patients were identified from the main database. The mean ± SD logistic EuroSCORE was 7.6 ± 8.3, mean ± SD additive EuroSCORE was 6.1 ± 2.7, and mean ± SD EuroSCORE II was 2.9 ± 4.2. EuroSCORE logistic model performed with substantial accuracy of 0.78, EuroSCORE additive performed with accuracy of 0.78, and EuroSCORE II performed as almost perfect 0.82. Model calibration was poor in EuroSCORE II (χ = 17.57, P = 0.02), calibration for logistic EuroSCORE was also poor (χ = 140.58, P < 0.01), and additive model also (χ = 94.95, P < 0.01). The area under the curve was high in all algorithms; logistic EuroSCORE was 0.78 (95% confidence interval = 0.71-0.85), additive EuroSCORE was 0.79 (95% confidence interval = 0.71-0.86), and EuroSCORE II was 0.82 (95% confidence interval = 0.75-0.89). In overall settings, original EuroSCORE and EuroSCORE II perform poorly in minimally invasive operation conditions. Data suggest that EuroSCORE could not be used for estimating operative risks correctly. New risk score should be explored, developed, and implemented for selective minimally invasive cohorts.


Effect of gastrin-releasing peptide receptor number on receptor affinity, coupling, degradation, and modulation.
The relationship between receptor number and agonist-induced intracellular responses has been well studied in receptors coupled to adenylate cyclase; however, for receptors coupled to phospholipase C (PLC), very little is known about the effect of receptor number on receptor-mediated processes. To explore this issue, we investigated the effect of the number of receptors for gastrin-releasing peptide (GRP) on ligand affinity and on the ability to activate intracellular messengers [PLC, tyrosine phosphorylation of p125 focal adhesion kinase (p125FAK)] and cause receptor modulation (internalization, desensitization, down-regulation) and ligand degradation. Three BALB 3T3 cell lines were made that stably expressed the gastrin-releasing peptide receptor (GRP-R) with receptor numbers varying by 280-fold (GRP-R-Low, GRP-R-Med, and GRP-R-Hi). Each cell line had the same affinity for agonist. The efficacy for bombesin to increase [3H]inositol phosphates but not tyrosine phosphorylation of p125FAK correlated well with receptor number. In contrast, the EC50 value for [3H]inositol phosphate generation for bombesin was the same in each cell line. Receptor number did not alter internalization. In the absence of protease inhibitors, there was an inverse correlation between receptor number and receptor down-regulation and desensitization. However, with protease inhibitors present, GRP-R-Med and GRP-R-Hi down-regulated significantly less than the GRP-R-Low. Similarly, GRP-R-Low desensitized significantly more than GRP-R-Med or GRP-R-Hi. GRP-R-Hi caused significantly greater ligand degradation than GRP-R-Low, and protease inhibitors completely inhibited degradation by GRP-R-Low and inhibited degradation by 70% for GRP-R-Hi. In conclusion, we show that for the PLC-coupled GRP-R, receptor number had little or no effect on binding affinity, potency for activating PLC, tyrosine phosphorylation of p125FAK, or extent of receptor internalization. In contrast, receptor number had an effect on ligand degradation, down-regulation, desensitization, and efficacy of PLC activation without altering the efficacy of tyrosine phosphorylation of p125FAK. These results demonstrate that the effect of receptor number differs for the different functions mediated by the GRP receptor and differs from that reported for adenylate cyclase-coupled receptors such as receptors mediating the action of adrenergic agents, secretin, and opioids.


MOLECULAR EPIDEMIOLOGY OF AVIAN POXVIRUS IN THE ORIENTAL TURTLE DOVE (STREPTOPELIA ORIENTALIS) AND THE BITING MIDGE (CULICOIDES ARAKAWAE) IN THE REPUBLIC OF KOREA.
A total of 600 wild birds were analyzed for the causes of mortality in the Republic of Korea (ROK) from 2011 to 2013. Avian poxvirus (APV) infections were identified as the primary cause of mortality in 39% (29/74) Oriental Turtle Doves (Streptopelia orientalis). At necropsy, all 29 S. orientalis birds, of which, 76% (22/29) were juveniles, had severe diphtheritic lesions in their oral and nasal cavities and on their eyelids, which were the lesions of APV that resulted in mortality. We detected APV infection by chorioallantoic membrane inoculation and molecular study of the partial region of the P4b gene. All isolates belonged to the same APV strain and were identical to strains isolated from several different pigeon species in South Africa. Phylogenetically, the APV strain identified in S. orientalis belonged to subclade A2, which includes isolates from several species of pigeons from different parts of the world, including the United Kingdom, Germany, India, Egypt, Hawaii, Georgia, Hungary, South Africa, Tanzania, and the ROK. This identity indicated that this diphtheritic APV strain may be a potential pathogen of other pigeon species in the ROK and neighboring countries throughout the range of S. orientalis. However, reticuloendotheliosis virus insertion into the APV genome was not detected by PCR in any of the 29 APV infections. An identical strain of APV observed in S. orientalis was also detected in Culicoides arakawae (biting midge), with annual peak populations corresponding to the presence of APV in S. orientalis. Culicoides arakawae may be a primary vector of APV in S. orientalis. Active surveillance of APVs in wild birds and C. arakawae is needed to better understand the epidemiology of APVs, host-vector relationships, and its ecological effects on S. orientalis in the ROK.


Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6.
The in vivo appearance of soluble interleukin (IL)-6 receptor (sIL-6R) in serum from patients with inflammatory bowel disease was examined using an enzyme linked immunosorbent assay (ELISA). The serum sIL-6R concentrations in patients with active disease (ulcerative colitis, 148.4 (5.1); Crohn's disease, 142.3 (9.3) ng/ml; mean (SEM)) were significantly raised compared with those in patients with inactive disease (ulcerative colitis, 116.2 (7.2); Crohn's disease, 114.3 (7.1) ng/ml), some other type of colitis (104.8 (11.6) ng/ml), or in normal subjects (107.3 (2.4) ng/ml). These differences were also seen in paired samples examined during both active and inactive phases. Additionally, serum sIL-6R and IL-6 concentrations correlated significantly with C-reactive protein levels in both ulcerative colitis and Crohn's disease patients (r = 0.23 and 0.56, respectively; p < 0.05 for both). Furthermore, gel filtration analysis of serum from these patients showed two major peaks of immunoreactive IL-6-one peak corresponding to free IL-6 and another peak to sIL-6R-bound IL-6-this was further confirmed by a luminescence sandwich ELISA. These results, together with its in vitro effects, indicate that natural sIL-6R may function as a powerful enhancer of the IL-6-dependent immune processes observed in inflammatory bowel disease.


ANCA-associated vasculitis causing nasopalatal destruction.
Autoimmune disorders and their manifestations can be very problematic to diagnose and manage. The symptoms can be ambiguous and debilitating. Early intervention is necessary to counter the unforgiving consequences of delayed intervention, such as loss of sight or hearing and destruction of affected tissues. Vasculitis in the head and neck region is rare. A case of ANCA-associated vasculitis causing extensive destruction is presented to enhance our understanding of this devastating multisystem disorder.


Precision Medicine Approach to Anaplastic Thyroid Cancer: Advances in Targeted Drug Therapy Based on Specific Signaling Pathways.
Personalized medicine is a set of diagnostic, prognostic and therapeutic approaches in which medical interventions are carried out based on individual patient characteristics. As life expectancy increases in developed and developing countries, the incidence of diseases such as cancer goes up among people in the community. Cancer is a disease that the response to treatment varies from one person to another and also it is costly for individuals, families, and society. Among thyroid cancers, anaplastic thyroid carcinoma (ATC) is the most aggressive, lethal and unresponsive form of the disease. Unfortunately, current drugs are not targetable, and therefore they have restricted role in ATC treatment. Consequently, mortality of this cancer, despite advances in the field of diagnosis and treatment, is one of the most important challenges in medicine. Cellular, molecular and genetic evidences play an important role in finding more effective diagnostic and therapeutic approaches. Review of these evidences confirms the application of personalized medicine in cancer treatment including ATC. A growing body of evidence has elucidated that cellular and molecular mechanisms of cancer would pave the way for defining new biomarkers for targeted therapy, taking into account individual differences. It should be noted that this approach requires further progress in the fields of basic sciences, pharmacogenetics and drug design. An overview of the most important aspects in individualized anaplastic thyroid cancer treatment will be discussed in this review.


