Pathology case of the month. 39-year-old woman with abdominal pain and weight loss. Takayasu's arteritis (TA).
A 39-year-old white woman presented with a history of aortoiliac occlusive disease diagnosed in 1992 attributed to oral contraceptive use. Shortly thereafter, aortoiliac replacement was performed. Mild hyperlipidemia was diagnosed in 2001. At the current clinic visit, she presented to her primary care physician with a 3-month history of postprandial midepigastric abdominal pain relieved by vomiting and a 30-pound weight loss. Her evaluation included an esophagogastroduodenoscopy, a colonoscopy, and an abdominal ultrasound, all of which were within normal limits. Because of her medical history, the patient underwent an arteriogram, which revealed brachiocephalic stenosis (Figure 1), occlusion of the left subclavian artery (Figures 2a and 2b), and narrowing of the superior and inferior mesenteric arteries (not shown). Since she had discontinued her oral contraceptives in 1992 and her hyperlipidemia was mild, the rheumatology service was consulted to evaluate this patient. On physical examination, she had decreased left brachial and radial pulses and a right carotid bruit. Laboratory evaluation revealed a normal complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, and C - reactive protein. Subsequent testing included a prothrombin time, activated partial thromboplastin time, protein S, protein C, reptilase time, antithrombin III, anticardiolipin antibody, antiphospholipid antibody, lupus anticoagulant, homocysteine, RPR, and a lipid profile. All test results were within normal limits. Due to the severity of her abdominal pain, the patient underwent superior mesenteric artery (SMA) bypass surgery. Sections from the aorta resected in 1992 are shown in Figures 3 and 4.


Nature of the Schwann cell electrical potential. Effects of the external ionic concentrations and a cardiac glycoside.
The effects on the Schwann cell electrical potential of external ionic concentrations and of K-strophanthoside were investigated. Increasing (K)(o) depolarized the cell. The potential is related to the logarithm of (K)(o) in a quasi-linear fashion. The linear portion of the curve has a slope of 45 mv/ten-fold change in (K)(o). Diminutions of (Na)(o) and (Cl)(o) produced only small variations in the potential. Calcium and magnesium can be replaced by 44 mM calcium without altering the potential. Increase of (Ca)(o) to 88 mM produced about 10 mv hyperpolarization. The cell was hyperpolarized by 11 mv and 4 mv within 1 min after applying K-strophanthoside at concentrations of 10(-3) and 10(-5)M, respectively. No variations of cellular potassium, sodium, or chloride were observed 3 min after applying the glycoside. The hyperpolarization caused by 10(-3)M K-strophanthoside was not observed when (K)(o) was diminished to 1 or 0.1 mM or was increased to 30 mM. At a (K)(o) of 30 mM, 10(-2)M strophanthoside was required to produce the hyperpolarizing effect. In high calcium, the cell was further hyperpolarized by the glycoside. The initial hyperpolarization caused by the glycoside was followed by a gradual depolarization and a decrease of the cellular potassium concentration. The results indicate that the Schwann cell potential of about -40 mv is due to ionic diffusion, mainly of potassium, and to a cardiac glycoside-sensitive ion transport process.


Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer.
There is a continuing debate about the proportion of cancer patients that benefit from precision oncology, attributable in part to conflicting views as to which molecular alterations are clinically actionable. To quantify the expansion of clinical actionability since 2017, we annotated 47,271 solid tumors sequenced with the MSK-IMPACT clinical assay using two temporally distinct versions of the OncoKB knowledge base deployed 5 years apart. Between 2017 and 2022, we observed an increase from 8.9% to 31.6% in the fraction of tumors harboring a standard care (Level 1 or 2) predictive biomarker of therapy response and an almost halving of tumors carrying non-actionable drivers (44.2% to 22.8%). In tumors with limited or no clinical actionability, TP53 (43.2%), KRAS (19.2%) and CDKN2A (12.2%) were the most frequently altered genes.


Genetic risk scores, sex and dietary factors interact to alter serum uric acid trajectory among African-American urban adults.
Serum uric acid (SUA), a causative agent for gout among others, is affected by both genetic and dietary factors, perhaps differentially by sex. We evaluated cross-sectional (SUAbase) and longitudinal (SUArate) associations of SUA with a genetic risk score (GRS), diet and sex. We then tested the interactive effect of GRS, diet and sex on SUA. Longitudinal data on 766 African-American urban adults participating in the Healthy Aging in Neighborhood of Diversity across the Lifespan study were used. In all, three GRS for SUA were created from known SUA-associated SNP (GRSbase (n 12 SNP), GRSrate (n 3 SNP) and GRStotal (n 15 SNP)). Dietary factors included added sugar, total alcohol, red meat, total fish, legumes, dairy products, caffeine and vitamin C. Mixed-effects linear regression models were conducted. SUAbase was higher among men compared with that among women, and increased with GRStotal tertiles. SUArate was positively associated with legume intake in women (γ=+0·14; 95 % CI +0·06, +0·22, P=0·001) and inversely related to dairy product intake in both sexes combined (γ=-0·042; 95 % CI -0·075, -0·009), P=0·010). SUAbase was directly linked to alcohol consumption among women (γ=+0·154; 95 % CI +0·046, +0·262, P=0·005). GRSrate was linearly related to SUArate only among men. Legume consumption was also positively associated with SUArate within the GRStotal's lowest tertile. Among women, a synergistic interaction was observed between GRSrate and red meat intake in association with SUArate. Among men, a synergistic interaction between low vitamin C and genetic risk was found. In sum, sex-diet, sex-gene and gene-diet interactions were detected in determining SUA. Further similar studies are needed to replicate our findings.


ANESTHETIC MANAGEMENT OF AN INDO-PACIFIC BOTTLENOSE DOLPHIN (TURSIOPS ADUNCUS) REQUIRING SURGICAL DEBRIDEMENT OF A TAIL ABSCESS.
This report describes the anesthetic management of a 14-yr-old, 160-kg, female Indo-Pacific bottlenose dolphin ( Tursiops aduncus ) that underwent surgical debridement for a refractory subcutaneous abscess twice within a 6-mo interval. The animal was otherwise in good physical condition at each anesthetic procedure. Following premedication with intramuscular midazolam and butorphanol, anesthesia was induced with propofol and maintained with sevoflurane by intubation. During surgery ventilation was controlled. Blood pressure was indirectly estimated using either oscillometric or pulse oximetry. Presumed hypotension was managed by adjusting the sevoflurane concentration and infusion of dopamine. During recovery, the dolphin regained adequate spontaneous respiration following intravenous administration of flumazenil and doxapram. The dolphin was extubated at 85 min and 53 min after the first and second surgeries, respectively. Successful weaning from the ventilator and initiation of spontaneous respiration was the most important complication encountered. Establishment of a reliable blood pressure measurement technique is critical to success for anesthesia in this species.


Serial or Parallel Metastasis of Cutaneous Melanoma? A Study of the German Central Malignant Melanoma Registry.
For more than a century the Halstedian hypothesis of contiguous metastasis from the primary tumor through the lymphatics to distant sites shaped lymph node surgery for melanoma. We challenge this dogma of serial metastatic dissemination. A single-center series of 2,299 patients with cutaneous metastatic melanoma was investigated to analyze overall survival and distant metastasis-free survival of stage IV patients with or without primary lymphatic metastasis. Results were then compared with those of 2,134 patients from three independent centers of the German Central Malignant Melanoma Registry. A multivariate binary logistic regression model was used to identify risk factors for the initial metastatic pathway. Distant metastasis-free survival (hazard ratio = 1.02; 95% confidence interval = 0.91-1.14; P = 0.76) and overall survival (HR = 1.09; 95% CI = 0.96-1.23; P = 0.177) did not differ between stage IV patients with primary hematogenous or primary lymphatic metastasis. Melanoma localization was the only significant risk factor for the initial metastatic pathway. These findings indicate that regional and distant metastases originate from the primary tumor itself in a rather parallel than serial fashion and could explain the lack of survival benefit associated with immediate complete lymph node dissection in sentinel lymph node-positive melanoma patients.


[Psychotic Experiences in the Adaptation Process to a New Social Environment].
To evaluate the association between psychotic experiences (PEs) and social stress and discrimination during adaptation to a new social context. First-term university students (n: 164) were screened to determine if they had had any PEs, social adaptation-related stress, and/or perceived discrimination in the prior six months. The positive dimension of the Community Assessment of Psychic Experiences (CAPE) was used to define PEs. Social relations and discrimination in the students' new social contexts (both narrow (i.e., their class) and wider (i.e., urban environment) were screened with relevant questionnaires regarding social capital and discrimination. Responders were classified as either the "High CAPE" group (first and second quartiles; n: 82) or the "Low CAPE" group (third and fourth quartiles; n: 82), which was used as the baseline/control group. Analyses included associations between these two groups and social stress, discrimination, and demographic/non-demographic variables. Results were re-analyzed after excluding irregular students and regrouping with the first and fourth quartiles in CAPE. High CAPE scores were associated with perceived discrimination in narrow and wider social environments (adjusted 0,08; 95% CI: 0,01-0,11), and with adaptation-related stress in narrow social environment (adjusted 0,02; 95% CI: 0,01-0,05). In addition, high CAPE scores were associated with smoking and lower maternal educational level. Associations were stronger when the data was re-analyzed based on the first and fourth quartiles. However, associations between discrimination, social stress, and high CAPE scores were attenuated after exclusion of irregular students. Adaptation-related social stress and perceived discrimination in a new social context may increase the risk of PEs. This particular association seems to be more prominent in groups with higher social stress (e.g., those with academic failure or high perceived discrimination).


