High levels of antimicrobial resistance in Escherichia coli and Salmonella from poultry in Ecuador.
To describe antimicrobial resistance profiles of Escherichia coli and Salmonella spp. isolated from chicken carcasses and the antimicrobials commonly used in animals in Ecuador and provide information on antimicrobial resistance patterns for implementing evidence-based corrective measures. Meat samples were collected from chicken carcasses in 199 slaughterhouses across Ecuador as part of a national pilot study for monitoring antimicrobial resistance in agricultural sources in 2019. Samples were tested for E. coli and Salmonella spp. Sensitivity to 10 critically important and three highly important antimicrobials (from a human health perspective) was assessed. The country report submitted to the World Organization for Animal Health was accessed to extract the quantity of antimicrobials produced or imported for use in animals. Of 383 samples, E. coli was isolated from 148 (39%) and Salmonella spp. from 20 (5%) samples. Ninety percent of the isolates were resistant to at least one critically important antimicrobial. Resistance was highest to erythromycin (E. coli 76%; Salmonella spp. 85%) and tetracycline (E. coli 71%; Salmonella spp. 90%). Critically or highly important antimicrobials (colistin, tetracycline, trimethoprim/sulfamethoxazole) formed the bulk (87%) of antimicrobials used in animals as per the World Organization for Animal Health report. High prevalence of antimicrobial resistance in poultry in Ecuador calls for the development of guidelines and regulations on the use of antimicrobials and for engagement with livestock producers. The existing surveillance system needs to be strengthened to improve the monitoring of antimicrobial use and evolving resistance patterns.


Translucent titanium coating altered the composition of focal adhesions and promoted migration of osteoblast-like MG-63 cells on glass.
"TiGlass" was designed and was known to promote initial adhesion and increase migration of rat calvarial osteoblats. In this article, migration study and a series of epifluorescence microscopic studies were conducted to find out the composition of focal adhesion on titanium surface. The translucent titanium surface was applied in random migration analysis and immunofluorescence cell staining. In the immunofluorescent double staining, phosphorylated focal adhesion kinase was tested with vinculin. Various integrin subunits were then tested with vinculin to study the composition of activated focal adhesions. Integrin subunit α5 and αV were tested against β3; integrin subunits α5, αV, β3, and αVβ3 were tested with F-actin, respectively. The MG-63 cells began migration earlier and migrated faster on "TiGlass." Immunofluorescent double staining revealed that all focal adhesion kinase in the focal adhesions were activated on both the surfaces. The osteoblast was inferred to made adhesion to titanium and glass through integrins. The focal adhesions on glass were found to be composed of integrin subunits αV and β3. However, on "TiGlass," integrin subunits α5 might have supplemented the adhesion to titanium. Results from double staining of integrin subunits α5, αV, β3, and αVβ3 with F-actin also supported integrin subunits α5 might have involved in adhesion of titanium.


Molecular pathways: the role of primary cilia in cancer progression and therapeutics with a focus on Hedgehog signaling.
Abnormal Hedgehog (Hh) pathway activity has been reported in many cancers, including basal cell carcinomas, medulloblastomas, rhabdomyosarcomas, glioblastomas, and breast and prostate cancers. For this reason, the Hh pathway is a flourishing area for development of anticancer drugs such as Hh ligand antagonists (e.g., 5E1 and robotnikinin), Smo inhibitors (e.g., GDC-0449 and IPI-926), and Gli transcriptional activity inhibitors (e.g., GANT58 and GANT61). It is now clear that primary cilia are required for activation of the Hh pathway in normal vertebrate cells. It is in the primary cilium that both positive and negative effectors of the Hh pathway are processed by posttranslational modifications. In many cancers, preliminary results suggest that primary cilia are lost. As drugs that inhibit different steps of the Hh pathway are developed, it will be important to consider how these drugs will function in the context of primary cilia in the tumor environment. Here, we discuss why some of the Hh inhibitors may be ineffective if primary cilia are lost on cancer cells. Understanding the relationships between clinical inhibitors of the Hh pathway and the presence or absence of primary cilia may turn out to be critical for targeting these therapeutics to the correct population of patients and improving their efficacy. Further work is needed in this area to maximize the potential of these exciting therapeutic targets.


[Systemic fibrinolysis following resuscitation or temporary electrostimulation].
Short-term systemic thrombolytic treatment with 1.5 million I.U. streptokinase or 1.8 million I.U. urokinase or APSAC was carried out in 13 patients with acute myocardial infarction (11 men, 2 women, mean age 61 [44-73] years) after cardiopulmonary resuscitation (n = 11) or transvenous electrostimulation (n = 2). In seven of the patients the infarct vessel was found to be patent after the course of thrombolytic therapy. No haemorrhagic complications occurred. Two patients died: one of a reinfarct at 3 months and the other suddenly at home at 6 months. These results show that short-term high dosage systemic thrombolytic treatment can be successfully performed in individual cases even after resuscitation or central venous catheterization, provided that any serious traumatic lesions or inadvertent arterial punctures have been avoided.


Prospective comparison of acute confusion severity with duration of post-traumatic amnesia in predicting employment outcome after traumatic brain injury.
Measurement of the duration of post-traumatic amnesia (PTA) is common practice, serving as an important index of the severity of traumatic brain injury (TBI) and a predictor of functional outcome. However, controversy exists regarding the nature of PTA; some studies indicate that it is a confusional state with symptoms that extend beyond disorientation and amnesia. To evaluate the contribution of the severity of acute confusion 1 month after TBI to prediction of employment at 1 year after injury, comparing it with PTA duration. Prospective study involving 171 participants with complete data, who met the study criteria, from 228 consecutive TBI Model System admissions. Outcome measures included weekly administration of the Delirium Rating Scale-Revised-98 (DelRS-R98) to measure the severity of acute confusion. Evaluations closest to 1 month after injury were used for study purposes. Duration of PTA was defined as the interval from injury until two consecutive Galveston Orientation and Amnesia Test scores of > or = 76 were obtained within a period of 24-72 h. Univariable and multivariable logistic regression were used to predict employment status at 1 year after injury. Age, education and DelRS-R98 were significant predictors accounting for 34% of outcome variance. Individuals with greater confusion severity at 1 month after injury, older age and lower levels of education were less likely to be employed at 1 year after injury. Severity of confusion was more strongly associated with employment outcome (r(s) = -0.39) than was PTA duration (r(s) = -0.34). In addition to demographic indices, severity of acute confusion makes a unique contribution to predicting late outcome after TBI.