Amniotic fluid cardiac troponin T in pathological pregnancies with evidence of chronic fetal hypoxia.
To determine if prenatally measured cardiac troponin T in the amniotic fluid (Am-TnT) could be used as a marker of fetal myocardial hypoxia and necrosis in pathological pregnancy characterized by increased concentration of amniotic fluid erythropoietin (Am-EPO) as a sign of chronic fetal hypoxia. We measured Am-TnT and Am-EPO in 29 pathological and 5 uncomplicated pregnancies. Samples of amniotic fluid were collected prospectively during elective amniocentesis (n=15), cesarean sections (n=17), and before elective induction of labor in two pregnancies with stillbirth. Am-TnT and Am-EPO were determined by chemiluminescent immunological method. Am-TnT was undetectable in normal pregnancies, but it was detectable in 9 of 29 amniotic fluid samples from pathological pregnancies, with a median value of 0.030 microg/L (range, 0.010-111.6 microg/L). Am-EPO values were above normal values (>11 U/L) in all pathological pregnancies. Am-EPO concentration showed positive correlation with the Am-TnT concentration (r=0.526, P=0.003). Median concentration of Am-EPO in 9 pregnancies with detectable Am-TnT was 198 U/L (range, 16-3,378 U/L). In 20 pathologic pregnancies with undetectable Am-TnT, the median concentration of Am-EPO was 39 U/L (range, 12-293 U/L). There was no statistically significant difference between the groups (P=0.051). Am-TnT is measurable in some pathological pregnancies with signs of fetal chronic hypoxia and myocardial involvement and could be potentially used as a biochemical marker of fetal myocardial injury.


Recent changes in pregnancy and lactation labeling: retirement of risk categories.
The rapid development and increased availability of novel pharmacologic therapies and pharmaceutical products has amplified the potential for drug exposure during pregnancy. Many drugs are beneficial for disease state management during pregnancy and provide significant fetal and maternal health benefits. However, a paucity of safety data combined with the imprecision of the current risk category system renders risk versus benefit assessment difficult. In response to decades of criticism, the U.S. Food and Drug Administration (FDA) is implementing a new pregnancy and lactation labeling rule designed to improve risk versus benefit assessment of drugs used in pregnant and nursing mothers. These recommendations will provide clear and detailed information for both patients and health care providers, and they will include three main categories: risk summary, clinical considerations, and data. The new labeling rules remove the previous letter risk categorization system (A, B, C, D, X). In this review, we summarize the upcoming FDA labeling changes and discuss their potential consequences on clinical practice.


A critical appraisal of the selegiline transdermal system for major depressive disorder.
The selegiline transdermal system (STS) is the first antidepressant transdermal medication approved by the US FDA for the treatment of major depressive disorder. Its unique antidepressant delivery system allows for steady release of selegiline over 24 h with minimal fluctuation in drug serum levels. It is able to deliver high enough central nervous system concentrations required for an antidepressant effect without substantially inhibiting Monoamine oxidase-A in the gastrointestinal and hepatic system, thereby reducing the risk of tyramine hypertensive crises especially at the lowest doses. Patient adherence theoretically could be improved due to ease of use and once-daily dosing when compared to oral counterparts' need for multiple daily doses. Clinical trials have established that doses between 6 and 12 mg over 24 h have been effective for major depressive disorder and tolerated among patients. Episodes of hypertensive crisis with STS have been minimally reported thus far. Overall, STS appears to be an effective agent for major depressive disorder when held to regulatory standards and post marketing analyses. This paper reviews the pharmacologic characteristics of STS and results of studies investigating its clinical efficacy and safety.


Wegener's granulomatosis upper respiratory tract and pulmonary radiographic manifestations in 30 cases with pathogenetic consideration.
Although the radiographic manifestations and pathologic features of Wegener's granulomatosis have been well described, their relationship to two variants of anti-neutrophil cytoplasmic antibodies (c- and p-ANCA) remains unclear. The purposes of this study are to analyze the radiographic and pathologic findings in 30 patients with Wegener's granulomatosis and to correlate c- and p-ANCA with such findings. Major histologic findings included parenchymal necrosis, necrotizing vasculitis, and granulomatous inflammations. Nodular lesions were more often associated with arteritis whereas patchy fluffy lesions associated with hemorrhagic capillaritis. ANCAs, particularly c-ANCA, instead of p-ANCA, were present in a high percentage of patients tested. These findings suggest that c-ANCA could play an important pathogenetic role in Wegener's granulomatosis which showed dual pathologic processes: vasculitis and granulomatous inflammation manifested radiographically as either nodular or pneumonia-like lesions, whereas p-ANCA was more often associated with patchy fluffy lung lesions as the consequence of hemorrhagic capillaritis.


Parathyroid carcinoma detected within the thyroid.
Parathyroid carcinoma (PC) is a rare disease accounting for approximately 1% of primary hyperparathyroidism cases. The preoperative differentiation of PC is critical because PC can occasionally metastasise and invade the local tissue. However, this is challenging in asymptomatic cases and when the tumour is adjacent to the thyroid. Herein, we report a rare case of PC without clinical symptoms. Fine needle aspiration was performed, despite being contraindicated in PC, and an intrathyroidal tumour was preoperatively suggested.


Comparison of image quality and portal vein visualization in IADSP using iopamidol, 76% urografin, and 38% urografin.
The image quality of intra-arterial digital subtraction portography (IADSP) was studied in 50 randomly assigned patients using one of three contrast agents: iopamidol, (IOP, 20 cases), 76% Na-meglumine diatrizoate (76% UG, 20 cases), and 38% Na-meglumine diatrizoate (38% UG, 10 cases). Sharpness and contrast of images, and portal vein visualization were evaluated in these groups. IOP provided better image quality and portal vein visualization than 76% UG. There was no significant difference between them in terms of side effects, such as contrast medium-induced pain and feeling of warmth, or changes in physiological parameters like blood pressure and heart rate. When a low osmolar contrast agent like IOP passes through the mesentery capillary bed, the eflux of the contrast agent into the interstitial space and the influx of water into the capillary may be less, resulting in less dilution of the contrast agent in the superior mesenteric vein. This might explain the better image quality and portal vein visualization of IOP.


FRACTURES OF THE LARYNX.
It is advised that in significant laryngeal trauma open exploration be done as soon as the general condition of the patient permits. The authors believe that the exact nature and severity of a laryngeal injury cannot otherwise be known, and that no method of closed reduction and fixation will accomplish as good results as open repair. Conservative expectant treatment will in many cases result in a much greater morbidity and a poor ultimate result.


[Development and validation of risk score model for acute myocardial infarction in China: prognostic value thereof for in hospital major adverse cardiac events and evaluation of revascularization].
To develop a simple risk score model of in-hospital major adverse cardiac events (MACE) including all-cause mortality, new or recurrent myocardial infarction (MI), and evaluate the efficacy about revascularization on patients with different risk. The basic characteristics, diagnosis, therapy, and in-hospital outcomes of 1512 ACS patients from Global Registry of Acute Coronary Events (GRACE) study of China were collected to develop a risk score model by multivariable stepwise logistic regression. The goodness-of-fit test and discriminative power of the final model were assessed respectively. The best cut-off value for the risk score was used to assess the impact of revascularization for ST-elevation MI (STEMI) and non-ST elevation acute coronary artery syndrome (NSTEACS) on in-hospital outcomes. (1) The following 6 independent risk factors accounted for about 92.5% of the prognostic information: age > or =80 years (4 points), SBP < or =90 mm Hg (6 points), DBP > or =90 mm Hg (2 points), Killip II (3 points), Killip III or IV (9 points), cardiac arrest during presentation (4 points), ST-segment elevation (3 points) or depression (5 points) or combination of elevation and depression (4 points) on electrocardiogram at presentation. (2) CHIEF risk model was excellent with Hosmer-Lemeshow goodness-of-fit test of 0.673 and c statistics of 0.776. (3)1301 ACS patients previously enrolled in GRACE study were divided into 2 groups with the best cut-off value of 5.5 points. The impact of revascularization on the in-hospital MACE of the higher risk subsets was stronger than that of the lower risk subsets both in STEMI [OR (95% CI) = 0.32 (0.11, 0.94), chi2 = 5.39, P = 0.02] and NSTEACS [OR (95% CI) = 0.32 (0.06, 0.94), chi2 =4.17, P = 0.04] population. However, both STEMI (61.7% vs. 78.3%, P = 0.000) and NSTEACS (42.0% vs 62.3%, P = 0.000) patients with the risk scores more than 5.5 points had lower revascularization rates. The risk score provides excellent ability to predict in-hospital death or (re) MI quantitatively and accurately. The patients undergoing revascularization with risk score greater than 5.5 have lower incidence rates of endpoint.