Progressing Towards Same-Day Discharges After Robotic-Assisted Radical Prostatectomy; Safe and Cost Effective to Discharge Without Routine Blood Tests.
Changing population demographics and the recent SARS-CoV-2 pandemic have forever changed healthcare, with increasing demands on straining systems. The economic cost is yet to be fully realised, with growing concerns around the current system's ability to accommodate the ageing comorbid population. Consequently, a paradigm shift has taken place in healthcare systems, prioritizing cost accountability. In the absence of established guidelines or robust literature, the use of laboratory tests postoperatively is often guided solely by clinician preference. This study presents a retrospective analysis that investigates the utility and cost implications of routine postoperative investigation following robotic-assisted radical prostatectomies. The findings aim to emphasise the importance of evidence-based practices and cost-effective approaches in postoperative care. A retrospective analysis was performed on all robotic-assisted radical prostatectomies (RARP) identified from a single institution between 29th June 2017 to 28th June 2019. This interval was chosen in an attempt to avoid bias or confounding variables associated with the SRS-CoV-2 pandemic. A single clinician conducted a comprehensive medical record review using unit record numbers corresponding to identified procedural codes. Demographics and variables were recorded, including postoperative test results, hospital length of stay and 30-day readmission rates. Patients were assigned to either 'Routine Postoperative tests' (RPOT) or 'No Routine Postoperative tests' (No RPOT) and a comparative analysis was performed. Using the Australian National Pharmaceutical Benefits Scheme (PBS) pricing guide, total expenditure was calculated. A total of 319 patients were included in the study with an average of 2.5 tests per patient within the first 24 hours. Routine postoperative tests had no bearing on outcomes, with comparable readmission rates between cohorts, and a significantly shorter length of stay in the "No routine postoperative tests" group when compared to the "Routine Postoperative Tests". A total of 1028 tests were performed within the first 48 hours following surgery with expenditure on routine testing totalling $20,516 based on the Australian PBS pricing schedule. Abnormal results were returned on 96% of patients. In the RPOT group, 18 out of the 20 common interventions occurred from 302 RARP. Among the patients in the RPOT group, eight individuals underwent blood transfusions. However, none of these patients met the hospital-specific criteria for transfusion, which require a hemoglobin level below 70 or symptomatic presentation with a hemoglobin level below 80. The data suggests routine postoperative laboratory has no bearing on re-admission rates, with patients experiencing significantly shorter hospital stays. Furthermore, our results indicate inefficient use of routine postoperative laboratory, with few clinical interventions, frequent abnormal results, and significant accumulative expenses.


Arsenic trioxide inhibits the Hedgehog pathway which is aberrantly activated in acute promyelocytic leukemia.
Dysregulated Hedgehog (Hh) signaling has been implicated in several human malignancies. Hh signaling inhibitors are predicted to have a minimal effect when the Smoothened receptor is mutated. Implications that Gli proteins are molecular targets of arsenic trioxide (ATO) action prompted us to investigate the expression of Hh signaling in acute promyelocytic leukemia (APL) and the influence of ATO on the Hh signaling pathway in APL. Quantitative real-time reverse transcription polymerase chain reaction and Western blot were employed to analyze the expression of Hh pathway components and the influence of ATO on the Hh signaling pathway in APL. The expression of Hh pathway components was significantly upregulated in APL. In newly diagnosed APL patients, Gli2 expression was significantly positively correlated with Gli1 (R = 0.57, p < 0.001) and Smo (R = 0.56, p < 0.001) and the expression of Hh pathway components was significantly higher in the high WBC group (p < 0.05). ATO can significantly downregulate the expression of Hh pathway components in vitro and in vivo (p < 0.05). The Hh pathway is aberrantly activated in APL and associated with a bad prognostic factor. ATO can effectively inhibit the expression of the Hh pathway. The obtained data give the first clinical evidence for the application of ATO in tumors exhibiting an aberrantly activated Hh pathway.


An analysis of skeletal muscle response to selection for rapid growth in Japanese quail (Coturnix coturnix Japonica).
A line of Japanese quail selected for high body weight at 4 weeks of age (P line) was compared to an unselected control (C) line at 10, 23 and 56 days of age. The increase in the weight of the pectoralis major and supracoracoideus muscles in the P line was paralleled by an increase in total DNA, RNA and protein content of the muscles when compared to comparable age C line. DNA, RNA and protein concentrations and RNA/DNA and protein/DNA ratios were similar between lines within age. Greater muscle mass in the P line was accomplished primarily through an increase in the total number of muscle nuclei rather than through an increase in DNA unit size. Ca2+-activated myosin ATPase, total phosphorylase and succinic dehydrogenase enzyme activities were similar between lines and across ages in the pectoralis major and supracoracoideus muscles. The semimembranosus muscle possessed 59% more alpha fibers and only 7% more beta fibers in the P line when compared to the C line. Semimembranosus alpha fiber diameters were not significantly different between lines within age, while beta fiber diameters were significantly greater in the P line. Estimated beta fiber contribution to total semimembranosus muscle cross sectional area revealed no significant difference between lines within age. There was a significant increase in the length of the femur and humerus in the P line when compared to C line within age, indicating that some of the increased muscle weight of the P line quail was due to an increase in muscle length in addition to an increase in muscle cross-sectional area.


Chief complaints and diagnoses of displaced Israelis seeking medical treatment during the 2006 Israel-Lebanon War.
To examine patterns of visits by residents of northern Israel displaced during the Israel-Lebanon War of 2006 to an urgent care system in central Israel and to compare these patterns with those of local patients. Retrospective analysis of electronic medical records. Urgent care clinic system in and around Jerusalem, Israel. Patients residing in northern Israel who presented from July 12 to August 21, 2006. Local patients who presented during the same time period were used for comparison. None. Chief complaints, discharge diagnoses, demographics, and visit characteristics. There were a total of 1,175 visits for 938 northern patients, reflecting 6.7 percent of total visits to this system. Overall age distribution of northerners was generally similar. As a proportion of visits, adult northerners were less likely to visit for chief complaints of injury or laceration and more likely to visit for complaint of back pain. They were more likely to have a discharge diagnosis of chest pain, anxiety, or hypertension. Northern children and adolescents were less likely to visit due to injury or fall or to have a discharge diagnosis of fracture. They were more likely to have a discharge diagnosis of gastroenteritis or tonsillitis. Patterns of common discharge diagnoses were generally similar between northern and local residents, with the exception of fewer injury-related visits and more anxiety-related visits. Urgent care appears to have served an important function for displaced individuals during this war, mostly for routine medical needs.


Good Relationships With Parents During Childhood as Buffers of the Association Between Childhood Disadvantage and Adult Susceptibility to the Common Cold.
Children reared by parents of low socioeconomic status (SES) go on to have elevated rates of physical health problems and premature mortality. However, many children reared in low-SES families remain healthy throughout the life-span. Here, secondary analyses of archival data tested the hypothesis that a positive relationship with parents during childhood acts as a buffer of the increased risk of adult susceptibility to infectious illness associated with low childhood SES. One hundred seventy-six healthy adults reported their childhood SES and the quality of their relationships with their parents during childhood. Relationship quality was defined as parental care, love and support, lack of conflict with parents, and family cohesiveness. Afterward, participants were exposed to a respiratory virus and monitored in quarantine for 5 days for the development of a "common cold" as indicated by infection and objective markers of illness. The increased risk of developing a cold associated with being reared in a low SES household was attenuated by a positive relationship with parents during childhood (b(SE) = 0.08 (0.03), p = .010). This buffering of disease risk held up across the four components of relationship quality (p values < .05). The association was independent of adult SES, demographics, prechallenge immunity to the virus, current levels of neuroticism and stress, parental divorce during childhood, and number of siblings (p values < .05). Individuals with positive relationships with their parents during childhood are buffered from the increased risk of adult susceptibility to an infectious disease associated with low childhood SES.


Adaptation to noise in normal and impaired hearing.
Many aspects of hearing function are negatively affected by background noise. Listeners, however, have some ability to adapt to background noise. For instance, the detection of pure tones and the recognition of isolated words embedded in noise can improve gradually as tones and words are delayed a few hundred milliseconds in the noise. While some evidence suggests that adaptation to noise could be mediated by the medial olivocochlear reflex, adaptation can occur for people who do not have a functional reflex. Since adaptation can facilitate hearing in noise, and hearing in noise is often harder for hearing-impaired than for normal-hearing listeners, it is conceivable that adaptation is impaired with hearing loss. It remains unclear, however, if and to what extent this is the case, or whether impaired adaptation contributes to the greater difficulties experienced by hearing-impaired listeners understanding speech in noise. Here, we review adaptation to noise, the mechanisms potentially contributing to this adaptation, and factors that might reduce the ability to adapt to background noise, including cochlear hearing loss, cochlear synaptopathy, aging, and noise exposure. The review highlights few knowns and many unknowns about adaptation to noise, and thus paves the way for further research on this topic.


[A study on reversion of the human activated c-Ha-ras-transformed cells].
Two mutant cell lines, R-1 and R-2, have been isolated from EJ/NIH (NIH/3T3 transformed by a human activated c-Ha-ras gene) by treatment with ethyl-methane-sulfonate (EMS). They reveal various characteristics of normal cells, and seem to have reversed to the original cells. Especially, R-1 shows a very flat morphology, complete contact inhibition, anchorage dependent cell growth and no tumorigenecity. Although transformed phenotypes are intensively suppressed, R-1 does not seem to secrete suppressive factors to the parent cell line. The activated c-Ha-ras (EJ-ras) could be detected as a 6.6 kb BamHI fragment in R-1 as well as in EJ/NIH. The level of transcription and translation in R-1 was also the same as that in EJ/NIH. Moreover, the DNA isolated from R-1 cells had a high transforming activity to NIH/3H3, suggesting that R-1 contained the EJ-ras as an activated oncogene. The levels of transcription of c-myc, c-fos, p53 and other ras family genes was unchanged between EJ/NIH and R-1. Further, R-1 cells are resistant to retransformation by EJ-ras, v-src, v-mos and SV40T genes, and DNAs isolated from EJ/NIH or NIH/3T3 could not transform R-1 cells. All these findings suggest that some genes necessary for transformation by EJ-ras, except for c-myc, c-fos, p53 and ras proto-oncogenes, are defective or some inhibitory genes against transformation are enhanced in R-1 cells.


Late onset asthma clinical and immunological data: importance of allergy.
In people over 65 years of age (mean age 72) late onset asthma (LOA) is often mistaken for chronic obstructive pulmonary disease (COPD). Furthermore, it is generally believed that true allergic asthma starts very seldom in old age and that, in this case, it is actually intrinsic asthma i.e., without any sensitization to aeroallergens. The aim of this study was to show that LOA is not an uncommon entity and is often allergic. Among a population of 1,888 subjects (over 65 years of age) in a general medicine ward we found 21 patients (1.1%) corresponding to this entity. The diagnosis of asthma was assessed according to clinical data, pulmonary function and nasal provocation tests, and blood eosinophilia. The diagnosis of atopy was assessed on total IgE, prick tests and RAST for the commonest allergens of our area. This group of 21 patients was compared to three groups of age-matched subjects including: 68 patients afflicted with chronic bronchitis, a group of 14 patients who had asthma before the age of 65 (presenile asthma), and 20 normal controls. A group of 15 asthmatics under age 65 was also included (young asthma mean age 37). We found a rather high incidence of allergy (72%), mostly to Dermatophagoides pteronyssinus, but also to the pollens Parietaria judaica, grasses and Olea europea. Although the average age (except in the young asthma group) and the severity of symptoms were the same in the four groups, unexpectedly mean RAST and skin test values were higher in LOA than in the two groups of young asthmatics and presenile asthmatics. It was concluded that LOA is not uncommon among elderly patients over 65, which is in contrast with most previous studies; 72% of our cases were allergic, the main allergens being mite, and Parietaria judaica pollen.