Trafficking macrophage migration using reporter gene imaging with human sodium iodide symporter in animal models of inflammation.
The aim of this study was to investigate the feasibility of nuclear molecular imaging using the human sodium iodide symporter (hNIS) as a reporter gene to monitor macrophage migration toward the inflammatory foci. A stable macrophage cell line coexpressing hNIS and green fluorescent protein (GFP) genes (RAW264.7/hNIS-GFP and R(NIS) cell) was established from an immortalized macrophage cell line (RAW264.7 cells). (125)I uptake was determined (for hNIS protein functional activity), and flow cytometry analysis (to examine GFP gene expression), a cell proliferation assay, a cytokine assay, and a phagocytic activity assay were performed. (99m)Tc-pertechnetate images were acquired at 1 d after subcutaneous inoculation of R(NIS) cells in nude mice. Chemical inflammation was induced for in vivo imaging in the thigh of nude mice by turpentine oil injection. Small-animal PET with (18)F-FDG and (124)I was performed with an intravenous administration of RAW264.7 or R(NIS) cells in inflammation-induced animals. The expression of hNIS and GFP genes was confirmed in R(NIS) cells by flow cytometry and immunofluorescent staining. (125)I uptake was about 67 times higher in R(NIS) cells than in RAW264.7 cells. No significant difference was observed in cell proliferation, cytokine production, and phagocytic activity between RAW264.7 and R(NIS) cells. (99m)Tc-pertechnetate imaging revealed increased tracer uptake at the inoculation site. PET with (124)I demonstrated a donut-shaped uptake, correlating with uptake shown by the (18)F-FDG PET images, at the inflammation site of mice administered R(NIS) cells. (124)I uptake (percentage injected dose per gram) was about 2.12 times higher at the inflammation site in the R(NIS) mice than in RAW264.7 mice. By immunohistochemistry, the migration of macrophages was further confirmed by positive staining for GFP and hNIS at the inflammation site of R(NIS) mice. These data support the feasibility of hNIS reporter gene imaging to monitor the macrophage migration toward an inflammatory lesion. Macrophages expressing hNIS may provide a new strategy to investigate the cellular behavior seen with inflammatory response in a preclinical model.


Proteins from Mucuna pruriens and enzymes from Echis carinatus venom: characterization and cross-reactions.
Mucuna pruriens seeds have been widely used against snakebite in traditional medicine. The antivenin property of a water extract of seeds was assessed in vivo in mice. The serum of mice treated with extract was tested for its immunological properties. Two proteins of Echis carinatus venom with apparent molecular masses of 25 and 16 kDa were detected by Western blot analysis carried out using IgG of mice immunized with extract or its partially purified protein fractions. By enzymatic in-gel digestion and electrospray ionization-mass spectrometry/mass spectrometry analysis of immunoreactive venom proteins, phospholipase A(2,) the most toxic enzyme of snake venom, was identified. These results demonstrate that the observed antivenin activity has an immune mechanism. Antibodies of mice treated with non-lethal doses of venom reacted against some proteins of M. pruriens extract. Proteins of E. carinatus venom and M. pruriens extract have at least one epitope in common as confirmed by immunodiffusion assay.


The ineffectiveness of random donor platelet transfusion in splenectomized, alloimmunized recipients.
The effect of splenectomy on the response to random donor platelet transfusion in 15 multitransfused thrombocytopenic patients is presented. Eight patients responded poorly, with low corrected platelet count increments at 1 and 24 hours posttransfusion. These eight patients were clinically alloimmunized and had lymphocytotoxic antibody ( LCTAb ) in their sera. They responded well to closely HLA-matched transfusions. In contrast, seven splenectomized patients responded well to random donor platelets. Five of these patients had no LCTAb and no other evidence of immunization. Two patients who responded well to random donor platelets had "weak" LCTAb , and one responded to platelets presplenectomy in the presence of this antibody. Splenectomy does not improve the response to random donor platelets in alloimmunized recipients.


Myelodysplastic syndromes. A clinical and pathologic analysis of 109 cases.
A total of 109 patients with myelodysplastic syndromes (MDS) was analyzed to determine the clinical and pathologic features of the five recently defined French-American-British Cooperative Group (FAB) subtypes, and to assess the utility of this classification system in predicting survival, evolution to acute nonlymphocytic leukemia (ANLL), and cause of death. All patients with MDS presented with anemia; additional cytopenias were present in patients with refractory anemia with excess blasts (RAEB), chronic myelomonocytic leukemia (CMML) and refractory anemia with excess blasts in transformation to ANLL (RAEB/Tr). Thirty-two patients received some form of antileukemic therapy for MDS. ANLL developed in 16 of the 77 remaining untreated patients, including 18% (2/11), 0% (0/21), 22% (5/23), 33% (2/6), and 44% (7/16) of patients with refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), RAEB, CMML, and RAEB/Tr, respectively (P = 0.02). The FAB subtype was highly predictive of survival with median survivals ranging from 71 months for RARS to 5 months for RAEB/Tr (P = less than 0.0001). Patients with RAEB, CMML, and RAEB/Tr frequently died of direct consequences of MDS, while patients with RA and especially RARS generally survived or died from unrelated disorders (P = less than 0.0001). MDS encompass a spectrum of disorders. RA and RARS, are relatively indolent and often do not lead to the patient's demise. RAEB, CMML, and RAEB/Tr are aggressive disorders which are often responsible for the patient's death whether or not actual progression to overt leukemia occurs. FAB subtype predicts survival, evolution to ANLL, and cause of death, although the five morphologic subtypes appear to separate into only two disease groups, especially with regard to survival and cause of death.