Modular and Processable Fluoropolymers Prepared via a Safe, Mild, Iodo-Ene Polymerization.
Fluoropolymers have infiltrated society as coatings and insulators. However, low processability, few opportunities for polymer functionalization, and explosive monomers hampering academic investigation of these materials have precluded the extension of the unique properties of perfluorocarbons to the cutting edge of material science. Here, we present semifluorinated iodo-ene polymers as a scaffold to overcome fluoropolymer limitations. A sodium dithionate initiated polymerization of perfluorodiiodides and dienes allows for high-molecular-weight polymers (>100 kDa) to be prepared in the presence of oxygen and water with up to 59 wt % fluorine content. These conditions are sufficiently mild to enable the polymerization of functional dienes, leading to biodegradable fluoropolymers. The iodo-ene polymerization results in the addition of polarizable iodine atoms, which improve polymer processability; yet, these atoms can be removed after processing for enhanced stability. Displacement of the iodine atoms with thiols or azides facilitates covalent surface modification and cross-linking. Finally, the low bond dissociation energy of the C-I bond allows allyl group addition as well as photo-cross-linking. Collectively, the simple synthesis and modular nature of the semifluorinated iodo-ene polymers will enable the convergence of perfluorocarbons and advanced materials.


Effects of Computer-assisted Cognitive Rehabilitation Training on the Cognition and Static Balance of the Elderly.
[Purpose] The purpose of this study was to investigate the effects of a six-week-long computer-assisted cognitive rehabilitation training program on the improvement of cognition and balance abilities of the elderly. [Subjects] Thirty healthy elderly people, aged 65 to 80, were randomly assigned either to the training group (n=15) or the control group (n=15). [Methods] Cognitive functions were evaluated using MMSE-K, and the BioRescue AP 153 (RMINGENIERIE, France) was used to examine subjects' changes in static balance. [Results] The MMSE-K score showed a significant change over the course of the treatment period in the training group, but not in the control group. The sway area and sway path length decreased significantly in the training group, but it did not show any changes in the control group. [Conclusion] Computer-assisted cognitive rehabilitation training is an effective intervention method for the improvement of the cognition and balance abilities of the elderly.


Florid cemento-osseous dysplasia and peripheral giant cell granuloma in a patient with neurofibromatosis 1.
We report a 35-year-old mulatto female patient with neurofibromatosis Type 1 who presented with facial asymmetry. The patient had two lesions: florid cemento-osseous dysplasia associated with peripheral giant cell granuloma. She was referred for surgical treatment of the peripheral giant cell granuloma and the florid cemento-osseous dysplasia was treated conservatively by a multidisciplinary team. So far, no changes have been observed in the patient's clinical status. We observed no recurrence of peripheral giant cell granuloma. To the best of our knowledge, the present case is the first report of a patient with neurofibromatosis Type 1 associated with a giant cell lesion and florid cemento-osseous dysplasia.


Mammalian alpha-polymerase: cloning of partial complementary DNA and immunobinding of catalytic subunit in crude homogenate protein blots.
A new polyclonal antibody against the alpha-polymerase catalytic polypeptide was prepared by using homogeneous HeLa cell alpha-polymerase. The antibody neutralized alpha-polymerase activity and was strong and specific for the alpha-polymerase catalytic polypeptide (Mr 183,000) in Western blot analysis of crude extracts of HeLa cells. The antibody was used to screen a cDNA library of newborn rat brain poly(A+) RNA in lambda gt11. A positive phage was identified and plaque purified. This phage, designated lambda pol alpha 1.2, also was found to be positive with an antibody against Drosophila alpha-polymerase. The insert in lambda pol alpha 1.2 (1183 base pairs) contained a poly(A) sequence at the 3' terminus and a short in-phase open reading frame at the 5' terminus. A synthetic oligopeptide (eight amino acids) corresponding to the open reading frame was used to raise antiserum in rabbits. Antibody affinity purified from this serum was found to be immunoreactive against purified alpha-polymerase by enzyme-linked immunosorbent assay and was capable of immunoprecipitating alpha-polymerase. This indicated the lambda pol alpha 1.2 insert encoded an alpha-polymerase epitope and suggested that the cDNA corresponded to an alpha-polymerase mRNA. This was confirmed in hybrid selection experiments using pUC9 containing the cDNA insert and poly(A+) RNA from newborn rat brain; the insert hybridized to mRNA capable of encoding alpha-polymerase catalytic polypeptides. Northern blot analysis of rat brain poly(A+) RNA revealed that this mRNA is approximately 5.4 kilobases.


Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD.
Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and poorly recognized complication of hematopoietic stem cell transplantation (HSCT) associated with excessive complement activation, likely triggered by endothelial injury. An important missing piece is the link between endothelial injury and complement activation. We hypothesized that neutrophil extracellular traps (NETs) mechanistically link endothelial damage with complement activation and subsequent TA-TMA. Neutrophil activation releases granule proteins together with double-stranded DNA (dsDNA) to form extracellular fibers known as NETs. NETs have been shown to activate complement and can be assessed in humans by quantification of dsDNA in serum. We measured levels of dsDNA, as a surrogate for NETs in 103 consecutive pediatric allogeneic transplant recipients at day 0, +14, +30, +60, and +100. A spike in dsDNA production around day +14 during engraftment was associated with subsequent TA-TMA development. Peak dsDNA production around day +14 was associated with interleukin-8-driven neutrophil recovery. Increased dsDNA levels at days +30, +60, and +100 were also associated with increased mortality and gastrointestinal graft-versus-host disease (GVHD). NETs may serve as a mechanistic link between endothelial injury and complement activation. NET formation may be one mechanism contributing to the clinical overlap between GVHD and TA-TMA.


Knee Arthroplasty in Klippel-Trénaunay Syndrome with 3-Dimensional-Printed Patient-Specific Instruments: A Case Report.
Using a multidisciplinary team approach, a cemented posterior-stabilized total knee arthroplasty was performed using 3-dimensional-printed patient-specific instruments (PSI) in a 34-year-old man with symptomatic end-stage knee osteoarthritis secondary to Klippel-Trénaunay syndrome (KTS). At 1-year follow-up, the patient was able to walk without pain and return to work. Knee arthroplasty is rare in patients with KTS. Compared with traditional instrumentation, PSI provides the benefit of minimal tissue dissection which can be advantageous in patients with altered anatomy such as KTS. Multidisciplinary cooperation is vital in terms of dealing with multiple comorbidities in KTS.


Characterization of human neural differentiation from pluripotent stem cells using proteomics/PTMomics--current state-of-the-art and challenges.
Stem cells are unspecialized cells capable of self-renewal and to differentiate into the large variety of cells in the body. The possibility to differentiate these cells into neural precursors and neural cells in vitro provides the opportunity to study neural development, nerve cell biology, neurological disease as well as contributing to clinical research. The neural differentiation process is associated with changes at protein and their post-translational modifications (PTMs). PTMs are important regulators of proteins physicochemical properties, function, activity, and interaction with other proteins, DNA/RNA, and complexes. Moreover, the interplay between PTMs is essential to regulate a range of cellular processes that abnormalities in PTM signaling are associated with several diseases. Altogether, this makes PTMs very relevant to study in order to uncover disease pathogenesis and increase the understanding of molecular processes in cells. Substantial advances in PTM enrichment methods and mass spectrometry has allowed the characterization of a subset of PTMs in large-scale studies. This review focuses on the current state-of-the-art of proteomic, as well as PTMomic studies related to human neural differentiation from pluripotent stem cells. Moreover, some of the challenges in stem cell biology, differentiation, and proteomics/PTMomics that are not exclusive to neural development will be discussed.


Herbal Extracts Combination (WNK) Prevents Decline in Spatial Learning and Memory in APP/PS1 Mice through Improvement of Hippocampal Aβ Plaque Formation, Histopathology, and Ultrastructure.
To investigate the cognitive enhancement effect of WNK, an extracts combination of P. ginseng, G. biloba, and C. sativus L. and possible mechanisms, 5-month-old APP/PS1 transgenic mice were used in this study. After 3 months of administration, all mice received Morris water maze (MWM) training and a probe test. Mouse brain sections were detected by immunohistochemistry, HE staining, and transmission electron microscopy. MWM results showed significant difference between transgenic mice and nontransgenic littermates (P < 0.05, P < 0.01). WNK-treated mice exhibited enhanced maze performance over the training progression, especially better spatial memory retention in probe test compared to transgenic mice (P < 0.05, P < 0.01) and better spatial learning and memory at the fourth day of MWM test compared to EGB761- (G. biloba extract-) treated ones (P < 0.05). Hippocampal Aβ plaque burden significantly differed between APP/PS1 and littermate mice (P < 0.001), while decreased Aβ plaque appeared in WNK- or EGB761-treated transgenic brains (P < 0.05). Neurodegenerative changes were evident from light microscopic and ultrastructural observations in transgenic brains, which were improved by WNK or EGB761 treatment. These data indicate WNK can reduce the decline in spatial cognition, which might be due to its effects on reducing Aβ plaque formation and ameliorating histopathology and ultrastructure in hippocampus of APP/PS1 mouse brain.