NS1 antigen testing for the diagnosis of dengue in returned Israeli travelers.
Antigen testing with NS1 provides rapid diagnosis of dengue in endemic regions during the febrile phase of illness before appearance of IgM in serum. This study aimed to determine the diagnostic accuracy of NS1 antigen testing in travelers presenting with febrile illness and serologically confirmed dengue infection, upon return from dengue endemic countries to Israel, a region endemic for West Nile virus (WNV). Cases were sera obtained from febrile returning travelers with positive dengue-IgM antibodies. Sera of non-travelers with confirmed WNV disease and sera of returning travelers with confirmed non-dengue febrile illnesses were used as controls. All sera were tested for NS1 antigen using the Panbio Dengue Early ELISA assay within 21 days of symptoms. Demographic data, travel destination, and interval between disease onset and testing were retrieved from patient files. Fifty-eight sera from 40 dengue-infected travelers, 26 sera from 26 WNV- infected patients, and 15 sera of returning travelers with non-dengue febrile illness were tested. Sensitivity of NS1 testing in dengue patients was 87% during the first 3 days of symptoms and declined to about 70% after 12 days. No cases tested positive for NS1 after day 12. Specificity was 92% for the entire testing period. The NS1 Panbio assay is sensitive for the detection of dengue viral infection in returning travelers during the febrile phase of illness, and is highly specific in a region where WNV co-circulates.


[Response to everolimus in patients with giant cell astrocytoma associated to tuberous sclerosis complex].
Subependymal giant cell astrocytomas (SEGA) appear in 5-20% of patients with tuberous sclerosis complex (TSC) and are the most common brain tumours in TSC. They are benign tumours, of a glioneural stock, that develop mainly in the first two decades of life, generally close to the foramen of Monro, and can trigger hydrocephalus and intracranial hypertension. It is one of the leading causes of death in TSC. Recently mTOR inhibitors have proved to be a therapeutic alternative to surgical excision. AIM. To describe our experience of using everolimus to treat patients with SEGA and TSC. We conducted a prospective study of the responses of patients with TSC and at least one SEGA undergoing growth. Three females and three males with a mean age of 12.3 years received treatment. One patient had previously undergone surgery due to SEGA with hydrocephalus. The maximum mean diameter of the SEGA on beginning treatment was 15.3 mm (range: 11.3-24.8 mm). Treatment was established with everolimus, 2.5 mg/day administered orally in patients with a body surface area < 1.2 m2, and 5 mg/day in patients with a body surface area > 1.2 m2. Two patients presented hypertriglyceridemia; one, anorexia; another, a mouth ulcer; and one, amenorrhoea. The mean reduction in the volume of the SEGA at three months of treatment was 46%, and the reduction remained steady in later control examinations (6-25 months). Treatment with everolimus reduces the size of SEGA associated with TSC with an adequate safety profile, and constitutes an alternative to surgery in certain cases.


Acute Smc5/6 depletion reveals its primary role in rDNA replication by restraining recombination at fork pausing sites.
Smc5/6, a member of the conserved SMC family of complexes, is essential for growth in most organisms. Its exact functions in a mitotic cell cycle are controversial, as chronic Smc5/6 loss-of-function alleles produce varying phenotypes. To circumvent this issue, we acutely depleted Smc5/6 in budding yeast and determined the first cell cycle consequences of Smc5/6 removal. We found a striking primary defect in replication of the ribosomal DNA (rDNA) array. Each rDNA repeat contains a programmed replication fork barrier (RFB) established by the Fob1 protein. Fob1 removal improves rDNA replication in Smc5/6 depleted cells, implicating Smc5/6 in the management of programmed fork pausing. A similar improvement is achieved by removing the DNA helicase Mph1 whose recombinogenic activity can be inhibited by Smc5/6 under DNA damage conditions. DNA 2D gel analyses further show that Smc5/6 loss increases recombination structures at RFB regions; moreover, mph1∆ and fob1∆ similarly reduce this accumulation. These findings point to an important mitotic role for Smc5/6 in restraining recombination events when protein barriers in rDNA stall replication forks. As rDNA maintenance influences multiple essential cellular processes, Smc5/6 likely links rDNA stability to overall mitotic growth.


Income Inequality and Self-Reported Health Among Older Adults in Brazil.
This study analyzes the association between income inequality and self-reported health (SRH) in older adults, and separately for the young-old and very-old groups, residing in each of the 27 Brazilian capitals. The sample consisted of 4,912 individuals aged 60 or older residing in Brazilian capitals in 2013. Bayesian multilevel models were applied to the whole sample and separately for individuals aged 60 to 79 (young-old), and 80 or more (very-old). Our results show significant associations between income inequality and SRH, even after controlling for individual and contextual factors. We found greater odds of poor SRH among older adults living in areas with medium (odds ratio [OR] = 1.66, 95% confidence interval [CI]: 1.49-1.86) and high-income inequality (OR = 2.21, 95% CI: 2.05-2.38). The negative association between income inequality and health, independently of the individual and contextual characteristics, suggests that living in unequal areas can have a detrimental effect on the health of older adults.


Utilization of tracheostomy in craniomaxillofacial trauma at a level-1 trauma center.
The decision to perform a tracheostomy on patients with maxillofacial trauma is complex. There is little data exploring the role of tracheostomy in facial fracture management. We sought to profile the utilization of tracheostomy in the context of maxillofacial trauma at our institution by comparing patients who required tracheostomy with and without facial fractures versus those with facial fractures not requiring tracheostomy. All patients admitted to the Trauma Service at Legacy Emanuel Hospital and Health Center (LEHHC), Portland, OR, from 1993 to 2003 that sustained facial fractures or underwent tracheostomy were identified and data were retrospectively reviewed using patient charts and the trauma registry. Variables such as age, gender, death, injury severity score (ISS), facial injury severity score (FISS), Glasgow coma score (GCS), intensive care days (ICU), hospital length of stay (LOS), facial fracture profile, and oral and maxillofacial surgery (OMFS) operative intervention were tabulated and analyzed. Data were divided into 3 groups for comparison: group 1 (ffxT) consisted of patients who underwent a tracheostomy procedure and repair of their facial fracture during the SAME operation by the OMFS department (N = 125); group 2 (ffxNT) were those patients who had repair of their facial fractures by OMFS and did not require a tracheostomy (N = 224); and group 3 (NffxT) were patients who did not have facial fractures but received a tracheostomy during their hospitalization (N = 259). Ten-year data were used to analyze the ffxT and 5-year data were used to analyze the ffxNT and NffxT. Analysis of variance and chi2 testing was used for statistical analysis. A total of 18,187 patients were admitted to the trauma LEHHC Trauma Service during the study period, of which 1,079 (5.9%) patients sustained facial fractures and 788 (4.3%) required a tracheostomy. One hundred twenty-five patients (0.69% of total; 11.6% of facial fracture) received a tracheostomy at the same time as the facial fracture repair. All patients had their facial fractures successfully managed, regardless of the type of method used to stabilize the airway. There were no known cases of tracheal stenosis, severe bleeding requiring a return to the operating room, airway obstruction, or loss of secured airway. Males were the predominate gender in all 3 groups. The NffxT group (mean, 44.9 years) was much older compared with the ffxT (mean, 36.2 years) and ffxNT (mean, 30.9 years) groups. The incidence of death was higher in the tracheostomy groups compared with 0% with the non-tracheostomy group. The ffxNT group had a statistically significant higher GCS with an average of 12.4 when compared with the tracheostomy groups (ffxT = 6.8; NffxT = 6.7). ISS was nearly the same in the tracheostomy group (ffxT = 28.45; NffxT = 30.04), but higher when compared with the ffxNT (ISS = 17.33). All 3 groups were much different in terms of LOS and ICU days, in which the NffxT group had an average hospital LOS and ICU days of 34.4 and 16.56, respectively. This was higher when compared with the ffxT (LOS = 19.71 days; ICU = 7.21 days) and ffxNT (LOS = 6.82 days; ICU = 1.33 days) groups. The FISS averaged 6.22 in the ffxT group and was higher compared with an FISS of 3.16 in the ffxNT group. Overall, the fracture profile was different between the tracheostomy and non-tracheostomy groups. There was a higher prevalence of mandibular fractures, multiple mandibular fractures, and Le Fort III fractures in the ffxT group compared with the ffxNT group. Tracheostomy is commonly performed in the context of multisystem trauma and is a safe method for airway stabilization in patients with craniomaxillofacial trauma. Multi-institutional collaboration and a prospective, randomized trial measuring outcome, resource utilization, and length of ICU stay is necessary to determine if tracheostomy is indeed of measurable benefit to patients with complex injuries.


Prescribing patterns of analgesics and other medicines by dental practitioners in Australia from 2001 to 2012.
Dental practitioners are able to prescribe a variety of medicines subsidized on the Pharmaceutical Benefits Schedule (PBS), the main categories of which are analgesics and antibiotics. We aimed to investigate the patterns of PBS prescribing of non-antimicrobial medicines by dental practitioners in Australia from 2001 to 2012. Data were collected from Medicare Australia on prescriptions from dental practitioners dispensed to concessional beneficiaries between 2001 and 2012. We examined patterns of use over time. There was an overall increase in number of prescriptions and in dispensed use (standardized by dose and population) of analgesic medicines for the concessional population over the 12-years period. The use of dentally prescribed analgesics increased 15%, with use of nonsteroidal anti-inflammatory drugs increasing by 41% and opioid analgesics by 12%. Prescribing of the oxycodone 5-mg tablet increased 344% between 2005 and 2012, and dental prescription of the benzodiazepines diazepam and temazepam increased by 51% and 229%, respectively, over the observation period. Injectable corticosteroid use increased by 19%. Conversely, use of carbamazepine and anti-emetics decreased by 39% and 10%, respectively. Dental prescribing of analgesics, anti-inflammatories and benzodiazepines in the concessional population has increased significantly over the past decade. These data can form the baseline to further examine appropriate medicine use in the management of dental conditions.