Fetal inflammatory response at the fetomaternal interface: A requirement for labor at term and preterm.
Human parturition at term and preterm is an inflammatory process synchronously executed by both fetomaternal tissues to transition them from a quiescent state t an active state of labor to ensure delivery. The initiators of the inflammatory signaling mechanism can be both maternal and fetal. The placental (fetal)-maternal immune and endocrine mediated homeostatic imbalances and inflammation are well reported. However, the fetal inflammatory response (FIR) theories initiated by the fetal membranes (amniochorion) at the choriodecidual interface are not well established. Although immune cell migration, activation, and production of proparturition cytokines to the fetal membranes are reported, cellular level events that can generate a unique set of inflammation are not well discussed. This review discusses derangements to fetal membrane cells (physiologically and pathologically at term and preterm, respectively) in response to both endogenous and exogenous factors to generate inflammatory signals. In addition, the mechanisms of inflammatory signal propagation (fetal signaling of parturition) and how these signals cause immune imbalances at the choriodecidual interface are discussed. In addition to maternal inflammation, this review projects FIR as an additional mediator of inflammatory overload required to promote parturition.


Patient Characteristics Independently Associated With Knee Osteoarthritis Symptom Severity at Initial Orthopedic Consultation.
The objective of this study was to identify patient and disease characteristics associated with the symptomatic severity of knee osteoarthritis (OA) at the time of initial knee OA diagnosis by an orthopedist. This medical records review included patients initially diagnosed with knee OA during 2016 to 2017 by a single orthopedic surgeon in a university-based tertiary care setting. All variables were assessed at first OA diagnosis. Main outcomes were subscales of the Knee Injury and Osteoarthritis Outcome Score-Pain, other Symptoms, knee-related quality of life, and function in daily living. Multivariable regression analyses examined the following predictors of main outcomes: sex, race, age, insurance type, body mass index, Charlson comorbidity index, and radiographic OA severity (Kellgren-Lawrence grade). Of the 559 patients included in the study, most were African American (52.1%), female (71.7%), and had severe radiographic OA (Kellgren-Lawrence grade, 4; 68.7%). Female sex, African American racial/ethnic group, Medicaid insurance, younger age, and severe radiographic OA were independently statistically significantly associated with worse symptoms, pain, and function (p < 0.05 for all). Body mass index and Charlson comorbidity index were not statistically significant predictors of any outcome. This study identified disparities in the perception of knee OA problems at initial orthopedist diagnosis based on sex, age, race, insurance, and radiographic OA severity. Because most of these variables are also associated with more rapid progression of OA, identifying their biopsychosocial underpinnings may help determine which interventions are most likely to redress these disparities and delay progression to end-stage knee OA.


Translating E-Mental Health Into Practice: What Are the Barriers and Enablers to E-Mental Health Implementation by Aboriginal and Torres Strait Islander Health Professionals?
With increasing evidence for the effectiveness of e-mental health interventions for enhancing mental health and well-being, a growing challenge is how to translate promising research findings into service delivery contexts. A 2012 e-mental health initiative by the Australian Federal Government (eMHPrac) has sought to address the issue through several strategies, one of which has been to train different health professional workforces in e-mental health (e-MH). The aim of the study was to report on the barriers and enablers of e-MH uptake in a cohort of predominantly Aboriginal and Torres Strait Islander health professionals (21 Indigenous, 5 non-Indigenous) who occupied mainly support or case management roles within their organizations. A 3- or 2-day e-MH training program was followed by up to 5 consultation sessions (mean 2.4 sessions) provided by the 2 trainers. The trainer-consultants provided written reports on each of the 30 consultation sessions for 7 consultation groups. They were also interviewed as part of the study. The written reports and interview data were thematically analyzed by 2 members of the research team. Uptake of e-MH among the consultation group was moderate (22%-30% of participants). There were significant organizational barriers to uptake resulting from procedural and administrative problems, demanding workloads, prohibitive policies, and a lack of fit between the organizational culture and the introduction of new technologies. Personal barriers included participant beliefs about the applicability of e-MH to certain populations, and workers' lack of confidence and skills. However, enthusiastic managers and tech-savvy champions could provide a counter-balance as organizational enablers of e-MH; and the consultation sessions themselves appear to have enhanced skills and confidence, shifted attitudes to new technologies, and seeded a perception that e-MH could be a valuable health education resource. A conclusion from the program was that it was important to match e-MH training and resources to work roles. In the latter stages of the consultation sessions, the Aboriginal and Torres Strait Islander health professionals responded very positively to YouTube video clips and apps with a health education dimension. Therapy-oriented apps and programs may fit less well within the scope of practice of some workforces, including this one. We suggest that researchers broaden their focus and definitions of e-MH and give rather more weight to e-MH's health education possibilities. Developing criteria for evaluating apps and YouTube videos may empower a rather greater section of health workforce to use e-MH with their clients.


Remote Symptom Monitoring to Enhance the Delivery of Palliative Cancer Care in Low-Resource Settings: Emerging Approaches from Africa.
This paper brings together researchers, clinicians, technology developers and digital innovators to outline current applications of remote symptom monitoring being developed for palliative cancer care delivery in Africa. We outline three remote symptom monitoring approaches from three countries, highlighting their models of delivery and intended outcomes, and draw on their experiences of implementation to guide further developments and evaluations of this approach for palliative cancer care in the region. Through highlighting these experiences and priority areas for future research, we hope to steer efforts to develop and optimise remote symptom monitoring for palliative cancer care in Africa.