Topology specific stabilization of promoter over telomeric G-quadruplex DNAs by bisbenzimidazole carboxamide derivatives.
Various potential G-quadruplex forming sequences present in the genome offer a platform to modulate their function by means of stabilizing molecules. Though G-quadruplex structures exhibit diverse structural topologies, the presence of G-quartets as a common structural element makes the design of topology specific ligands a daunting task. To address this, the subtle structural variations of loops and grooves present in the quadruplex structures can be exploited. To this end, we report the design and synthesis of quadruplex stabilizing agents based on bisbenzimidazole carboxamide derivatives of pyridine, 1,8-naphthyridine, and 1,10-phenanthroline. The designed ligands specifically bind to and stabilize promoter quadruplexes having parallel topology over any of the human telomeric quadruplex topologies (parallel, hybrid, or antiparallel) and duplex DNAs. CD melting studies indicate that ligands could impart higher stabilization to c-MYC and c-KIT promoter quadruplexes (up to 21 °C increment in Tm) than telomeric and duplex DNAs (ΔTm ≤ 2.5 °C). Consistent with a CD melting study, ligands bind strongly (Kb = ∼10(4) to 10(5) M(-1)) to c-MYC quadruplex DNA. Molecular modeling and dynamics studies provide insight into how the specificity is achieved and underscore the importance of flexible N-alkyl side chains attached to the benzimidazole-scaffold in recognizing propeller loops of promoter quadruplexes. Overall, the results reported here demonstrate that the benzimidazole scaffold represents a potent and powerful side chain, which could judiciously be assembled with a suitable central core to achieve specific binding to a particular quadruplex topology.


Therapy processes and outcomes of psychological interventions for women diagnosed with gynecological cancers: A test of the generic process model of psychotherapy.
Little attention has been paid to the role of nonspecific therapy processes in the efficacy of psychological interventions for individuals diagnosed with cancer. The goal of the current study was to examine the three constructs from the generic model of psychotherapy (GMP): therapeutic alliance, therapeutic realizations, and therapeutic openness/involvement in the treatment outcome of women with gynecological cancers attending either a 7-session supportive counseling intervention or a coping and communication skills intervention. Two hundred and three women completed measures of alliance, realizations, and openness after Intervention Sessions 2, 3, and 6, as well as measures of depressive symptoms after these sessions and 6 months after the pre-intervention assessment (posttreatment). Consistent with the GMP, in early sessions, therapeutic bond predicted openness in terms of positive affect experienced during sessions, and both aspects of openness (positive and negative affect), in turn, predicted more therapeutic realizations. Therapeutic realizations predicted perceptions of greater session progress, and greater therapeutic bond predicted more therapeutic realizations. When early session GMP variables were used to predict later GMP processes and outcomes and posttreatment outcomes, early therapeutic bond predicted later session therapeutic realizations directly and indirectly via emotional arousal, emotional arousal predicted session progress, session progress predicted lower postsession depressive symptoms, and depressive symptoms as rated after Session 6 predicted depressive symptoms 3 months posttreatment. However, a number of additional associations among GMP processes were found. Our results suggest that therapy processes played a role in predicting both short- and long-term treatment outcomes.


Correlated response in litter size components in rabbits selected for litter size variability.
A divergent selection experiment for the environmental variability of litter size (Ve) over seven generations was carried out in rabbits at the University Miguel Hernández of Elche. The Ve was estimated as the phenotypic variance within the female, after correcting for year-season and parity-lactation status. The aim of this study was to analyse the correlated responses to selection in litter size components. The ovulation rate (OR) and number of implanted embryos (IE) in females were measured by laparoscopy at 12 day of the second gestation. At the end of the second gestation, the total number of kits born was measured (TB). Embryonic (ES), foetal (FS) and prenatal (PS) survival were computed as IE/OR, TB/IE and TB/OR, respectively. A total of 405 laparoscopies were performed. Data were analysed using Bayesian methodology. The correlated response to selection for litter size environmental variability in terms of the litter size components was estimated as either genetic trends, estimated by computing the average estimated breeding values for each generation and each line, or the phenotypic differences between lines. The OR was similar in both lines. However, after seven generations of selection, the homogenous line showed more IE (1.09 embryos for genetic means and 1.23 embryos for phenotypic means) and higher ES than the heterogeneous one (0.07 for genetic means and 0.08 for phenotypic means). The probability of the phenotypic differences between lines being higher than zero (p) was 1.00 and .99, respectively. A higher uterine overcrowding of embryos in the homogeneous line did not penalize FS; as a result, this line continued to show a greater TB (1.01 kits for genetic means and 1.30 kits for phenotypic means, p = .99, in the seventh generation). In conclusion, a decrease in litter size variability showed a favourable effect on ES and led to a higher litter size at birth.


Coping Action Patterns as Mechanisms of Change Across Psychotherapies: Three Case Examples of Personality Disorders With Recurrent Major Depression.
Maladaptive coping has been shown to be related to increased symptoms of distress and lower levels of well-being, whereas the use of adaptive coping has been shown to diminish distress and improve functioning. This suggests that change in coping may constitute a significant mechanism of change in psychotherapy. Utilizing a novel observer-rating method for assessing coping, the current report examined changes in overall coping functioning (OCF) in three participants with diverse personality disorders who were undergoing two different types of psychotherapy (cognitive-behavioral therapy and dynamic therapy) for recurrent major depression. Results showed that overall coping functioning improved in two cases and remained stable in a third. Preliminary findings, based on a detailed examination of changes in specific coping patterns, suggest that improvement may differ according to severity of personality pathology. As hypothesized, coping improved in both types of psychotherapy. Thus, overall results suggest that coping may constitute an important general mechanism of change.


PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study.
Cyclooxygenase-2 (COX-2), which is rapidly upregulated by inflammation, is a key enzyme catalyzing the rate-limiting step in the synthesis of several inflammatory prostanoids. Successful positron emission tomography (PET) radioligand imaging of COX-2 in vivo could be a potentially powerful tool for assessing inflammatory response in the brain and periphery. To date, however, the development of PET radioligands for COX-2 has had limited success. The novel PET tracer [11C]MC1 was used to examine COX-2 expression [1] in the brains of four rhesus macaques at baseline and after injection of the inflammogen lipopolysaccharide (LPS) into the right putamen, and [2] in the joints of two human participants with rheumatoid arthritis and two healthy individuals. In the primate study, two monkeys had one LPS injection, and two monkeys had a second injection 33 and 44 days, respectively, after the first LPS injection. As a comparator, COX-1 expression was measured using [11C]PS13. COX-2 binding, expressed as the ratio of specific to nondisplaceable uptake (BPND) of [11C]MC1, increased on day 1 post-LPS injection; no such increase in COX-1 expression, measured using [11C]PS13, was observed. The day after the second LPS injection, a brain lesion (~ 0.5 cm in diameter) with high COX-2 density and high BPND (1.8) was observed. Postmortem brain analysis at the gene transcript or protein level confirmed in vivo PET results. An incidental finding in an unrelated monkey found a line of COX-2 positivity along an incision in skull muscle, demonstrating that [11C]MC1 can localize inflammation peripheral to the brain. In patients with rheumatoid arthritis, [11C]MC1 successfully imaged upregulated COX-2 in the arthritic hand and shoulder and apparently in the brain. Uptake was blocked by celecoxib, a COX-2 preferential inhibitor. Taken together, these results indicate that [11C]MC1 can image and quantify COX-2 upregulation in both monkey brain after LPS-induced neuroinflammation and in human peripheral tissue with inflammation. ClinicalTrials.gov NCT03912428. Registered April 11, 2019.