Post-irradiation carcinosarcoma of uterus--a case report.
The carcinosarcoma (malignant mixed mullerian tumour) of uterus is an aggressive neoplasm composing of malignant glands in the malignant stroma showing biphasic appearance. A 55 year old woman presented with discharge per vaginum of one month duration. Earlier she was given radiotherapy for squamous cell carcinoma of vulva, six years back. Abdominal examination was insignificant. USG suggested presence of post-radiation effect with uterine mass. Panhysterectomy was done and on histopathology, the diagnosis of carcinosarcoma (heterologous variant) was made. The case is being reported and discussed.


Molecular characterization of Streptococcus agalactiae isolated from bovine mastitis in Eastern China.
One hundred and two Streptococcus agalactiae (group B streptococcus [GBS]) isolates were collected from dairy cattle with subclinical mastitis in Eastern China during 2011. Clonal groups were established by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE), respectively. Capsular polysaccharides (CPS), pilus and alpha-like-protein (Alp) family genes were also characterized by molecular techniques. MLST analysis revealed that these isolates were limited to three clonal groups and were clustered in six different lineages, i.e. ST (sequence type) 103, ST568, ST67, ST301, ST313 and ST570, of which ST568 and ST570 were new genotypes. PFGE analysis revealed this isolates were clustered in 27 PFGE types, of which, types 7, 8, 14, 15, 16, 18, 23 and 25 were the eight major types, comprising close to 70% (71/102) of all the isolates. The most prevalent sequence types were ST103 (58% isolates) and ST568 (31% isolates), comprising capsular genotype Ia isolates without any of the detected Alp genes, suggesting the appearance of novel genomic backgrounds of prevalent strains of bovine S. agalactiae. All the strains possessed the pilus island 2b (PI-2b) gene and the prevalent capsular genotypes were types Ia (89% isolates) and II (11% isolates), the conserved pilus type providing suitable data for the development of vaccines against mastitis caused by S. agalactiae.


Understanding the Biology of Self-Renewing Macrophages.
Macrophages reside in specific territories in organs, where they contribute to the development, homeostasis, and repair of tissues. Recent work has shown that the size of tissue macrophage populations has an impact on tissue functions and is determined by the balance between replenishment and elimination. Macrophage replenishment is mainly due to self-renewal of macrophages, with a secondary contribution from blood monocytes. Self-renewal is a recently discovered trait of macrophages, which can have a major impact on their physiological functions and hence on the wellbeing of the organism. In this review, I discuss our current understanding of the developmental origin of self-renewing macrophages and the mechanisms used to maintain a physiologically stable macrophage pool.


Morbid obesity-related changes in the expression of lipid receptors, transporters, and HSL in human sperm.
To study the location and expression of receptors (SR-BI/CLA-1, SR-BII, and LDLr) and transporter (ABCA1) involved in uptake and efflux of cholesterol in human spermatozoa and assess whether obesity alters its location/expression and whether this could be related to infertility. Observational study. None PATIENT(S): Ten controls and 20 obese patients. Anthropometric parameters. Serum and semen samples were collected. Spermatozoon concentration, immunolocalization, and protein expression in semen. Spermatozoon concentration and motility was decreased in morbidly obese patients. SR-BI/CLA-1, SR-BII, LDLr, and ABCA1 are located in the spermatozoon cell membrane and the localization does not change between obese patients and controls. Control spermatozoa showed high SR-BI expression, and less expression for the rest of the receptors analyzed, indicating that SR-BI/CLA-1 is relevant in human spermatozoon cholesterol uptake/efflux. On the contrary, spermatozoa of obese patients showed less SR-BI/CLA-1 expression than controls, and more intense positive staining for SR-BII, LDLr, and ABCA1. Finally, human sperm expresses the 130- and 82-kDa hormone-sensitive lipase (HSL) isoforms. The 130-kDa isoform is expressed in the control sperm, and the expression disappears in the obese patients. The presence of lipid receptors/transporters and HSL in human spermatozoa suggests their role in the process of maturation/capacitation. The changes in the expression of lipid receptors/transporters and the lack of the 130-kDa HSL isoform in obese patients prevent the hydrolysis of cholesterol esters internalized by these receptors, and favor their accumulation in the cytoplasm of the spermatozoa that could contribute to lipotoxicity and infertility.


Looking into the Graft without a Biopsy: Biomarkers of Acute Rejection in Renal Transplantation.
Immunosuppression in kidney transplantation is still largely driven by center-specific protocols and adjusted according to the presence of graft dysfunction, drug toxicity or infection. Due to the current inability to titrate immunosuppression to the needs of every single patient, this approach is burdened by an increased risk of under or over-immunosuppression. To extend allograft survival, immunosuppression should be decided based on reliable biomarkers capable of quantifying the alloimmune response and/or noninvasively diagnosing acute rejection. Emerging data indicate that many assays, likely used in panels rather than singularly, have potential to be diagnostic and predictive of short- and also long-term outcomes. Many cross-sectional and retrospective studies showed associations between these biomarkers and clinically relevant post-transplantation outcomes, but data from prospective studies are still scarce, thereby preventing widespread implementation in the clinic. Prospective, randomized, multicenter studies are currently ongoing to test the hypothesis that biomarker-driven immunosuppression provides better outcomes than standard, protocol-driven immunosuppression. These projects and other future studies are highly warranted to improve outcomes of kidney transplant patients.


Molecular rules governing the structural polymorphism of amyloid fibrils in neurodegenerative diseases.
Amyloid fibrils are hallmarks of various neurodegenerative diseases. The structural polymorphism of amyloid fibrils holds significant pathological importance in diseases. This review aims to provide an in-depth overview on the complexity of amyloid fibrils' structural polymorphism and its implications in disease pathogenesis. We firstly decipher the molecular rules governing the structural polymorphism of amyloid fibrils. We then discuss pivotal factors that contribute to the assortment of fibril structural polymorphs, including post-translational modifications (PTMs), disease mutations, and interacting molecules, and elucidate the structural basis of how these determinants influence amyloid fibril polymorphism. Furthermore, we underscore the need for a comprehensive understanding of the relationship between diverse fibril polymorphs and pathological activities, as well as their potential roles in therapeutic applications.


Properties of the principal anion-exchange mechanism in human neutrophils.
As part of our ongoing studies aimed at understanding the physiology of human neutrophil function, we have been investigating the nature of the principal anion-exchange mechanism in these cells. This countertransport system functions physiologically as a Cl-/HCO3- exchanger in intracellular pH regulation from alkalinization (Simchowitz and Roos, 1985). In summarizing the results of our work, it is worthwhile to keep in mind the well-defined properties of the classic inorganic anion-exchange carrier of red blood cells, as important differences between the two are evident. Inhibitor Profile In our original articles on Cl- movements (Simchowitz and De Weer, 1986; Simchowitz et al., 1986), we had identified CHC, which suppresses monocarboxylate transport in mitochondria (Halestrap and Denton, 1975), as a relatively weak inhibitor. Several structural analogues, including alpha-methylcinnamate and alpha-phenylcinnamate, exhibited enhanced activity against anion exchange. The most potent compound thus far identified was UK-5099, which was approximately 300-fold more active than CHC. The inhibitory effect of each member of this series of compounds was strictly competitive in nature: both the drug and Cl ions appeared to bind to the same external translocation site on the exchange carrier. The inhibition by several other unrelated agents (e.g., MK-473, niflumate, flufenamate, and NAP-taurine), all weak organic acids, was also of the competitive type, which suggests that these compounds bind to the carrier by virtue of their negatively charged carboxyl or sulfonic groups. In marked contrast to erythrocytes, the anion-exchange carrier of neutrophils is rather insensitive to the disulfonic stilbenes SITS and DIDS (Simchowitz and De Weer, 1986): little or no effect can be detected in 148 mM Cl-. However, under conditions of low external Cl- (5-35 mM), SITS can in fact be shown to interact weakly with the anion binding site of the exchange carrier. In a comparable vein, several other drugs, all of which have been reported to suppress Cl- fluxes in red cells (for reviews, see Sachs et al., 1975; Gunn, 1979; Knauf, 1979; Lowe and Lambert, 1983), were either completely inactive against anion exchange in neutrophils at a concentration of 1 mM or only marginally effective at doses several orders of magnitude greater than those required in red blood cells. This list included furosemide, picrylsulfonate, maleic anhydride, 5,5'-dithio-bis(2-nitrobenzoate), salicylate, 2-methoxy-5-nitrotropone, and aldrithiol.4+he external


Detecting entanglement using a double-quantum-dot turnstile.
We propose a scheme based on using the singlet ground state of an electron spin pair in a double-quantum-dot nanostructure as a suitable setup for detecting entanglement between electron spins via the measurement of an optimal entanglement witness. Using time-dependent gate voltages and magnetic fields the entangled spins are separated and coherently rotated in the quantum dots and subsequently detected at spin-polarized quantum point contacts. We analyze the coherent time evolution of the entangled pair and show that by counting coincidences in the four exits an entanglement test can be done. This setup is close to present-day experimental possibilities and can be used to produce pairs of entangled electrons "on demand."


Clinical trials in autism spectrum disorder: evidence, challenges and future directions.
The purpose of this manuscript is to review the evidence generated by clinical trials of pharmaceuticals in autism spectrum disorder (ASD), describe challenges in the conduct of such trials, and discuss future directions RECENT FINDINGS: Clinical trials in ASD have produced several compounds to adequately support the pharmacological treatment of associated symptom domains: attention deficit hyperactivity disorder (methylphenidate, atomoxetine, and alpha agonists), irritability/aggression (risperidone and aripiprazole), sleep (melatonin), and weight gain associated with atypical antipsychotic use (metformin). However, there is no evidence yet to support the routine use of pharmaceuticals for the treatment of core symptom domains. Challenges in the field include biological heterogeneity within ASD, lack of biomarkers that clarify biological heterogeneity or predict response to treatment, lack of data across the lifespan, and suboptimal outcome measures. Several compounds have evidence for the treatment of co-occurring symptoms in children and youth with ASD, although pharmacological interventions for core symptoms are still lacking. Identifying the various biologies underling ASD and developing biomarkers that stratify biologically homogeneous populations are both necessary to realize the promise of precision medicine in ASD.