Effectiveness of a new perforated 0.15 mm poly-p-dioxanon-foil versus titanium-dynamic mesh in reconstruction of the orbital floor.
In recent years a new perforated PDS (poly-p-dioxanon) foil (0.15 mm) has become available and has not yet been proven to be successful in reconstruction of the orbital floor after blow-out-fractures in randomized studies. The main aim of this clinical trial is to compare this new PDS foil with titanium dynamic mesh (0.3 mm) (TD), which is well established in reconstruction of the orbital floor. In a prospective multicentre randomized trial, conducted between 1997 and 1998, out of 42 patients with fractures of the orbital floor, 28 patients needing material for reconstruction were randomized to receive either PDS foil or TD. In a comprehensive preoperative and postoperative protocol patients were monitored by the surgeon, radiologist and ophthalmologist with a postoperative follow-up of least 6 months. Maximum defects of the orbital floor were comparable in both groups (PDS group: 13.3 mm, TD group: 13.9 mm). In both groups the surgical procedure was well tolerated, and functional and cosmetic results were evaluated as satisfactory by all patients. Ophthalmological evaluation, performed up to 6 months postoperatively, revealed double vision or vertical strabismus in nine patients (five PDS group, four titanium group). This was not confirmed subjectively in each single patient. Also ex- or enophthalmos, registered in seven patients of the PDS and four of the TD group (mainly + /- 1 mm) were not considered as relevant by the patients. The new 0.15 mm perforated PDS foil was comparable to 0.3 mm titanium mesh concerning functional and cosmetic outcome. Obviously, persisting ophthalmometric disorders were compensated very well in both groups. PDS foil is felt to be the preferred material since it is bioresorbable and more convenient to handle.


Role of endogenous cytokines secretion in radioprotection conferred by the immunomodulator ammonium trichloro(dioxyethylene-0-0')tellurate.
The immunomodulator ammonium trichloro(dioxyethylene-0-0')tellurate (AS101) has previously been found by us to have radioprotective properties when injected into mice before sublethal and lethal doses of irradiation. AS101 also was found to protect mice from hematopoietic damage caused by various chemotherapeutic drugs. Based on these findings, phase II clinical trials with cancer patients treated with AS101, in combination with chemotherapy, are currently underway. In the present study, we wanted to assess the role of several cytokines in the radioprotection conferred by AS101. We show that the administration of neutralizing antibodies against interleukin-1 (IL-1) receptor, IL-6 receptor, IL-6, tumor necrosis factor (TNF), or stem cell factor (SCF) completely abrogates the ability of AS101 to increase the survival of lethally irradiated mice. Moreover, the injection of each of these antibodies reduces the ability of AS101 to increase the number of BM, spleen cells, and the number of circulating neutrophils, lymphocytes, and platelets in irradiated mice. In addition, these antibodies abrogate the enhancing effect of AS101 on the secretion of IL-3, IL-6, and granulocyte-macrophage colony-stimulating factor, all of which decrease significantly in sublethally irradiated mice. By contrast, the injection of anti-IL-2 receptor antibody or control Igs to AS101-treated mice does not interfere with the radioprotective effects of the compound. These results suggest a role for IL-1, IL-6, TNF alpha, and SCF in the radioprotective effect of AS101. Because cytokine toxicity remains a significant concern, the clinical application of AS101, which has no toxicity, is particularly valuable.


Does third trimester cervical length predict duration of first stage of labor?
To examine the association between third trimester cervical length (CL) measurement and duration of the first stage of labor. This prospective cohort study included women with a singleton pregnancy who had routine CL measurements taken by transvaginal ultrasonography between 37 and 39 weeks gestation. Subjective duration of the first stage of labor was defined as the duration of contractions that the women subjectively had from the onset of regular contractions to full effacement of the cervix. Objective duration of first stage of labor was defined as 3 cm cervical dilation independent of cervical effacement until full effacement of the cervix. Associations between variables were analyzed using nonparametric correlations coefficients. A model relating the duration of labor to predictors was built using linear regression. In this analysis a total of 129 women were included. There was no significant correlation between CL and subjective duration of labor (ρ = -0.037, p = 0.695); however, a reduction in CL increased the objective duration of the first stage of labor (ρ = -0.269, p = 0.013). In univariate analysis parity (p = 0.018), hypertensive disorders (p = 0.013) and induction of labor (p = 0.022) were significantly associated with subjective duration of the first stage of labor. A long cervix in the third trimester is not associated with a prolonged first stage of labor. Induction of labor and multiparity were associated with a shorter first stage of labor while hypertension was associated with a longer duration of labor.


The relationship of impulsivity-inattention and verbal ability to overt and covert antisocial behaviors in children.
Research has linked many risk factors in childhood and early adolescence to antisocial behaviors in later adolescence and early adulthood; however, less attention has focused on the interaction among factors in the prediction of distinct forms of antisocial behaviors. This study investigated the additive and synergistic association of inattention-impulsivity and verbal ability with overt and covert antisocial behaviors using a high risk community sample of 270 (49.8% female) children. Multiple regression analyses indicated kindergarten inattention-impulsivity was significantly related to overt and covert antisocial behaviors and the interaction of inattention-impulsivity and verbal ability significantly predicted covert but not overt antisocial behaviors during kindergarten and first grade. Kindergarten verbal ability did not buffer the association of impulsivity-inattention with covert antisocial behavior; rather higher verbal ability was associated with increased risk for covert antisocial behavior in the presence of high levels of impulsivity-inattention. The association of inattention-impulsivity with higher levels of overt and covert antisocial behavior begins during childhood, and may set off developmental trajectories associated with the acceleration of antisocial behavior in adolescence.


Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice.
To investigate the signaling mechanism of anti-oxidative action by curcumin and its impact on glucose disposal. Male C57BL/6J mice were fed with either a normal diet (n = 10) or a high fat diet (HFD) (n = 20) to induce obesity and insulin resistance. After 16 wk, 10 HFD-fed mice were further treated with daily curcumin oral gavage at the dose of 50 mg/kg body weight (BW) (HFD + curcumin group). After 15 d of the curcumin supplementation, an intraperitoneal glucose tolerance test was performed. Fasting blood samples were also collected for insulin and glucose measurements. Insulin-sensitive tissues, including muscle, adipose tissue and the liver, were isolated for the assessments of malondialdehyde (MDA), reactive oxygen species (ROS) and nuclear factor erythroid-2-related factor-2 (Nrf2) signaling. We show here that in a HFD mouse model, short-term curcumin gavage attenuated glucose intolerance without affecting HFD-induced BW gain. Curcumin also attenuated HFD-induced elevations of MDA and ROS in the skeletal muscle, particularly in its mitochondrial fraction, but it had no such an effect in either adipose tissue or the liver of HFD-fed mice. Correspondingly, in skeletal muscle, the levels of total or nuclear content of Nrf2, as well as its downstream target, heme oxygenase-1, were reduced by HFD-feeding. Curcumin intervention dramatically reversed these defects in Nrf2 signaling. Further analysis of the relationship of oxidative stress with glucose level by a regression analysis showed a positive and significant correlation between the area under the curve of a glucose tolerance test with MDA levels either in muscle or muscular mitochondria. These findings suggest that the short-term treatment of curcumin in HFD-fed mice effectively ameliorates muscular oxidative stress by activating Nrf2 function that is a novel mechanism for its effect in improving glucose intolerance.


Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials.
We performed a meta-analysis of randomized clinical trials to determine the risks of adverse events associated with testosterone replacement in older men. The MEDLINE database was searched from 1966 to April 2004, using testosterone as the indexing term; limits included human, male, > or =45 years old, and randomized controlled trial. Of the 417 studies thus identified, 19 met the inclusion criteria: testosterone replacement for at least 90 days, men > or =45 years old with low or low-normal testosterone level, randomized controlled trial, and medically stable men. Odds ratios (ORs) were pooled using a random effects model, assuming heterogeneous results across studies, and were weighted for sample size. In the 19 studies that met eligibility criteria, 651 men were treated with testosterone and 433 with placebo. The combined rate of all prostate events was significantly greater in testosterone-treated men than in placebo-treated men (OR = 1.78, 95% confidence interval [CI], 1.07-2.95). Rates of prostate cancer, prostate-specific antigen (PSA) >4 ng/ml, and prostate biopsies were numerically higher in the testosterone group than in the placebo group, although differences between the groups were not individually statistically significant. Testosterone-treated men were nearly four times as likely to have hematocrit >50% as placebo-treated men (OR = 3.69, 95% CI, 1.82-7.51). The frequency of cardiovascular events, sleep apnea or death was not significantly different between the two groups. Testosterone replacement in older men was associated with a significantly higher risk of detection of prostate events and of hematocrit >50% than was placebo; hematocrit increase was the most frequent adverse event associated with testosterone replacement. These data reaffirm the need to monitor hematocrit, PSA, and digital examination of the prostate during testosterone replacement in older men.


Transenteric rupture of pancreatic pseudocysts: management of pseudocystenteric fistulas.
Among the protean presentations of pancreatic pseudocyst, spontaneous transenteric perforation is being reported with increasing frequency. Review of the literature revealed 37 cases in which the diagnosis of transenteric perforation of a pseudocyst could be substantiated, 21 reported since 1960. Five additional cases are described, including the first case of pseudocystesophageal fistulization. Of the 26 recent cases, chronic alcoholism was associated with fistulization in 73 per cent (19/26), males outnumbered females 2:1, and the age at diagnosis ranged from 23-74. No predilection for any particular segment of intestine was apparent. All the patients had symptomatology suggestive of pancreatic disease. In addition, 54 per cent (14/26) had intestinal hemorrhage. In that group of patients with a palpable abdominal mass, the sudden disappearance of the mass as transenteric decompression occurred was pathognomonic. Defivitive diagnosis was best established by a combination of ultrasound and barium intestinal studies. The overall mortality rate was 27 per cent (7/26), all of the deaths occurring in those patients with hemorrhage complicating the pseudocystenteric fistula. Since spontaneous closure of the fistula may be expected, surgery should be reserved for those patients with incomplete spontaneous drainage or uncontrollable hemorrhage.


[An unusual cause of laryngeal stridor: the Shy-Drager syndrome].
A case of laryngeal stridor in an adult patient is presented and the diagnose of syndrome of Shy-Drager is proposed. This syndrome is the result of a degeneration of the central nervous system. Some autonomic functions are involved in this process. The leading symptoms are an orthostatic hypotension, parkinson-like symptoms and laryngeal stridor. The last symptom results from a neurogenic paralysis of both posterior crico-arytenoideus muscles. A depletion of neurotransmitters in the central nervous system would be the cause of the syndrome. The treatment is symptomatic. Concerning the laryngeal stridor, tracheotomy, eventually followed by a crico-arytenoidopexy, is the only treatment which can be proposed.


XIAP Regulation by MNK Links MAPK and NFκB Signaling to Determine an Aggressive Breast Cancer Phenotype.
Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked EGFR (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors. XIAP drove constitutive NFκB transcriptional activity, which mediated ALDH positivity (a marker of stem-like cells), in vivo tumor growth, and an IBC expression signature in patient-derived IBC cells. Using pathway inhibitors and mathematical models, we defined a new role for the MAPK interacting (Ser/Thr)-kinase (MNK) in enhancing XIAP expression and downstream NFκB signaling. Furthermore, targeted XIAP knockdown and treatment with a MNK inhibitor decreased tumor cell migration in a dorsal skin fold window chamber murine model that allowed for intravital imaging of local tumor growth and migration. Together, our results indicate a novel role for XIAP in the molecular cross-talk between MAPK and NFκB pathways in aggressive tumor growth, which has the potential to be therapeutically exploited.Significance: Signaling by the MNK kinase is essential in inflammatory breast cancer, and it can be targeted to inhibit XIAP-NFκB signaling and the aggressive phenotype of this malignancy. Cancer Res; 78(7); 1726-38. ©2018 AACR.