Impacts of intensive follow-up on the long-term prognosis of percutaneous coronary intervention in acute coronary syndrome patients - a single center prospective randomized controlled study in a Chinese population.
To investigate the impact of cardiologist-coordinated intensive follow-up on the long-term prognosis of percutaneous coronary intervention in Chinese patients. We recruited 964 patients who had acute coronary syndrome and underwent successful percutaneous coronary intervention in the First Hospital Affiliated to Henan University of Science and Technology, China. Participants were randomly assigned into the intensive follow-up (n = 479) and usual follow-up group (control group, n = 485). They received secondary prevention education during hospitalization and telephone follow-ups after discharge. The control group received telephone calls from nurses, while the intensive follow-up group received telephone calls and medical consultations from cardiologists. Both groups were followed up for 36 months. (1) At 36 months, the proportions of all-cause death, cardiac death and cumulative major adverse cardiovascular events (MACEs) were 5.3%, 4.4% and 18.6% in the intensive follow-up group. These events were significantly lower than in the control group (10.1%, 9.3 % and 28.8% (p = 0.004, p = 0.003 and p < 0.001). (2) Multivariable Cox regression analysis identified intensive follow-up as an independent predictor of survival, cardiac death-free survival and MACE-free survival. (hazard ratio (HR) = 0.487, 95% confidence interval (CI) 0.298-0.797, p = 0.004; HR = 0.466, 95% CI 0.274-0.793, p = 0.005; HR = 0.614, 95% CI 0.464-0.811, p = 0.001). Kaplan-Meier analysis revealed that patients in the intensive follow-up groups had longer survival (log rank = 8.565, p = 0.003), cardiac death-free survival (log rank = 8.769, p = 0.003) and MACE-free survival (log rank = 15.928, p < 0.001). (3) The average medical cost was significantly less in the intensive follow-up group, especially the cost for re-hospitalization (US$582.74 ± 1753.20 vs. US$999.32 ± 2434.57, p = 0.003). The bleeding events were similar. (4) Patients in the intensive follow-up group had significantly better controls of cardiovascular risk factors and medication adherence. A cardiologist-coordinated intensive follow-up program markedly decreased cardiovascular risk factors, reduced medical costs, promoted medication adherence and improved the long-term prognosis of patients after percutaneous coronary intervention in the Chinese population.


Sub-Saharan African migrant youths' help-seeking barriers and facilitators for mental health and substance use problems: a qualitative study.
Many young migrants and their parents are reluctant to seek help for mental health and substance use problems. Help-seeking delays can result in longer duration of untreated problems and poorer outcomes. In this study, we aimed to identify the help-seeking barriers and facilitators for anxiety, depression and alcohol and drug use problems in young people from recently established sub-Saharan African migrant communities. A qualitative study, incorporating individual, in-depth interviews and focus group discussions, was undertaken in Melbourne, Australia. Twenty-eight young sub-Saharan African migrants participated in the individual interviews, and 41 sub-Saharan African-born parents and key community leaders participated in 4 focus groups. All participants were aged 16 years or over. A thematic analysis of the data was undertaken. Themes and related sub-themes were abstracted from the data, reflecting the young people's, parents' and key community leaders' beliefs about barriers and facilitators to help-seeking for mental health and substance use problems. Four help-seeking barriers were identified: stigma of mental illness, lack of mental health literacy in parents and young people, lack of cultural competency of formal help sources, and financial costs deterring access. Five help-seeking facilitators were abstracted: being open with friends and family, strong community support systems, trustworthiness and confidentiality of help-sources, perceived expertise of formal help-sources, increasing young people's and parents' mental health literacy. Programs that identify and build on help-seeking facilitators while addressing help-seeking barriers are needed to address mental health issues among young sub-Saharan African migrants. Strategies to address help-seeking barriers should consider counteracting stigma and increasing mental health literacy in sub-Saharan African communities, increasing health providers' cultural competency and perceived trustworthiness, and addressing financial barriers to accessing services.


Day-length encoding through tonic photic effects in the retinorecipient SCN region.
The circadian clock in the suprachiasmatic nucleus (SCN) plays a critical role in seasonal processes by sensing ambient photoperiod. To explore how it measures day-length, we assessed the state of SCN oscillators using markers for neuronal activity (c-FOS) and the clock protein (PER1) in Syrian hamsters housed in long (LD, 16 : 8 h light : dark) vs. short days (SD, 8 : 16 h light : dark). During SD, there was no detectable phase dispersion across the rostrocaudal extent of the nucleus. In contrast, during LD, rhythms in the caudal SCN phase led those in the mid- and rostral SCN by 4-8 h and 8-12 h, respectively. Importantly, some neurons in the retinorecipient core SCN were unique in that they were FOS-positive during the dark phase in LD, but not SD. Transfer of LD animals to constant darkness or skeleton photoperiod revealed that dark-phase FOS expression depends on tonic light exposure rather than on intrinsic clock properties. By transferring animals from SD to LD, we next discovered that there are two separate populations of SCN cells, one responding to acute and the other to tonic light exposure. The results suggest that the seasonal encoding of day-length by the SCN entails reorganization of its constituent oscillators by a subgroup of neurons in the SCN core that respond to tonic photic cues.


Circulating Protein Disulfide Isomerase Is Associated with Increased Risk of Thrombosis in JAK2-Mutated Myeloproliferative Neoplasms.
Thromboembolic events (TE) are the most common complications of myeloproliferative neoplasms (MPN). Clinical parameters, including patient age and mutation status, are used to risk-stratify patients with MPN, but a true biomarker of TE risk is lacking. Protein disulfide isomerase (PDI), an endoplasmic reticulum protein vital for protein folding, also possesses essential extracellular functions, including regulation of thrombus formation. Pharmacologic PDI inhibition prevents thrombus formation, but whether pathologic increases in PDI increase TE risk remains unknown. We evaluated the association of plasma PDI levels and risk of TE in a cohort of patients with MPN with established diagnosis of polycythemia vera (PV) or essential thrombocythemia (ET), compared with healthy controls. Plasma PDI was measured at enrollment and subjects followed prospectively for development of TE. A subset of patients, primarily those with JAK2-mutated MPN, had significantly elevated plasma PDI levels as compared with controls. Plasma PDI was functionally active. There was no association between PDI levels and clinical parameters typically used to risk-stratify patients with MPN. The risk of TE was 8-fold greater in those with PDI levels above 2.5 ng/mL. Circulating endothelial cells from JAK2-mutated MPN patients, but not platelets, demonstrated augmented PDI release, suggesting endothelial activation as a source of increased plasma PDI in MPN. The observed association between plasma PDI levels and increased risk of TE in patients with JAK2-mutated MPN has both prognostic and therapeutic implications.


First comparative analysis of complete chloroplast genomes among six Hedysarum (Fabaceae) species.
Hedysarum is one of the largest genera in the Fabaceae family, mainly distributed in the Northern Hemisphere. Despite numerous molecular studies on the genus Hedysarum, there is still a lack of research aimed at defining the specific characteristics of the chloroplast genome (cp genome) of the genus. Furthermore, the interrelationships between sections in the genus based on the cp genome have not yet been studied. In this study, comprehensive analyses of the complete cp genomes of six Hedysarum species, corresponding to sections Multicaulia, Hedysarum, and Stracheya were conducted. The complete cp genomes of H. drobovii, H. flavescens, and H. lehmannianum were sequenced for this study. The cp genomes of six Hedysarum species showed high similarity with regard to genome size (except for H. taipeicum), gene sequences, and gene classes, as well as the lacking IR region. The whole cp genomes of the six species were found to contain 110 genes ranging from 121,176 bp to 126,738 bp in length, including 76 protein-coding genes, 4 rRNA genes, and 30 tRNA genes. In addition, chloroplast SSRs and repetitive sequence regions were reported for each species. The six Hedysarum species shared 7 common SSRs and exhibited 14 unique SSRs. As well, three highly variable genes (clpP, accD, and atpF) with high Pi values were detected among protein-coding genes. Furthermore, we conducted phylogenetic analyses using the complete cp genomes and 76 protein-coding genes of 14 legume species, including the seven Hedysarum species. The results showed that the Hedysarum species form a monophyletic clade closely related to the genera Onobrychis and Alhagi. Furthermore, both of our phylogenetic reconstructions showed that section Stracheya is more closely related to section Hedysarum than to section Multicaulia. This study is the first comprehensive work to investigate the genome characteristics of the genus Hedysarum, which provides useful genetic information for further research on the genus, including evolutionary studies, phylogenetic relationships, population genetics, and species identification.