Subacute cutaneous lupus erythematosus.
A 31-year-old female soldier developed subacute cutaneous lupus erythematosus, which remained undiagnosed for 4 years. Referral to dermatology and a punch biopsy confirmed the diagnosis and effective treatment was instituted. The presence of an unresolving annular rash in light-exposed areas, especially in a young woman, should prompt thorough investigation and referral if necessary. The prognosis for this condition is generally good, although a small proportion of patients will go on to develop systemic lupus erythematosus. The occupational implications of this condition require thoughtful management in the military population.


Periodontitis increases rheumatic factor serum levels and citrullinated proteins in gingival tissues and alter cytokine balance in arthritic rats.
This study investigated some immunological features by experimental periodontitis (EP) and rheumatoid arthritis (RA) disease interact in destructive processes in arthritic rats. Rats were assigned to the following groups: EP +RA; RA; EP; and Negative Control. RA was induced by immunizations with type-II collagen and a local immunization with Complete Freund's adjuvant in the paw. Periodontitis was induced by ligating the right first molars. The serum level of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACCPA) were measured before the induction of EP (T1) and at 28 days after (T2) by ELISA assay. ACCPA levels were also measured in the gingival tissue at T2. The specimens were processed for morphometric analysis of bone loss, and the gingival tissue surrounding the first molar was collected for the quantification of interleukin IL-1β, IL-4, IL-6, IL-17 and TNF-α using a Luminex/MAGpix assay. Paw edema was analyzed using a plethysmometer. Periodontitis increased the RF and ACCPA levels in the serum and in the gingival tissue, respectively. Besides, the level of paw swelling was increased by EP and remained in progress until the end of the experiment, when EP was associated with RA. Greater values of IL-17 were observed only when RA was present, in spite of PE. It can be concluded that periodontitis increases rheumatic factor serum levels and citrullinated proteins level in gingival tissues and alter cytokine balance in arthritic rats; at the same time, arthritis increases periodontal destruction, confirming the bidirectional interaction between diseases.


Clinical Profile and Visual Outcome of Ocular Bartonellosis in Malaysia.
Background. Ocular bartonellosis can present in various ways, with variable visual outcome. There is limited data on ocular bartonellosis in Malaysia. Objective. We aim to describe the clinical presentation and visual outcome of ocular bartonellosis in Malaysia. Materials and Methods. This was a retrospective review of patients treated for ocular bartonellosis in two ophthalmology centers in Malaysia between January 2013 and December 2015. The diagnosis was based on clinical features, supported by a positive Bartonella spp. serology. Results. Of the 19 patients in our series, females were predominant (63.2%). The mean age was 29.3 years. The majority (63.2%) had unilateral involvement. Five patients (26.3%) had a history of contact with cats. Neuroretinitis was the most common presentation (62.5%). Azithromycin was the antibiotic of choice (42.1%). Concurrent systemic corticosteroids were used in approximately 60% of cases. The presenting visual acuity was worse than 6/18 in approximately 60% of eyes; on final review, 76.9% of eyes had a visual acuity better than 6/18. Conclusion. Ocular bartonellosis tends to present with neuroretinitis. Azithromycin is a viable option for treatment. Systemic corticosteroids may be considered in those with poor visual acuity on presentation.


Effect of dose rate and timing of administration of pegbovigrastim on white blood cell responses in grazing dairy cows.
Transition dairy cows experience a decline in immune function that increases the risk of peripartum disease. One strategy to improve peripartum immune function involves the use of a commercially available cytokine: bovine granulocyte-colony stimulating factor, with the addition of polyethylene glycol to increase duration of effectiveness. Treatment with Imrestor (15 mg pegbovigrastim; Elanco) one week before expected calving date (d -7) and again on the day of calving (d 0) was previously reported to increase the neutrophil number and improve neutrophil function; as a result, the incidence of clinical mastitis was reduced. We conducted 2 experiments over consecutive years to investigate the effect of a lower dose rate (half or quarter dose rate) of Imrestor in grazing dairy cattle and reduced administration frequency: one dose instead of the recommended 2. White blood cell counts were measured to determine changes in relative cell populations in response to treatment. Neutrophil function was assessed by measuring myeloperoxidase activity. Imrestor treatment increased the numbers of neutrophils, band cells, lymphocytes, and monocytes until 14 d postcalving in a dose-dependent manner; it also increased neutrophil myeloperoxidase activity. One dose of Imrestor increased white blood cell counts and myeloperoxidase activity, but the timing, degree, and duration of the response were different relative to the recommended 2 doses and were also dependent upon when Imrestor treatment was given. One dose at d -7 relative to expected calving date did not have a lasting effect postcalving, whereas one dose only on d 0 caused a delayed effect relative to cows that received 2 doses. There was no effect of Imrestor on milk yield or on blood indicators of transition cow health. A lower dose rate of Imrestor or a single dose of Imrestor on the day of calving may be sufficient to improve neutrophil function during the early postpartum in grazing dairy cows. Large-scale field studies are required to determine whether the smaller response from lower dose rates or the timing of the immunological response to drug delivery affect animal health in early lactation.


Properties of some nuclear nucleases of rat thymocytes and their changes in radiation-induced apoptosis.
Three nuclease activities have been found and characterized in rat thymocyte nuclear extracts. A Mn(2+)-dependent nuclease is loosely bound to nuclear components and can be extracted with 0.35 M NaCl. The enzyme is activated by Mn2+ but not by Mg2+, Ca2+, or both. Its molecular mass is 36-40 kDa when measured by gel filtration and 37 kDa by SDS/PAGE. An acidic nuclease is independent of divalent ions, produces DNA strand breaks with 5'-OH ends, its molecular mass is about 37 kDa. Two fractions of Ca2+/Mn(2+)-dependent nuclease, differing in binding to CM-Sepharose but identical in other respects, are active in the presence of Mn2+ but can be additionally activated by Ca2+. They are inactive in the presence of Mg2+ or Ca2+ but cleave DNA in Ca2+/Mg(2+)-containing medium. The molecular mass of the enzyme is 22 kDa as determined by both gel filtration and electrophoresis. The dependence of nuclease activities on pH, ions, and sulfhydryl reagents is described. Cycloheximide injection to both control and irradiated animals strongly inhibits the activities of Ca2+/Mn(2+)-dependent nuclease from thymocyte nuclei separated by chromatography on CM-Sepharose and does not change the activities of Mn(2+)-dependent and acidic nucleases. Nuclease activity in thymocyte nuclei from irradiated rats is increased in Ca2+/Mg(2+)-containing and Ca2+/Mn(2+)-containing media whereas there is no change in the activity of acidic nuclease. Ca2+/Mn(2+)-dependent nuclease is extracted from thymocyte nuclei of irradiated rats with 0.35 M NaCl but from control nuclei only with 0.5 M NaCl. Possible reasons of labilization of Ca2+/Mn(2+)-dependent-nuclease binding to the nuclear structures in dying thymocytes are discussed.


Microvascular structure of the human epididymis.
The microvascular anatomy of the human epididymal duct system from rete testis to vas deferens was studied using microangiography and histology. Various segments of the duct system show significant differences in the density and arrangement of the small blood vessels. The rete testis is poorly vascularized while the first lobulated segment of the epididymis, which is formed by the efferent ducts is provided with a dense subepithelial capillary bed. The more distal segments of the epididymis have less dense capillarization surrounding the epididymal duct. In the vas deferens the blood vessels form a double capillary network. The outer capillary network surrounds the smooth muscle layers and the inner is located immediately beneath the duct epithelium. The organization of blood capillaries in the human epidymis and the differences seen in different portions of the excurrent duct system follow basically the general pattern seen in some experimental animals.


Two-step models to predict binding affinity of chemicals to the human estrogen receptor alpha by three-dimensional quantitative structure-activity relationships (3D-QSARs) using receptor-ligand docking simulation.
Binding of chemicals to the estrogen receptor (ER) is known to be a key mode of action of endocrine disruption effects. In this study, combined quantitative structure-activity relationship (QSAR) models from discriminant and multilinear regression (MLR) analyses, termed a two-step model, were developed. These were used to predict the binding potency to human ERalpha of four chemical groups, namely alkylphenols, phthalates, diphenylethanes and benzophenones. These groups are considered to be important chemical classes of ER-binders. The descriptors investigated were calculated following the simulation of docking between the receptor and ligand. Discriminant analysis in the first step of a two-step model was applied to distinguish binders from non-binders. It had a concordance, following leave-one-out (LOO), of greater than 87% for all chemical classes. Binders were defined as chemicals whose IC50 was reliably measured in a competitive binding assay. The MLR analysis in the second step was performed for the quantitative prediction of the binding affinity of chemicals that were previously discriminated as binders. The q2 values for alkylphenols and diphenylethanes were 0.75 and 0.74, respectively. However good MLR relationships were not obtained for phthalates and benzophenones as the observed binding affinities of chemicals in these categories were weak and in a too narrow range.


Genetic heterogeneity in the foot-and-mouth disease virus Leader and 3C proteinases.
The Leader and 3C proteinases of foot-and-mouth disease virus (FMDV) are responsible for almost all the proteolytic processing events of the viral polyprotein precursor. Investigation into the genetic heterogeneity of the regions encoding these proteins from isolates of six FMDV serotypes revealed the 3C proteinase to be more conserved than the Leader proteinase. Maximum likelihood analysis indicated similar phylogenetic groupings for the non-structural protein coding regions of both the Leader and 3C. These groupings were different from the structural VP1 protein coding region which, as shown previously, grouped according to serotype. Two distinct clades were apparent for both the Leader and 3C coding regions: one comprising of serotypes A, O and C together with SAT (South African Territories) isolates from eastern Africa. The other clade consisted of SAT isolates originating from southern Africa. Only one virus isolate, obtained from a buffalo in Uganda, did not conform to this phylogenetic pattern. This SAT 1 virus grouped with types A, O and C in the Leader analysis, but with the southern African SAT types in the 3C analysis, implicating intertypic recombination. The leader proteinases of southern African SAT type isolates differed from those present in European type isolates, particularly in the self-processing region. A three-dimensional structure was modeled for the Leader proteinase of one of the SAT type viruses, ZIM/7/83/2, and compared with the previously elucidated crystal structure of O(1)Kaufbeuren Leader proteinase. The active sites of the two leaders were found to superimpose closely, despite the observed sequence variation between the two molecules. Comparison of the 3C proteinase P1 cleavage sites suggested that the FMDV 3C proteinase may possess a broader substrate specificity, as observed in hepatitis A virus 3C proteinase.