Uniquantal release through a dynamic fusion pore is a candidate mechanism of hair cell exocytosis.
The mechanisms underlying the large amplitudes and heterogeneity of excitatory postsynaptic currents (EPSCs) at inner hair cell (IHC) ribbon synapses are unknown. Based on electrophysiology, electron and superresolution light microscopy, and modeling, we propose that uniquantal exocytosis shaped by a dynamic fusion pore is a candidate neurotransmitter release mechanism in IHCs. Modeling indicated that the extended postsynaptic AMPA receptor clusters enable large uniquantal EPSCs. Recorded multiphasic EPSCs were triggered by similar glutamate amounts as monophasic ones and were consistent with progressive vesicle emptying during pore flickering. The fraction of multiphasic EPSCs decreased in absence of Ca(2+) influx and upon application of the Ca(2+) channel modulator BayK8644. Our experiments and modeling did not support the two most popular multiquantal release interpretations of EPSC heterogeneity: (1) Ca(2+)-synchronized exocytosis of multiple vesicles and (2) compound exocytosis fueled by vesicle-to-vesicle fusion. We propose that IHC synapses efficiently use uniquantal glutamate release for achieving high information transmission rates.


Women's negative childbirth experiences and socioeconomic factors: Results from the Babies Born Better survey.
To investigate the association between women's socioeconomic status and overall childbirth experience and to explore how women reporting an overall negative birth experience describe their experiences of intrapartum care. We used both quantitative and qualitative data from the Babies Born Better (B3) survey version 2, including a total of 8317 women. First, we performed regression analyses to explore the association between women's socioeconomic status and labour and birth experience, and then a thematic analysis of three open-ended questions from women reporting a negative childbirth experience (n = 917). In total 11.7% reported an overall negative labour and birth experience. The adjusted odds ratio (OR) of a negative childbirth experience was elevated for women with non-tertiary education, for unemployed, students and not married or cohabiting. Women with lower subjective living standard had an adjusted OR of 1.70 (95% CI 1.44-2.00) for a negative birth experience, compared with those with average subjective living standard. The qualitative analysis generated three themes: 1) Uncompassionate care: lack of sensitivity and empathy, 2) Impersonal care: feeling objectified, and 3) Critical situations: feeling unsafe and loss of control. Important socioeconomic disparities in women's childbirth experiences exist even in the Norwegian setting. Women reporting a negative childbirth experience described disrespect and mistreatment as well as experiences of insufficient attention and lack of awareness of individual and emotional needs during childbirth. The study shows that women with lower socioeconomic status are more exposed to these types of experiences during labour and birth. Women with lower socioeconomic status are more exposed to negative experiences during labour and birth.


Biochar-Enhanced Resistance to Botrytis cinerea in Strawberry Fruits (But Not Leaves) Is Associated With Changes in the Rhizosphere Microbiome.
Biochar has been reported to play a positive role in disease suppression against airborne pathogens in plants. The mechanisms behind this positive trait are not well-understood. In this study, we hypothesized that the attraction of plant growth-promoting rhizobacteria (PGPR) or fungi (PGPF) underlies the mechanism of biochar in plant protection. The attraction of PGPR and PGPF may either activate the innate immune system of plants or help the plants with nutrient uptake. We studied the effect of biochar in peat substrate (PS) on the susceptibility of strawberry, both on leaves and fruits, against the airborne fungal pathogen Botrytis cinerea. Biochar had a positive impact on the resistance of strawberry fruits but not the plant leaves. On leaves, the infection was more severe compared with plants without biochar in the PS. The different effects on fruits and plant leaves may indicate a trade-off between plant parts. Future studies should focus on monitoring gene expression and metabolites of strawberry fruits to investigate this potential trade-off effect. A change in the microbial community in the rhizosphere was also observed, with increased fungal diversity and higher abundances of amplicon sequence variants classified into Granulicella, Mucilaginibacter, and Byssochlamys surrounding the plant root, where the latter two were reported as biocontrol agents. The change in the microbial community was not correlated with a change in nutrient uptake by the plant in either the leaves or the fruits. A decrease in the defense gene expression in the leaves was observed. In conclusion, the decreased infection of B. cinerea in strawberry fruits mediated by the addition of biochar in the PS is most likely regulated by the changes in the microbial community.


Review and Analysis of Mountaineering Accidents in the United States from 1947-2018.
DeLoughery, Emma P. and Thomas G. DeLoughery. Review and Analysis of Mountaineering Accidents in the United States from 1947-2018. High Alt Med Biol. 23:114-118, 2022. Introduction: Given the popularity of mountaineering, it is important to better understand accidents related to this sport. We undertook this review of accidents to better understand the demographics and locations involved in mountaineering accidents over 71 years. Methods: Data collected from "Accidents in North American Mountaineering" booklets from 1947 to 2018 included the date, state and location of the accident, sex and age of the victim, type of accident, injuries sustained, and distance fallen if a fall occurred. If at least 10 accidents occurred in an individual state and/or location, these sites were separately analyzed. Results: From 1947 to 2018, 2,799 people were reported to be involved in mountaineering accidents, and 43% of these accidents resulted in death. Women were involved in 12% of cases. Falls were the most common accident (68% incidence, 45% fatal), followed by falling rock (7%, 26% fatal), avalanche (6%, 75% fatal), and falling into a crevasse (2%, 52% fatal). The average age of victims was 30 years. California had the most accidents (18%), followed by Washington (16%) and Alaska (15%). Denali had the greatest frequency of both accidents and deaths (11%, 8% of deaths), followed by Mount Rainier (6%, 7% of deaths) and Mount Hood (2%, 3% of deaths). Conclusions: Accident victims tend to be young and predominantly male, and the accidents themselves are most often falls. Avalanches were identified as an accident cause with a high fatality rate.