Immunization-based scores as independent prognostic predictors in soft tissue sarcoma patients.
Background: The purpose of this study was to examine and compare the prognostic value of different immunization-based scoring systems in patients with soft tissue sarcoma (STS). Methods: We conducted a retrospective study evaluating a cohort of 165 patients diagnosed with STS between July 2007 and July 2014. The relative Glasgow prognostic score (GPS) of these patients was calculated using 3 different systems: the traditional GPS system (tGPS), the modified GPS system 1 (m1GPS), and the modified GPS system 2 (m2GPS). Then, we evaluated the relationships between each GPS system and clinicopathological characteristics. The mean follow-up for survivors in the cohort was 73.7 months as of March 2015. Results: The most favorable overall survival (OS) rate was associated with the score 0 groups, and the poorest progression-free survival (PFS) rate was associated with the score 2 groups, regardless of which system was used to calculate the score. Specifically, the m1GPS provided the greatest accuracy in predicting OS and PFS. Moreover, the same effect was observed in a separate analysis restricted to patients with metastases. Remarkably, in patients with a score of 2 as measured by all 3 systems, local treatment resulted in a poorer prognosis compared to patients with a score of 2 who did not receive local treatment. Conclusion: The GPS is a valuable prognostic marker and has the capability to predict the appropriate treatment strategy for STS patients with metastases. The modified GPS systems demonstrated superior prognostic and predictive value compared with the traditional GPS system.


Development of insulin resistance and hyperphagia in Zucker fatty rats.
The onset of hyperphagia in the Zucker fatty (fa/fa) rat occurs on a single day in postnatal development and could be driven by an increase in insulin sensitivity. To test this hypothesis, we performed insulin tolerance tests at several points in development. In rapidly growing juvenile rats, fatty rats are as insulin sensitive as lean rats at 4 wk of age but become increasingly insulin resistant as they became obese. During the suckling to weaning transition, fatty rats are insulin resistant at 2 wk of age, when they are exclusively suckling; they are also insulin resistant at 3 wk of age, when they are suckling and consuming solid food, but not hyperphagic. By 4 wk of age, when fatty rats are hyperphagic, they are as insulin sensitive as their lean littermates. These data indicate that fatty rats experience two phases of insulin resistance, punctuated by a brief period of insulin sensitivity that follows the onset of hyperphagia. To determine whether the increase in insulin sensitivity could be driving the onset of hyperphagia, insulin tolerance tests were performed from 21 to 27 days of age. Obese and lean rats became increasingly insulin resistant from 21 to 23 days of age and then became as insulin sensitive as lean rats by 25 days of age. These data show that increased insulin resistance precedes the onset of hyperphagia and increased insulin sensitivity follows the onset of hyperphagia. This pattern suggests that developmental perturbations in insulin signaling are likely to be involved in the onset of hyperphagia.


The activity of ventral tegmental area dopamine neurons during shock omission predicts safety learning.
We studied the role of dopamine [tyrosine hydroxylase (TH)] neurons in the rat ventral tegmental area (VTA) in safety learning. First, we used an AX +/BX-discrimination procedure to establish conditioned stimulus (CS) B as a learned safety signal that passed both summation and retardation tests of conditioned inhibition. Then, we combined this procedure with fiber photometry in TH-Cre rats to study the activity of VTA dopamine neurons during safety learning. We show that whereas footshock is associated with calcium transients in TH neurons across the VTA, shock omission during safety learning is selectively associated with calcium transients in dopamine neurons in the medial but not lateral VTA. Moreover, the magnitude of medial VTA calcium transients during shock omission accurately predicts the amount of safety that is learned and expressed during summation testing. Our findings are consistent with a common medial VTA dopamine mechanism contributing to the learned inhibition of fear in extinction and safety. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Knowledge, attitudes and practices about malaria in Cabo Verde: a country in the pre-elimination context.
Malaria in Cape Verde is unstable, with a sporadic and seasonal transmission of low endemicity. In this sense, the community perceptions regarding malaria transmission, their attitudes and practices against the disease are very important to understand and to better develop the best strategical policies to achieve malaria elimination goal. This study aim to assess the knowledge, attitudes and practices (KAP) of Cape Verdean population about malaria, a country in the elimination step of disease. A cross-sectional malaria KAP Survey was performed at the household level. A structured open questionnaire was developed and applied to residents of randomly selected households from 5 islands and 15 municipalities in Cape Verde. Correlation analyses were performed using a logistic regression model to determine the factors that are associated with the complete knowledge of the population about malaria. A total of 1953 fully completed questionnaires were analysed, with majority of questionnaires administered in Santiago island (68.3%), mainly in the capital city of Praia, 38.43%. About 88% of the population knew the correct form of transmission, 96% had knowledge that the entire population is at risk of malaria and identified the main symptoms. Regarding the attitudes, 58% seek treatment atthe nearest health structure upon the apparition of the symptoms, 64% in the first 24 h and 88% within the first 48 h. More than 97% have heard about mosquito nets but only 19% used it. In practice, 53% use coils, 45% rely on household sprays and 43% have benefited from IRS. About 90% received information about malaria from media, mainly the TV and the radio (83 and 43%, respectively). In summary, 54% of the population has complete knowledge of the disease. The population of Cape Verde has a high level of knowledge about malaria, including its transmission, main symptoms and preventive and control measures. However, some gaps and misunderstandings have been noticed and contribute to the insufficient community involvement in actions against malaria. Therefore, is necessary to increase the knowledge of the population, leading to their full ownership and participation in community actions to contribute to the malaria elimination in the country.


Maintaining placement of temporary enteral feeding tubes in adults: a critical appraisal of the evidence.
Maintaining placement of temporary enteral feeding tubes requires ongoing bedside nursing assessment. Tube placement verification is essential to detect and minimize adverse effects. A critical appraisal of current evidence and best practice recommendations regarding temporary feeding tubes is provided.


Congestive heart failure due to aortic incompetence with intestinal infarction due to endarteritis obliterans.
A 27-year-old man with congestive heart failure due to aortic incompetence and subsequent intestinal infarction was found at laparotomy to have extensive necrosis of the bowel due to proliferative endarteritis. Symptoms resolved following treatment with prednisolone and cyclophosphamide, and replacement of the aortic valve. The sub-total occlusion produced by endarteritis obliterans may lead to acute end-organ infarction if cardiac output is reduced.


Neurolin, the goldfish homolog of DM-GRASP, is involved in retinal axon pathfinding to the optic disk.
Young axons of new retinal ganglion cells (RGCs) in the continuously growing goldfish retina fasciculate with one another and their immediate forerunners on their path toward the optic disk and along the optic nerve. They express the immunoglobulin superfamily cell adhesion molecules (CAMs) neurolin (DM-GRASP) and the L1-like E587 antigen. Repeated injections of Fab fragments from polyclonal antisera against neurolin (neurolin Fabs) into the eye of 3. 4-cm-long and rapidly growing goldfish caused highly aberrant pathways of young RGC axon subfascicles in the dorsal retina. Many axons grew in circles and failed to reach the optic disk. In contrast, E587 Fabs, used in parallel experiments, disrupted the fascicles but did not interfere with the disk-directed growth. Neurolin Fabs also disturbed axonal fasciculation in vivo as well as in vitro but less severely than E587 Fabs. Coinjections of both Fabs increased defasciculation of the dorsal axons in both aberrant and disk-directed routes. They also disrupted the order of young RGC axons in the optic nerve more severely than E587 Fabs alone. This demonstrates that the development of tight and orderly fascicles in the dorsal retina and in the optic nerve requires both E587 antigen and neurolin. More importantly, our results suggest an involvement of neurolin in RGC axonal guidance from the retinal periphery to the optic disk. Because disrupted fascicles and errant axon routes were found only in the dorsal retinal half, a cooperation with so-called positional markers may be conceived.


Lessons learned from a fatal case of tuberculous meningitis with a rapid decline in an infant.
Tuberculous meningitis is a highly lethal, often underrecognized disease with characteristic clinical and imaging features which can be cured if the diagnosis and subsequent treatment are begun at early stages. Frequently, there is a delayed diagnosis of this condition due to unfamiliarity of clinicians in non-endemic areas about its presentation and diagnostic workup. This article presents a case of rapid decline and fatality due to tuberculous meningitis in an 11-month-old child from a non-TB-endemic area and describes the characteristic clinical presentation, imaging findings, and diagnostic pitfalls associated with this condition.