Synthesis and evaluation of novel glass ceramics as drug delivery systems in osteomyelitis.
In this study, a new generation of bioactive glass ceramics were developed using the wet chemical method. The synthetic conditions were strictly controlled to obtain the materials of a nanometric scale. As evaluated by scanning electron microscopy, bone-like apatite layers were produced in large amounts and completely covered their surfaces after immersion in phosphate buffer saline. On the basis of X-ray diffraction, X-ray fluorescence, and Fourier transform infrared spectroscopy results, PO₄³⁻ groups of hydroxyapatite (HA) were partially substituted by SiO₄⁴⁻ species. The defective chemical structures introduced provided materials that were more biologically active, compared with the parent HA. For effective treatment of infected bones, scaffolds containing the bioactive ceramics were prepared by chitosan cross-linking, and loaded with vancomycin (VCM). The drug-loaded scaffolds were not toxic to bone cells. About 75%-80% of the entrapped drug was released in a controlled pattern and the release was sustained over a 12-day period. The concentration of drug released was determined to be above 20 times the half maximal effective concentration of VCM on Staphylococcus aureus, and was sufficient for killing bacteria growing as biofilm. In summary, the synthesized bioceramics exhibited many of properties associated with an ideal material for implantable drug delivery system, and were suitable for testing the ability to cure bone diseases including osteomyelitis.


Nanorings and nanocrescents formed via shaped nanosphere lithography: a route toward large areas of infrared metamaterials.
This paper presents a new approach to nanosphere lithography, which overcomes undesirable manufacturing issues such as complex tilted-rotary evaporation and ion beam milling. A key innovation in this process is the use of non-conductive edge strips placed on top of the samples prior to metal removal. Such elements help to direct the flow of reactive ions during plasma etching and produce well-ordered arrays of metallic nanorings and nanocrescents over large areas of ∼1 cm(2). The obtained highly uniform nanocrescent array exhibits an electric resonance of 1.7 μm and a magnetic resonance of 3 μm. The absorption resonances of the fabricated nanorings depend on their diameters and shift toward shorter wavelengths (λ = 1.7 μm for do = 308 nm) as compared to larger rings (λ = 2.2 μm do = 351 nm). FDTD-based simulations match well with the experimental results. This 'shaped nanosphere lithography' approach creates opportunities to generate nanorings and nanocrescents that promise potential applications in chemical and biological sensing, for surface enhanced spectroscopy and in the field of infrared metamaterials.


Oral immunization of humans with dehydrated liposomes containing Streptococcus mutans glucosyltransferase induces salivary immunoglobulin A2 antibody responses.
Seven healthy adult volunteers each ingested an enteric-coated capsule containing 500 micrograms of Streptococcus mutans glucosyltransferase (GTF) in dehydrated liposomes for 3 consecutive days. The immunization regimen was repeated 28 days later. Parotid saliva and plasma were collected prior to and at a weekly interval for 8 weeks following the first immunization for analysis of anti-GTF activity by enzyme-linked immunosorbent assay. The levels of immunoglobulin A1 (IgA1) and IgA2 anti-GTF activities increased in the parotid saliva from 5 of 7 individuals after immunization. Increases in the mean level of IgA1 and IgA2 anti-GTF responses peaked on day 35 (77% and 175% increase over baseline, respectively), although variation was noted in the kinetics and subclass of responses between individuals. No salivary IgG or IgM responses were observed. Low plasma IgM, IgG and IgA anti-GTF responses were seen in immunized subjects. Oral immunization with a dehydrated liposome-protein vaccine was effective in inducing a secretory IgA antibody response, which was primarily of the IgA2 subclass. These results provide the first evidence for the use an oral dehydrated liposome-protein vaccine in humans.


Focal monophasic demyelinating leukoencephalopathy in advanced HIV infection.
A multiple sclerosis (MS)-like illness has been reported in human immunodeficiency virus (HIV)-infected patients, usually in the early stages of HIV infection. We report 3 patients with advanced HIV infection (CD4 lymphocyte count under 200/mm(3)) presenting with monophasic focal leukoencephalopathy, in whom biopsy demonstrated demyelinating lesions compatible with acute MS lesions. In 1 patient, recently started on highly active antiretroviral therapy, MS-like disease could represent an immune reconstitution syndrome. The lesions were reversible in 2 patients, but rapidly fatal in the third patient. These cases show that an MS-like disease may present in advanced HIV infection as focal monophasic leukoencephalopathy with either a reversible or fulminating course, mimicking progressive multifocal leukoencephalopathy.


Restriction endonuclease analysis of Staphylococcus epidermidis DNA may be a useful epidemiological marker.
We compared the epidemiological markers of 13 Staphylococcus epidermidis strains isolated from an adult inpatient during a febrile episode and 23 S. epidermidis strains isolated during a presumptive outbreak of nosocomial infection in a neonatal ward. The total DNA restriction endonuclease analysis (REA) was processed along with the following conventional markers: biotyping, serotyping, phage typing, antibiotic susceptibility profiles, and plasmid profiles. The REA method was reproducible, giving stable results both in vitro and in vivo. For the hospitalized adult patient, the conventional markers of the 13 strains were concordant and the restriction profiles were identical. Five restriction groups were demonstrated during the course of the outbreak. Within two of the groups, the identities of all of the markers were used to verify whether all of the isolates belonged to the same cell clone. In a third group, combined analysis of the conventional markers and REA had to be used to demonstrate isolate similarity. On the other hand, in another group, none of the markers were similar; interpretation was not easy. An epidemiological study of S. epidermidis infections in hospitals must take into account all of the epidemiological markers: biotypes, serotypes, phage types, antibiograms, plasmid profiles, and REA.


B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver.
Dysregulated Wnt signaling is seen in approximately 30% of hepatocellular carcinomas; thus, finding pathways downstream of the activation of Wnt signaling is key. Here, using cre-lox technology, we deleted the Apc gene in the adult mouse liver and observed a rapid increase in nuclear beta-catenin and c-Myc, which is associated with an induction of proliferation that led to hepatomegaly within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes, we analyzed the impact of inactivating APC in the context of deficiency of the potentially key effectors beta-catenin and c-Myc. beta-catenin loss rescues both the proliferation and hepatomegaly phenotypes after APC loss. However, c-Myc deletion, which rescues the phenotypes of APC loss in the intestine, had no effect on the phenotypes of APC loss in the liver. The consequences of the deregulation of the Wnt pathway within the liver are therefore strikingly different from those observed within the intestine, with the vast majority of Wnt targets being beta-catenin-dependent but c-Myc-independent in the liver.


Complement in renal transplantation: The road to translation.
Renal transplantation is the treatment of choice for patients with end-stage renal disease. The vital role of the complement system in renal transplantation is widely recognized. This review discusses the role of complement in the different phases of renal transplantation: in the donor, during preservation, in reperfusion and at the time of rejection. Here we examine the current literature to determine the importance of both local and systemic complement production and how complement activation contributes to the pathogenesis of renal transplant injury. In addition, we dissect the complement pathways involved in the different phases of renal transplantation. We also review the therapeutic strategies that have been tested to inhibit complement during the kidney transplantation. Several clinical trials are currently underway to evaluate the therapeutic potential of complement inhibition for the treatment of brain death-induced renal injury, renal ischemia-reperfusion injury and acute rejection. We conclude that it is expected that in the near future, complement-targeted therapeutics will be used clinically in renal transplantation. This will hopefully result in improved renal graft function and increased graft survival.


Free Fatty Acids Increase Intracellular Lipid Accumulation and Oxidative Stress by Modulating PPARα and SREBP-1c in L-02 Cells.
Excessive fat accumulation and increased oxidative stress contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, the mechanisms underlying the development of steatosis are not entirely understood. The present study was undertaken to establish an experimental model of hepatocellular steatosis with a fat overaccumulation profile in which the effects of oxidative stress could be studied in L-02 cells. We investigated the effects of free fatty acids (FFA) (palmitate:oleate, 1:2) on lipid accumulation and oxidative stress and their possible mechanisms in L-02 cells. High concentrations of fatty acids significantly induced excessive lipid accumulation and oxidative stress in L-02 cells, which could only be reversed with 50 μΜ WY14643 (the PPARα agonist). Immunoblotting and qPCR analyses revealed that FFA downregulated the expression of proliferator-activated receptor alpha (PPARα), which contributed to the increased activation of sterol regulatory element binding protein-1c (SREBP-1c). These results suggest that FFA induce lipid accumulation and oxidative stress in L-02 cells by upregulating SREBP-1c expression through the suppression of PPARα.


Human macrophage lectin specific for galactose/N-acetylgalactosamine is a marker for cells at an intermediate stage in their differentiation from monocytes into macrophages.
We studied the expression of a human macrophage lectin specific for galactose/N-acetylgalactosamine (hMGL) during macrophage differentiation. The expression of hMGL during the in vitro differentiation induced by human serum was examined by immunostaining and Western blotting with a specific mAb, MLD-1, as well as with RT-PCR analysis. hMGL was detected on cells at an intermediate stage of differentiation. These cells were round, slightly larger in size (12.7 +/- 0.2 microm) than monocytes (9.8 +/- 0.1 microm) and expressed the macrophage marker CD14, but lacked the dendritic cell marker CD1a. The highest levels of expression occurred after 2-4 days of culture. At this time point, MLD-1 prominently stained 20-40% of the cells. Monocytes cultured for 16 h or fully differentiated monocyte-derived macrophages were negative or weak for hMGL expression. Similar transient expression was also observed during granulocyte macrophage colony stimulating factor- or macrophage colony stimulating factor-dependent macrophage differentiation. The lectin was characterized as a functional endocytic receptor for glycosylated macromolecules, since the uptake of carbohydrate polymers was partially inhibited by the addition of MLD-1. The distribution of hMGL(+) cells in normal human skin was found by immunostaining to be mainly in the upper dermis distant from vascular structures. More than 90% of the hMGL(+) cells were double stained with anti-CD68 mAb and constituted approximately 20% of the CD68(+) cells. We suggest that the dermal hMGL(+) cells are a subset of differentiated cells derived from monocytes and that hMGL is a unique marker for cells at an intermediate stage of macrophage differentiation.