Physical Activity and Risk of Postoperative Delirium.
Regular physical activity (PA) has been associated with improved cognitive function, but its effect on postoperative delirium (POD) has not been established. Our objectives were to determine the effect of baseline PA on the incidence of POD in older patients undergoing elective orthopedic surgery and to determine whether these effects were independent of cognitive reserve. We hypothesize that PA protects against POD by bolstering physiologic reserve needed to withstand the stressors of surgery. Secondary analysis of a prospective, single-center, cohort study. Urban academic hospital. A total of 132 nondemented, English-speaking adults older than 60 years undergoing elective orthopedic surgery. Subjects were screened for POD and delirium severity using the Confusion Assessment Method and the Memorial Delirium Assessment Scale. Baseline cognitive activities and PAs were assessed with a validated Leisure Activity Scale. Regular PA was categorized as 6 to 7 days per week. The association of regular PA with incidence of POD was assessed using multivariable logistic regression, adjusting for age, sex, Charlson Comorbidity Index, cognitive reserve, and cognitive function. Linear regression was used to assess the association of delirium severity with regular PA. Of 132 patients, 41 (31.1%) developed POD. Regular PA was associated with a 74% lower odds of developing POD (odds ratio [OR] = 0.26; 95% confidence interval [CI] = 0.08-0.82). There was no significant interaction between PA and cognitive reserve (P = .70). Of 85 women, 25 (29.4%), and of 47 men, 16 (34.0%) developed POD. In stratified analysis, women who engaged in regular PA had dramatically lower odds of POD (OR = 0.08; 95% CI = 0.01-0.63) compared with men (OR = 0.93; 95% CI = 0.18-4.97). Regular PA is associated with decreased incidence of POD, especially among women. Future studies should address the basis of sex differences in PA benefits on delirium. J Am Geriatr Soc 67:2260-2266, 2019.


Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice.
Human apolipoprotein E (apoE) exists in three major isoforms: apoE2, apoE3 and apoE4. In the brain, apoE is produced mostly by astrocytes and transports cholesterol to neurons via apoE receptors. Among the gene alleles encoding the three isoforms, the APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), whereas APOE2 is protective. ApoE4 confers a gain of toxic function, a loss of neuroprotective function or a combination of both in AD pathogenesis. Given that therapeutic impacts of modulating apoE expression may be isoform-dependent, we sought to investigate the relationship between overexpressing apoE isoform and apoE-related functions in apoE-targeted replacement (TR) mice. Specifically, apoE isoform expression driven by the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter was built into an adeno-associated virus serotype 8 (AAV8) vector and injected into the ventricles of postnatal day 2 (P2) apoE3-TR or apoE4-TR mice. Upon confirmation of apoE isoform expression, effects on apoE lipidation and the levels of amyloid-β (Aβ) in the brain were assessed. AAV8-GFAP-apoE isoforms were specifically expressed in astrocytes throughout all brain regions, which led to overall increased apoE levels in the brain. Viral mediated overexpression of apoE4 in the apoE4-TR background increased poorly-lipidated apoE lipoprotein particles and decreased apoE-associated cholesterol in apoE4-TR mice. Conversely, apoE2 overexpression in apoE4-TR mice enhanced apoE lipidation and associated cholesterol. Furthermore, overexpression of apoE4 elevated the levels of endogenous Aβ, whereas apoE2 overexpression trended to lower endogenous Aβ. Overexpression of apoE isoforms induces differential effects in the apoE4-TR background: apoE4 decreases apoE lipidation and enhances Aβ accumulation, whereas apoE2 has the opposite effects. Our findings suggest that increasing apoE2 in APOE4 carriers is a beneficial strategy to treat AD, whereas increasing apoE4 in APOE4 carriers is likely harmful. We have also established novel methods to express apoE isoforms in mouse brain to study apoE-related pathways in AD and related dementia.


Temporal trends in healthcare resource utilization and costs following acute myocardial infarction.
Acute myocardial infarction (AMI) is associated with greater utilization of healthcare resources and financial expenditure. To evaluate temporal trends in healthcare resource utilization and costs following AMI throughout 2003-2015. AMI patients who survived the first year following hospitalization in a tertiary medical center (Soroka University Medical Center) throughout 2002-2012 were included and followed until 2015. Length of the in-hospital stay (LOS), emergency department (ED), primary care, outpatient consulting clinic visits and other ambulatory services, and their costs, were evaluated and compared annually over time. Overall 8047 patients qualified for the current study; mean age 65.0 (SD = 13.6) years, 30.3% women. During follow-up, LOS and the number of primary care visits has decreased significantly. However, ED and consultant visits as well as ambulatory-services utilization has increased. Total costs have decreased throughout this period. Multivariate analysis, adjusted for potential confounders, showed as significant trend of decrease in LOS and ambulatory-services utilization, yet an increase in ED visits with no change in total costs. Despite a decline in utilization of most healthcare services throughout the investigated decade, healthcare expenditure has not changed. Further evaluation of the cost-effectiveness of long-term resource allocation following AMI is warranted. Nevertheless, we believe more intense ambulatory follow-up focusing on secondary prevention and early detection, as well as high-quality outpatient chest pain unit are warranted.


Liver receptor homologue-1 is expressed in the adrenal and can regulate transcription of 11 beta-hydroxylase.
Liver receptor homologue-1 (LRH-1, designated NR5A2) is a mammalian homologue of Drosophila fushi tarazu factor (dFTZ-F1) and structurally belongs to the orphan nuclear receptor superfamily. LRH-1 can recognize the DNA sequence 5'-AAGGTCA-3', the canonical recognition motif for steroidogenic factor 1 (SF-1). Herein, we hypothesized that LRH-1 might play a role in the regulation of human adrenal expression of steroidogenic enzymes. To test this hypothesis, LRH-1 expression in human adult and fetal adrenal glands was examined by RT-PCR analysis. The fetal and adult adrenal glands, as well as liver and pancreas, were observed to express LRH-1 mRNA using RT-PCR. The ability of LRH-1 to enhance transcription of the gene encoding human 11 beta- hydroxylase (hCYP11B1) was then examined using the H295R adrenal cell line. LRH-1 co-transfection with hCYP11B1 luciferase promoter constructs caused a 25-fold induction of luciferase activity. Furthermore, co-transfection of a hCYP11B1 reporter construct containing a mutation in the SF-1 binding cis-element abolished the stimulatory effect of both SF-1 and LRH-1. Electrophoretic mobility shift assay (EMSA) demonstrated that LRH-1 could bind to the SF-1 response element. Taken together, our data suggested that LRH-1 is expressed in the adrenal, and can substitute for SF-1 to enhance transcription of genes encoding certain of the steroid-metabolizing enzymes. A role for LRH-1 in the regulation of adrenal or gonadal steroid hormone production should be further studied.