Physiological responses and performance in a simulated trampoline gymnastics competition in elite male gymnasts.
Physiological responses and performance were examined during and after a simulated trampoline competition (STC). Fifteen elite trampoline gymnasts participated, of which eight completed two routines (EX1 and EX2) and a competition final (EX3). Trampoline-specific activities were quantified by video-analysis. Countermovement jump (CMJ) and 20 maximal trampoline jump (20-MTJ) performances were assessed. Heart rate (HR) and quadriceps muscle temperature (Tm) were recorded and venous blood was drawn. A total of 252 ± 16 jumps were performed during the STC. CMJ performance declined (P < 0.05) by 3.8, 5.2 and 4.2% after EX1, EX2 and EX3, respectively, and was 4.8% lower (P < 0.05) than baseline 24 h post-competition. 20-MTJ flight time was ~1% shorter (P < 0.05) for jump 1-10 after EX2 and 24 h post STC. Tm increased (P < 0.05) to ~39°C after the warm-up, but declined (P < 0.05) 1.0 and 0.6ºC before EX2 and EX3, respectively. Peak HR was 95-97% HRmax during EX1-3. Peak blood lactate, plasma K(+) and NH3 were 6.5 ± 0.5, 6.0 ± 0.2 mmol · l(-1) and 92 ± 10 µmol · l(-1), respectively. Plasma CK increased (P < 0.05) by ~50 and 65% 0 and 24 h after STC. In conclusion, a trampoline gymnastic competition includes a high number of repeated explosive and energy demanding jumps, which impairs jump performance during and 24 h post-competition.


Shaping meiotic chromosomes with SUMO: a feedback loop controls the assembly of the synaptonemal complex in budding yeast.
The synaptonemal complex (SC) is a meiosis-specific chromosomal structure in which homologous chromosomes are intimately linked through arrays of specialized proteins called transverse filaments (TF). Widely conserved in eukaryote meiosis, the SC forms during prophase I and is essential for accurate segregation of homologous chromosomes at meiosis I. However, the basic mechanism overlooking formation and regulation of the SC has been poorly understood. By using the budding yeast Saccharomyces cerevisiae, we recently showed that SC formation is controlled through the attachment of multiple molecules of small ubiquitin-like modifier (SUMO) to a regulator of TF assembly. Intriguingly, this SUMOylation is activated by TF, implicating the involvement of a positive feedback loop in the control of SC assembly. We discuss the implication of this finding and possible involvement of a similar mechanism in regulating other processes.


Prevalence of thyroid dysfunction and its correlation with CD4 count in newly-diagnosed HIV-positive adults--a cross-sectional study.
Prevalence of subclinical hypothyroidism in HIV-positive patients is reported to be high in those with severe immune deficiency. However, there is paucity of literature in newly-diagnosed HIV-positive population. Our aim was to estimate the prevalence of thyroid dysfunction and study its correlation with CD4 count in this population. In this cross-sectional study, patients presenting to the antiretroviral therapy clinic were screened with thyroid function tests, including thyroid stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid peroxidase antibody levels at the time of diagnosis. Two hundred and twenty-five HIV-positive and an equal number of healthy volunteers were enrolled. The mean (SD) CD4 count in the study group was 147.1 (84) and 70.7% had advanced immune deficiency with CD4 count <200 cells/µL. The overall prevalence of thyroid dysfunction was 75.5% in the study group and 16% in the control group. Subclinical hypothyroidism was the commonest abnormality noted in almost 53%. Significant correlation was observed between CD4 count and thyroid stimulating hormone, free triiodothyronine, and free thyroxine levels (r = -0.86, r = 0.77, and r = 0.84, respectively, p < 0.0001 for all). The present study demonstrated high prevalence of thyroid dysfunction in HIV-positive patients. The dysfunction is subclinical in most cases and correlates well with declining CD4 counts.


Molecular digital pathology: progress and potential of exchanging molecular data.
Many of the demands to perform next generation sequencing (NGS) in the clinical laboratory can be resolved using the principles of telepathology. Molecular telepathology can allow facilities to outsource all or a portion of their NGS operation such as cloud computing, bioinformatics pipelines, variant data management, and knowledge curation. Clinical pathology laboratories can electronically share diverse types of molecular data with reference laboratories, technology service providers, and/or regulatory agencies. Exchange of electronic molecular data allows laboratories to perform validation of rare diseases using foreign data, check the accuracy of their test results against benchmarks, and leverage in silico proficiency testing. This review covers the emerging subject of molecular telepathology, describes clinical use cases for the appropriate exchange of molecular data, and highlights key issues such as data integrity, interoperable formats for massive genomic datasets, security, malpractice and emerging regulations involved with this novel practice.


The relationship between bilateral spike and wave complexes and focal discharges in patients with partial epilepsy.
The goal of this study was to investigate in patients with partial epilepsy the relationship between bilateral spike and wave (BSW) complexes of a generalized epilepsy and the focal spikes of partial epilepsy. For the study 300 patients were collected, all with focal epilepsy on their last hospital visit: 150 were well controlled (C) and 150 were uncontrolled (U), and the number of EEGs was 674 in the C and 804 in the U groups. BSW were seen at some time in 25% of all patients, more often in the U than C patients, especially the irregular 3/sec form. The bilateral complexes at times appeared at the onset of the epilepsy, usually at the same time with focal discharges, mainly from temporal or frontal areas. The U patients showed these complexes at a younger age than the C group and continued to be seen often into the 30s, occasionally into the 60s age group. The other presentation of the BSW was years after the onset of the focal discharges, usually temporal or frontal in location and more often seen in the U than C group. The U group showed spikes, many in number as active foci, more often than the C group. The discussion deals with the possibility that these bilateral spike and wave complexes may represent a reflection of a lowered threshold to a seizure.


House dust mite allergen levels in individual bedding components in New Zealand.
House dust mite allergen (Der p 1) levels are high in New Zealand and bedding Der p 1 levels have been shown to be associated with the clinical severity of asthma. The aim of this study was to measure Der p 1 levels in synthetic and feather duvets and other individual bedding items, and to examine factors affecting these levels. Reservoir dust samples were collected and analysed for Der p 1 content by ELISA from 65 duvets, 81 pillows, and 65 mattresses of 34 children and 31 adults in 34 households. Der p 1 geometric mean levels (95% confidence interval) were: 13.4 microg/g (9.5-18.9) in pillows; 29.4 microg/g (19.8-43.5) in duvets; and 53.8 microg/g (39.4-73.4) in mattresses. Synthetic pillows and duvets yielded significantly more Der p 1 than feather pillows and duvets (about 7-fold and 15-fold respectively). The presence of under-bedding resulted in significantly higher pillow and duvet Der p 1 levels. Mattresses >10 years old had significantly higher Der p 1 levels. Synthetic pillows and duvets contain higher levels of Der p 1 than feather pillows and duvets. Advise for house dust mite sensitized individuals to use synthetic bedding does not prevent house dust mite allergen exposure.


Radiotherapy for initial clinically positive internal mammary nodes in breast cancer.
Internal mammary lymph node (IMN) involvement is associated with poor prognosis in breast cancer. This study investigated the treatment outcomes of initial clinically IMN-positive breast cancer patients who received adjuvant radiotherapy (RT), including IMN irradiation, following primary breast surgery. We retrospectively reviewed data of 95 breast cancer patients with clinically detected IMNs at diagnosis treated with surgery and RT between June 2009 and December 2015. Patients received adjuvant RT to the whole breast/chest wall and regional lymph node (axillary, internal mammary, and supraclavicular) areas. Twelve patients received an additional boost to the IMN area. The median follow-up was 43.2 months (range, 4.5 to 100.5 months). Among 77 patients who received neoadjuvant chemotherapy, 52 (67.5%) showed IMN normalization and 19 (24.6%) showed a partial response to IMN. There were 3 and 24 cases of IMN failure and any recurrence, respectively. The 5-year IMN failure-free survival, disease-free survival (DFS), and overall survival (OS) were 96%, 70%, and 84%, respectively. IMN failure-free survival was significantly affected by resection margin status (97.7% if negative, 87.5% for close or positive margins; p = 0.009). All three patients with IMN failure had initial IMN size ≥1 cm and did not receive IMN boost irradiation. The median age of the three patients was 31 years, and all had hormone receptor-negative tumors. RT provides excellent IMN control without the support of IMN surgery. Intensity-modulated radiotherapy, including IMN boost for breast cancer patients, is a safe and effective technique for regional lymph node irradiation.