Tribological Behavior of Titanium Alloy Treated by Nitriding and Surface Texturing Composite Technology.
This study experimentally investigated the effect of surface textures on the tribological mechanism of nitrided titanium alloy (Ti⁻6Al⁻4V). The titanium alloy samples were nitrided at various temperatures ranging from 750 to 950 °C for 10 h in a plasma nitriding furnace. Then, surface textures were fabricated on the polished titanium alloy and plasma nitrided samples by laser process system. The surface roughness, microhardness, and constitution of samples treated by single nitriding and samples treated by composite technology were characterized. The tribological properties of the samples were investigated on a CSM ball-on-disc tribometer. The results show that plasma nitriding effectively enhances the wear resistance of the substrate. The wear rate decreases first and then increases with the increase of nitriding temperature, and the wear rate reaches the minimum at 900 °C. However, the increase in roughness caused by nitriding treatment leads to an increase in the friction coefficient. It is found that surface textures can obviously reduce the friction coefficient of the nitrided titanium alloy. In addition, it can also reduce the wear rate of titanium alloys after nitriding at 900 and 950 °C. It can be concluded that the nitriding and surface texturing combined treatment can obviously reduce the friction coefficient and wear rate at the nitriding temperatures of 900 and 950 °C. This is attributed to the combined effect of high hardness of nitride layers and the function of micro-trap for wear debris of surface textures.


[The implementation of legislation acts regarding prevention of occupational exposure to bloodborne pathogens from perspective of Poland as the ue country].
The paper presents the history of implementation of legislation related to prevention of occupational exposure to blood-borne pathogens in the U.S.A. and EU, including a detailed description of existing regulations. The pioneering role of American legislation in establishing relevant legal acts to prevent employees from sharp injuries is also stressed. In this context the European road towards safer work in the healthcare sector is discussed. The legal acts, currently functioning in the EU, including Council Directive 2010/32/EU of 10 May 2010, are described. The Directive implements the Framework Agreement on prevention from sharp injuries in the hospital and healthcare sector concluded by the European Hospital and Healthcare Employers' Association (HOSPEEM) and the European Federation of Public Service Unions (EPSU). The arguments for the universal implementation of legal acts, protecting medical staff in all EU Member States, are pointed out. As far as Poland is concerned, a great need for an urgent action mobilising all social partners (i.e., nurses, doctors, other employees at potential risk of acquiring an occupational infection, employers, professional organisations and scientific bodies) to develop relevant regulations and to assure sufficient funds for their broad implementation is underlined.


Diffuse light affects the contents of vitamin C, phenolic compounds and free amino acids in lettuce plants.
Enhancement of the diffuse solar radiation to which lettuce plants were exposed clearly affected the vitamin C content and the quantitative and qualitative patterns of phenolic compounds and free amino acids (AA) in the leaves. Although the enhanced level of diffuse light was detrimental to the contents of vitamin C and total phenolic compounds, lowering them by 10-46% and 8-11%, respectively, the content of di-caffeoyltartaric acid increased from 0.26 ± 0.19 to 0.52 ± 0.10 μmol 100 g-1 f.w. for plants harvested in summer. The effect of diffuse light on AA depended on the total amount of global radiation incident on the plants. Considering the lowest amount of global radiation, the enhanced diffuse light increased the AA content from 766 ± 89 to 849 ± 90 μmol 100 g-1 f.w. By contrast, under the highest level of global radiation, diffuse light decreased the amount of AA from 990 ± 16 to 830 ± 76 μmol 100 g-1 f.w.


Benign solitary fibrous tumour of the pleura: a clinical review and report of six cases.
Primary tumours of the pleura are commonly divided into two major categories: diffuse and localised. Whereas the diffuse variant is known for its association with asbestos and its poor outcome, the localised one is rare and remains a subject of controversy. Electron microscopy and immunohistochemistry have recently demonstrated that these tumours are of mesenchymal rather than mesothelial origin, and therefore the term "localised mesothelioma" was abandoned. Such tumours are now called solitary fibrous tumours of the pleura (SFTP). The Authors describe a series of 6 cases of benign solitary fibrous tumours of the pleura, surgically treated over the period 1982-2000.


Enhanced fructose oxidase activity in a galactose oxidase variant.
Galactose oxidase (GO; EC 18.104.22.168) catalyses the oxidation of a wide range of primary alcohols including mono-, oligo- and polysaccharides. High-resolution structures have been determined for GO, but no structural information is available for the enzyme with bound substrate or inhibitor. Previously, computer-aided docking experiments have been used to develop a plausible model for interactions between GO and the D-galactose substrate. Residues implicated in such interactions include Arg330, Gln406, Phe464, Phe194 and Trp290. In the present study we describe an improved expression system for recombinant GO in the methylotrophic yeast Pichia pastoris. We use this system to express variant proteins mutated at Arg330 and Phe464 to explore the substrate binding model. We also demonstrate that the Arg330 variants display greater fructose oxidase activity than does wild-type GO.


One-step synthesis of large-aspect-ratio single-crystalline gold nanorods by using CTPAB and CTBAB surfactants.
Gold nanorods were prepared in high yields by using a one-step seed-mediated process in aqueous cetyltripropylammonium bromide (CTPAB) and cetyltributylammonium bromide (CTBAB) solutions in the presence of silver nitrate. The diameters of the nanorods range from 3 to 11 nm, their lengths are in the range of 15 to 350 nm, and their aspect ratios are in the range of 2 to 70. The diameters of the Au nanorods obtained from one growth batch in CTPAB solutions decrease as their lengths increase, and their volumes decrease as the aspect ratios increase. The diameters of the Au nanorods obtained from one growth batch in CTBAB solutions first decrease and then slightly increase as their lengths increase, and their volumes increase as the aspect ratios increase. These Au nanorods are single-crystalline and are seen to be oriented in either the [100] or [110] direction under transmission electron microscopy imaging, irrespective of their sizes. To the best of our knowledge, this is the first report of the preparation by using wet-chemistry methods of single-crystalline Au nanorods with aspect ratios larger than 15.


Influence of the unloading conditions on capping and lamination: Study on a compaction simulator.
Capping and lamination are classical industrial issues that can be challenging during the scale up of solid dosage forms. Previous publications showed that changing the unloading conditions (triaxial decompression, loaded ejection) made it possible to mitigate capping. In the present study, a systematic study of the effect of the unloading conditions on capping and lamination was performed using a compaction simulator. One model formulation for capping and one for lamination were studied. When symmetrical decompression was performed, as on a rotary press, capping (on both side of the tablet) and lamination were obtained. Asymmetrical unloading (fixed lower punch during unloading) made it possible to suppress lamination and to limit capping to the upper face of the tablet. This unloading condition is similar to the unloading on an eccentric press with a stationary lower punch. Finally, loaded ejection (small pressure on both sides until the end of ejection) made it possible to eliminate both capping and lamination. By changing the unloading condition, it is possible to obtain defect free tablets even for formulations with a high capping or lamination tendency. Moreover, experiments performed on an eccentric press showed results similar to those obtained for asymmetrical unloading on a compaction simulator. Anticipation of tablets defects during the development on eccentric presses might thus be complicated especially in the case of lamination.


Antisense and dominant-negative AKT2 cDNA inhibits glioma cell invasion.
The aim of this study was to explore the potential role of AKT2 in glioma cell invasion. Therefore, dominant-negative (DN-AKT2) and antisense AKT2 constructs (AS-AKT2) were transfected into rat C6 glioma cells with elevated endogenous AKT2 expression. In situ hybridization and Western blot analysis were used to identify AKT2 expression. Spheroid culturing was used to assess cell migration and invasion in Matrigel from spheroids. Cell motility and invasion were also evaluated by scratch and Transwell invasion assays, respectively. The secretion of matrix metalloproteinases (MMPs), MMP2 and MMP9, was determined by gelatin zymography. AKT2 expression was inhibited in C6 cells transfected with AS-AKT2 but did not significantly change in cells transfected with DN-AKT2. The cell migration distance from spheroids or the number of cells migrating into the acellular space created by scratching was reduced in cells transfected with DN-AKT2 or AS-AKT2 compared to the control cells. The invasive distance of cells from the spheroids in Matrigel sandwich and the number of invading cells through the Matrigel were also decreased in the DN-AKT2- and AS-AKT2-transfected cells. Gelatin zymography showed that the production of MMP2 and MMP9 was inhibited in transfected cells. In conclusion, AKT2 plays an important role in glioma cell motility and invasion. Therapy based on AKT inhibition may complement currently available treatment to control glioma cell invasion.


[Cardiopulmonary capacity in patients before and after prosthetic valve replacement].
In this study we wanted to investigate if noninvasive cardiopulmonary exercise testing can be securely, accurately applied in patients with acquired cardiac valve disease pre- and postoperatively with any convenience. Furthermore, we looked if the cardiopulmonary exercise capacity (anaerobic threshold, etc.) was improved postoperatively (3 and 6 months) in 15 patients suffering from severe mitral valve disease as compared to the preoperative condition. The symptom-limited cardiopulmonary exercise testing was performed on a bike in a semi-supine position using a ramp program (+20 W/min). The following parameters were continuously monitored, and the breath-by-breath gas exchange values documented: cardiocirculatory parameters (heart rate; blood pressure; surface ECG; exercise capacity in Watts); gas-exchange parameters (O2-uptake VO2; CO2-production VCO2; respiratory anaerobic threshold VO2 AT; gas-exchange ratio VCO2/VO2; O2-pulse VO2/HR; aerobic capacity delta VO2/delta WR) and ventilatory parameters (respiratory rate; tidal volume Vt; minute ventilation VE; equivalent for O2: VE/VO2 and CO2: VE/VCO2). The 155 cardio-pulmonary exercise tests in 115 patients were practicable, safe (no emergency case) and accurate. In 100 patients late postoperatively (68.3 +/- 53.0 -102.9 +/- 41.2 months) after aortic or mitral valve replacement or both without signs of significant hemolysis or prosthetic valve dysfunction the NYHA classification was too imprecise to characterize the actual exercise capacity of the patients (e.g., NYHA class II: Weber class B to E). Patients with aortic valve prosthesis had a significantly better anaerobic threshold (57.4 +/- 19.1% pred. value max. VO2) as compared to those with mitral valve replacement (mean: 35.9% pred. value max. VO2).(ABSTRACT TRUNCATED AT 250 WORDS)


Hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C.
Dendritic cells (DC) are crucially involved in the induction of immune responses; however, reports on DC functions in chronic hepatitis C are controversial. Function of DC includes proper cell trafficking between sites of infection and lympho-cellular compartments. Thus, we analyzed DC compartmentalization and changes in DC migration in hepatitis C virus (HCV)-infected patients. We found significantly lower numbers of circulating BDCA1+ and BDCA2+ DC in HCV(+) patients (n = 20) than in healthy controls (n = 12) (P < .05). Analyzing liver samples from HCV(+) patients (n = 15), HCV(-) controls (n = 15), and disease controls (n = 10), we demonstrated chronic hepatitis C to be associated with intrahepatic DC enrichment (P < .05). In vitro studies indicated that HCV E2-induced secretion of RANTES efficiently attracts CCR5(+) immature DC. Incubation of DC with sera derived from HCV(+) patients made DC unresponsive to CCL21, the chemokine recruiting DC to lymphoid tissues for T cell priming. Unlike attraction of CCR5+ DCs via RANTES, direct inhibition of DC migration in response to CCL21 was specific for patients with chronic hepatitis C and could be attributed to interaction of HCV E2 with CD81 on DC. In conclusion, migration of DC is markedly affected by interaction of HCV E2 with CD81. Failure of DC to recirculate to lymphoid tissue may be critically involved in impaired T cell priming during HCV infection.


Update on the role of trabectedin in the treatment of intractable soft tissue sarcomas.
Soft tissue sarcomas (STS) represent a variety of tumors of mesenchymal origin, accounting for about 1% of all adult cancers. This group of tumors comprises over 60 different histotypes with different biology showing different sensitivity to therapeutic agents. For decades, the standard first-line systemic treatment of metastatic STS has comprised anthracycline based-chemotherapy. Second-line therapy options include agents such as ifosfamide, gemcitabine, and pazopanib, but the optimal sequential therapy for the management of metastatic disease has yet to be defined. Trabectedin is one of the new molecules approved for patients in progression after first-line chemotherapy with anthracyclines or for those unfit for these agents. The compound is characterized by multiple potential mechanisms of action combining cytotoxic, targeted, and immunological effects. This article takes an in-depth look at the role of trabectedin in the management of metastatic STS, including L-sarcoma and non-L-sarcoma.


Morphological and molecular characterization of Fusarium spp pathogenic to pecan tree in Brazil.
The occurrence of Fusarium spp associated with pecan tree (Carya illinoinensis) diseases in Brazil has been observed in recent laboratory analyses in Rio Grande do Sul State. Thus, in this study, we i) obtained Fusarium isolates from plants with disease symptoms; ii) tested the pathogenicity of these Fusarium isolates to pecan; iii) characterized and grouped Fusarium isolates that were pathogenic to the pecan tree based on morphological characteristics; iv) identified Fusarium spp to the species complex level through TEF-1α sequencing; and v) compared the identification methods used in the study. Fifteen isolates collected from the inflorescences, roots, and seeds of symptomatic plants (leaf necrosis or root rot) were used for pathogenicity tests. Morphological characterization was conducted using only pathogenic isolates, for a total of 11 isolates, based on the mycelial growth rate, sporulation, colony pigmentation, and conidial length and width variables. Pathogenic isolates were grouped based on morphological characteristics, and molecular characterization was performed by sequencing TEF-1α genes. Pathogenic isolates belonging to the Fusarium chlamydosporum species complex, Fusarium graminearum species complex, Fusarium proliferatum, and Fusarium oxysporum were identified based on the TEF-1α region. Morphological characteristics were used to effectively differentiate isolates and group the isolates according to genetic similarity, particularly conidial width, which emerged as a key morphological descriptor in this study.


Consistent description of electrohydrodynamics in narrow fluidic confinements in the presence of hydrophobic interactions.
Electrohydrodynamics in the presence of hydrophobic interactions in narrow confinements is traditionally represented from a continuum viewpoint by a Navier slip-based conceptual paradigm, in which the slip length carries the sole burden of incorporating the effects of substrate wettability on interfacial electromechanics, precluding any explicit dependence of the interfacial potential distribution on the substrate wettability. Here we show that this traditional way of treating electrokinetics-wettability coupling may lead to serious discrepancies in predicting the resultant transport characteristics as manifested through an effective zeta potential. We suggest that an alternative consistent description of the underlying physics through a free-energy-based formalism, in conjunction with considerations of hydrodynamic and electrical property variations consistent with the pertinent phase-field description, may represent the underlying consequences in a more rational manner, as compared to the traditional slip-based model coupled with a two-layer description. Our studies further reveal that the above discrepancies may not occur solely due to the slip-based route of representing the interfacial wettability, but may be additionally attributed to the act of "discretizing" the interfacial phase fraction distribution through an artificial two-layer route.


SSC1, a member of the 70-kDa heat shock protein multigene family of Saccharomyces cerevisiae, is essential for growth.
The genome of the yeast Saccharomyces cerevisiae contains a family of genes related to the HSP70 genes (encoding the 70-kDa heat shock protein) of other eukaryotes. Mutations in two of these yeast genes (SSC1 and SSD1), whose expression is increased a few fold after temperature upshift, were constructed in vitro and substituted into the yeast genome in place of the wild-type alleles. No phenotypic effects of the mutation in SSD1 were detected. However, a functional SSC1 gene is essential for vegetative growth. This result, in conjunction with experiments involving mutations in other members of this multigene family, indicates that at least three distinct functions are carried out by genes of the HSP70 family.


Beta2-selectivity of fenoterol. Comparison of intravenous and aerosol administration.
Aersol administration of fenoterol was compared with intravenous infusion in 30 patients who were undergoing induction of labour. In 11 cases, an increased uterine beta2-selectivity was demonstrated. This, apart from the ease of administration, makes aerosol the mode of administration of choice in some cases. Possible reasons for this are discussed.


Variant PIK3R1 Hypermorphic Mutation and Clinical Phenotypes in a Family with Short Statures, Mild Immunodeficiency and Lymphoma.
Background Heterozygous point mutations in the GT splice donor consensus sequence of exon 11 of the PIK3R1 gene (coding for p85α, p55α, and p50α regulatory subunits of PI3K) lead to exon skipping and thereby to an aberrant protein that leaves PI3K hyperactivated. Several patients with this particular variant of PI3 kinase delta syndrome (APDS) suffering from sinopulmonary infections and lymphoproliferation have been described. Methods (Whole exome) sequencing, evaluation of cellular and clinical phenotypes. Results We here report a family with a new heterozygous mutation in this gene, a 9 bp deletion (c.1418_1425+1del) that, however, leads to the same skipping of exon 11. The clinical phenotypes of their members partly overlap features of patients of other reports. Conclusions We found a new mutation in PIK3R1 and show how broad the resulting clinical spectrum can be.


Drug repositioning of COVID-19 based on mixed graph network and ion channel.
Research on the relationship between drugs and targets is the key to precision medicine. Ion channel is a kind of important drug targets. Aiming at the urgent needs of corona virus disease 2019 (COVID-19) treatment and drug development, this paper designed a mixed graph network model to predict the affinity between ion channel targets of COVID-19 and drugs. According to the simplified molecular input line entry specification (SMILES) code of drugs, firstly, the atomic features were extracted to construct the point sets, and edge sets were constructed according to atomic bonds. Then the undirected graph with atomic features was generated by RDKit tool and the graph attention layer was used to extract the drug feature information. Five ion channel target proteins were screened from the whole SARS-CoV-2 genome sequences of NCBI database, and the protein features were extracted by convolution neural network (CNN). Using attention mechanism and graph convolutional network (GCN), the extracted drug features and target features information were connected. After two full connection layers operation, the drug-target affinity was output, and model was obtained. Kiba dataset was used to train the model and determine the model parameters. Compared with DeepDTA, WideDTA, graph attention network (GAT), GCN and graph isomorphism network (GIN) models, it was proved that the mean square error (MSE) of the proposed model was decreased by 0.055, 0.04, 0.001, 0.046, 0.013 and the consistency index (CI) was increased by 0.028, 0.016, 0.003, 0.03 and 0.01, respectively. It can predict the drug-target affinity more accurately. According to the prediction results of drug-target affinity of SARS-CoV-2 ion channel targets, seven kinds of small molecule drugs acting on five ion channel targets were obtained, namely SCH-47112, Dehydroaltenusin, alternariol 5-o-sulfate, LPA1 antagonist 1, alternariol, butin, and AT-9283.These drugs provide a reference for drug repositioning and precise treatment of COVID-19.


The Effects of Anti-IL-23p19 Therapy on Atherosclerosis Development in ApoE-/- Mice.
The aim of this study is to detect the dynamic expression of interleukin-23 (IL-23) in ApoE-/- mice at different ages and to further examine the effects of anti-IL-23 therapy on atherosclerosis development. The levels of IL-23 in the sera, aortas, and lymph nodes of ApoE-/- mice were significantly increased compared with those of age-matched controls at 8, 12, 16, 20, and 24 weeks of age. Then, 12-week-old ApoE-/- mice were intraperitoneally injected with anti-IL-23p19 neutralizing antibodies, isotype controls, and phosphate-buffered saline for 8 weeks. The proinflammatory and anti-inflammatory mediators in atherosclerotic aortas, plaque areas, plaque necrotic cores, and the contents of major inflammatory cells in plaques were subsequently determined. The results showed that anti-IL-23p19 treatment significantly decreased the expression of IL-17A, IL-6, and TNF-α in the aortas of ApoE-/- mice, but had no obvious effect on the plaque area, plaque necrotic core, or content of major inflammatory cells in atherosclerotic plaques. Although anti-IL-23p19 therapy reduces the expression of several proinflammatory cytokines, it does not significantly suppress the progression of atherosclerosis in ApoE-/- mice.


Crohn's disease - genetic factors and progress of the disease.
Crohn's disease is a multifactorial inflammatory disease affecting mainly the gastrointestinal tract. The genetic factors that are involved in the disease include mainly three mutations of the gene NOD2/CARD15 (R702W, G908R, 3020insC). The aim of this study was to determine the relationship between the presence of these variants and disease phenotype. 70 patients with Crohn's disease were examined for the presence of the above-mentioned mutations. The researchers used the medical records to retrospectively obtain clinical data and together with the information obtained prospectively according to the protocol they analysed the connection between gene mutations and disease phenotype. At least one mutation was found in 22 patients with Crohn's disease (32%), four patients were found to have two different mutations (composed heterozygotes - 6%) and six patients (9%) were homozygotes for the 3020insC gene. No significant differences were found between the groups with wild-type form and the mutated form of the NOD2 / CARD15 gene with respect to age at the time of diagnosis, form of the disease or localization according to the Montreal classification. Mutations of the NOD2 / CARD15 gene did not significantly affect the frequency of reoperations, homozygotes with 3020insC gene mutations, however, represented a high risk group. The phenotype was not related significantly to the presence of the examined mutations.