Coexpression of UL20p and gK inhibits cell-cell fusion mediated by herpes simplex virus glycoproteins gD, gH-gL, and wild-type gB or an endocytosis-defective gB mutant and downmodulates their cell surface expression.
Syncytium formation in cells that express herpes simplex virus glycoprotein B (gB), gD, gH, and gL is blocked by gK (E. Avitabile, G. Lombardi, and G. Campadelli-Fiume, J. Virol. 77:6836-6844, 2003). Here, we report the results of two series of experiments. First, UL20 protein (UL20p) expression weakly inhibited cell-cell fusion. Coexpression of UL20p and gK drastically reduced fusion in a cell-line-dependent manner, with the highest inhibition in BHK cells. Singly expressed UL20p and gK localized at the endoplasmic reticulum and nuclear membranes. When they were coexpressed, both proteins relocalized to the Golgi apparatus. Remarkably, in cells that coexpressed UL20p and gK, the antifusion activity correlated with a downmodulation of gD, gB, gH, and gL cell surface expression. Second, gB(Delta867) has a partial deletion in the cytoplasmic tail that removed endocytosis motifs. Whereas wild-type (wt) gB was internalized in vesicles lined with the endosomal marker Rab5, gB(delta867) was not internalized, exhibited enhanced cell surface expression, and was more efficient in mediating cell-cell fusion than wt gB. The antifusion activity of UL20p and gK was also exerted when gB(delta867) replaced wt gB in the cell fusion assay. These studies show that the gB C tail carries a functional endocytosis motif(s) and that the removal of the motif correlated with increased gB surface expression and increased fusion activity. We conclude that cell-cell fusion in wt-virus-infected cells is negatively controlled by at least two mechanisms. The novel mechanism described here involves the concerted action of UL20p and gK and correlates with a moderate but consistent reduction in the cell surface expression of the fusion glycoproteins. This mechanism is independent of the one exerted through endocytosis-mediated downmodulation of gB from the plasma membrane.


The Role of MAPK Pathways in Airborne Fine Particulate Matter-Induced Upregulation of Endothelin Receptors in Rat Basilar Arteries.
Airborne fine particulate matter (PM(2.5)) increases the risk of cerebrovascular diseases. However, existing experimental data do not sufficiently explain how PM(2.5) affects cerebral vessels. This study sought to examine whether PM(2.5) alters endothelin (ET) receptor expression on rat cerebral arteries and the potential underlying mechanisms. Isolated rat basilar arteries were cultured with PM(2.5) aqueous suspension in the presence of mitogen-activated protein kinase (MAPK) pathway inhibitors. ET receptor-mediated vasomotor functions were recorded by a sensitive myograph. ET(A) and ET(B) receptor mRNA and protein expressions were assessed using quantitative real-time PCR, Western blotting, and immunohistochemistry, respectively. Compared with fresh and culture alone arteries, PM(2.5) significantly enhanced ET(A) and ET(B) receptor-mediated contractions and increased receptor mRNA and protein expressions in basilar arteries, indicating PM(2.5) upregulates ET(A) and ET(B) receptors. Culturing with SB386023 (MEK/ERK1/2 inhibitor), U0126 (ERK1/2 inhibitor), SP600125 [c-Jun N-terminal kinase (JNK) inhibitor], or SB203580 (p38 inhibitor) attenuated PM(2.5)-induced ETB receptor upregulation. PM(2.5)-induced enhancement of ET(A) receptor-mediated contraction and receptor expression was notably inhibited by SB386023 or U0126. However, neither SP600125 nor SB203580 had an effect on PM(2.5)-induced ET(A) receptor upregulation. In conclusion, PM(2.5) upregulates ET(A) and ET(B) receptors in rat basilar arteries. ET(B) receptor upregulation is involved in MEK/ERK1/2, JNK, and p38 MAPK pathways, and ET(A) receptors upregulation is associated with MEK/ERK1/2 pathway.


Granisetron reduces postoperative nausea and vomiting throughout menstrual cycle.
The incidence of postoperative nausea and vomiting (PONV) is influenced by menstruation. This study was undertaken to assess the efficacy of granisetron, a selective 5-hydroxytryptamine type 3 receptor antagonist, for preventing PONV in patients during two different phases of menstrual cycle. One hundred twenty female patients undergoing general anaesthesia for major gynaecological surgery were divided according to the phase of menstrual cycle into two groups: day one to eight (menstrual) and day nine to end of the cycle (non-menstrual) groups. In a randomized, double-blind manner, the patients received placebo (saline) or 40 micrograms.kg-1 granisetron i.v. immediately before the induction of anaesthesia. All patients received a standardized general and epidural anaesthesia and epidural morphine plus bupivacaine for postoperative analgesia. The incidence of PONV and other adverse events was recorded during the first 24 hr after anaesthesia. The treatment groups were similar with respect to patient demographics, types of surgery, anaesthetics administered and analgesics used postoperatively. The incidence of PONV was 72% and 32% in patients during menstruation receiving placebo or granisetron (P < 0.05), and was 46% and 20% in those during non-menstruation, respectively (P < 0.05). No differences in the incidence of other adverse events were observed among the groups. Granisetron was effective in reducing the incidence of PONV in both phases of the menstrual cycle studied.


Chronic pelvic pain in women.
The etiology of chronic pelvic pain in women is poorly understood. Although a specific diagnosis is not found in the majority of cases, some common diagnoses include endometriosis, adhesions, irritable bowel syndrome, and interstitial cystitis. The initial history and physical examination can narrow the diagnostic possibilities, guide any subsequent evaluation, and rule out malignancy or significant systemic disease. If the initial evaluation does not reveal a specific diagnosis, a limited laboratory and ultrasound evaluation can clarify the diagnosis, as well as rule out serious disease and reassure the patient. Few treatment modalities have demonstrated benefit for the symptoms of chronic pelvic pain. The evidence supports the use of oral medroxyprogesterone, goserelin, adhesiolysis for severe adhesions, and a multidisciplinary treatment approach for patients without a specific diagnosis. Less supporting evidence is available for oral analgesics, combined oral contraceptive pills, gonadotropin-releasing hormone agonists, intramuscular medroxyprogesterone, trigger point and botulinum A toxin injections, neuromodulative therapies, and hysterectomy.


[Monitoring of the residue of fosthiazate in water samples using solid-phase extraction coupled with gas chromatography/mass spectrometry].
Solid-phase extraction (SPE) coupled with gas chromatography/mass spectrometry (GC/MS) was used to determine the fosthiazate residue in water samples. The water samples were first filtered through cellulose filters (0.45 microm pore size). A 100 mL volume of filtered water, in which 1 mL of methanol has been added, was then passed through a pre-conditioned 3 cm C18 cartridge at a flow-rate of 1.5 mL/min. Elution was performed by 1 mL of methanol. The eluant was finally dried under reduced pressure for solvent evaporation. The volume was quantitatively adjusted to 0.5 mL with methanol. The analysis was carried out on GC/MS. The mass spectrometer was operated in selected ion monitoring (SIM) mode. According to mass spectrum of fosthiazate, three selected ions at m/z of 126, 195, 283, respectively, were monitored for identification and quantification. High sensitivity and selectivity were achieved by using this method. The limit of detection for fosthiazate in water samples was determined to be 56.4 ng/L. The linearity was demonstrated over a wide range of concentrations covering from 0.282 to 141 microg/L. The recoveries were more than 85.5% and the relative standard deviations for the overall procedure were less than 4.42%. The fosthiazate residue was detected in the water samples from a pool near cropland where fosthiazate was used. The results demonstrate the suitability of the SPE-GC/MS approach for the analysis of fosthiazate in water.


Reduced C(beta) statistical potentials can outperform all-atom potentials in decoy identification.
We developed a series of statistical potentials to recognize the native protein from decoys, particularly when using only a reduced representation in which each side chain is treated as a single C(beta) atom. Beginning with a highly successful all-atom statistical potential, the Discrete Optimized Protein Energy function (DOPE), we considered the implications of including additional information in the all-atom statistical potential and subsequently reducing to the C(beta) representation. One of the potentials includes interaction energies conditional on backbone geometries. A second potential separates sequence local from sequence nonlocal interactions and introduces a novel reference state for the sequence local interactions. The resultant potentials perform better than the original DOPE statistical potential in decoy identification. Moreover, even upon passing to a reduced C(beta) representation, these statistical potentials outscore the original (all-atom) DOPE potential in identifying native states for sets of decoys. Interestingly, the backbone-dependent statistical potential is shown to retain nearly all of the information content of the all-atom representation in the C(beta) representation. In addition, these new statistical potentials are combined with existing potentials to model hydrogen bonding, torsion energies, and solvation energies to produce even better performing potentials. The ability of the C(beta) statistical potentials to accurately represent protein interactions bodes well for computational efficiency in protein folding calculations using reduced backbone representations, while the extensions to DOPE illustrate general principles for improving knowledge-based potentials.