Immunoglobulin G1 enzyme-linked immunosorbent assay for diagnosis of Johne's Disease in red deer (Cervus elaphus).
This study was designed to develop a customized enzyme-linked immunosorbent assay (ELISA) for the serodiagnosis of Johne's disease (JD) in farmed deer. Two antigens were selected on the basis of their superior diagnostic readouts: denatured purified protein derivative (PPDj) and undenatured protoplasmic antigen (PpAg). ELISA development was based on the antigen reactivity of the immunoglobulin G1 (IgG1) isotype, which is a highly specific marker for mycobacterial disease seroreactivity in deer. Sensitivity estimates and test parameters were established using 102 Mycobacterium paratuberculosis-infected animals from more than 10 deer herds, and specificity estimates were determined using 508 uninfected animals from 5 known disease-free herds. A receiver-operated characteristic analysis determined that at a cut point of 50 ELISA units, there was a specificity of 99.5% and sensitivities of 84.0% with PPDj antigen, 88.0% with PpAg, and 91.0% when the antigens were used serially in a composite test. Estimated sensitivity was further improved using recombinant protein antigens unique for M. paratuberculosis, which identified infected animals that were unreactive to PPDj or PpAg. While 80% of animals that were seropositive in the IgG1 ELISA had detectable histopathology, the assay could also detect animals with subclinical disease. The test was significantly less sensitive (75%) for animals that were culture positive for M. paratuberculosis but with no detectable pathology than for those with pathological evidence of JD (>90%). When the IgG1 ELISA was used annually over a 4-year period in a deer herd with high levels of clinical JD, it eliminated clinical disease, increased production levels, and reduced JD-related mortality.


Simultaneous feeding by aboveground and belowground herbivores attenuates plant-mediated attraction of their respective natural enemies.
Herbivore-damaged plants emit volatile organic compounds that attract natural enemies of the herbivores. This form of indirect plant defence occurs aboveground as well as belowground, but it remains unclear how simultaneous feeding by different herbivores attacking leaves and roots may affect the production of the respective defence signals. We employed a setup that combines trapping of volatile organic signals and simultaneous measurements of the attractiveness of these signals to above and belowground natural enemies. Young maize plants were infested with either the foliar herbivore Spodoptera littoralis, the root herbivore Diabrotica virgifera virgifera, or with both these important pest insects. The parasitic wasp Cotesia marginiventris and the entomopathogenic nematode Heterorhabditis megidis were strongly attracted if their respective host was feeding on a plant, but this attraction was significantly reduced if both herbivores were on a plant. The emission of the principal root attractant was indeed reduced due to double infestation, but this was not evident for the leaf volatiles. The parasitoid showed an ability to learn the differences in odour emissions and increased its response to the odour of a doubly infested plant after experiencing this odour during an encounter with hosts. This first study to measure effects of belowground herbivory on aboveground tritrophic signalling and vice-versa reemphasizes the important role of plants in bridging interactions between spatially distinct components of the ecosystem.


[Seed vigor evaluation based on adversity resistance index of wheat seed germination under stress conditions.]
A total of 16 wheat cultivars were selected to detect seed vigor of different genotypes using standard germination test, seed germination test under stress conditions and field emergence test. The adversity resistance indices of seed vigor indices and field emergence percentage under different germination conditions were used as the indices to evaluate adversity resistance. Principal component analysis and cluster analysis were used for the comprehensive evaluation of seed vigor. Results showed that drought stress, artificial aging and cold soaking treatments affected seed vigor to some extent. The adversity resistance indices of the artificial aging and cold soaking tests were significantly positively correlated with the field emergence percentage, while the adversity resistance index of drought stress test had no significant correlation with the field emergence percentage. 16 wheat cultivars were classified as three groups based on the principal component analysis and cluster analysis. Yunong 949, Yumai 49-198, Luyuan 502, Zhengyumai 9987, Shimai 21, Shannong 23, and Shixin 828 belonged to high vigor seeds. Xunong 5, Yunong 982, Tangmai 8, Jimai 20, Jimai 22, Jinan 17, and Shannong 20 belonged to medium vigor seeds. The other two cultivars, Chang 4738 and Lunxuan 061, belonged to low vigor seeds.


Understanding recovery in the context of lived experience of personality disorders: a collaborative, qualitative research study.
Concepts of recovery increasingly inform the development and delivery of mental health services internationally. In the UK recent policy advocates the application of recovery concepts to the treatment of personality disorders. However diagnosis and understanding of personality disorders remains contested, challenging any assumption that mainstream recovery thinking can be directly translated into personality disorders services. In a qualitative interview-based study understandings of recovery were explored in extended, in-depth interviews with six people purposively sampled from a specialist personality disorders' service in the UK. An interpretive, collaborative approach to research was adopted in which university-, clinical- and service user (consumer) researchers were jointly involved in carrying out interviews and analysing interview data. Findings suggested that recovery cannot be conceptualised separately from an understanding of the lived experience of personality disorders. This experience was characterised by a complexity of ambiguous, interrelating and conflicting feelings, thoughts and actions as individuals tried to cope with tensions between internally and externally experienced worlds. Our analysis was suggestive of a process of recovering or, for some, discovering a sense of self that can safely coexist in both worlds. We conclude that key facilitators of recovery - positive personal relationships and wider social interaction - are also where the core vulnerabilities of individuals with lived experience of personaility disorders can lie. There is a role for personality disorders services in providing a safe space in which to develop positive relationships. Through discursive practice within the research team understandings of recovery were co-produced that responded to the lived experience of personality disorders and were of applied relevance to practitioners.


Dynamic real-time subtraction of stray-light and background for multiphoton imaging.
We introduce a new approach to reduce uncorrelated background signals from fluorescence imaging data, using real-time subtraction of background light. This approach takes advantage of the short fluorescence lifetime of most popular fluorescent activity reporters, and the low duty-cycle of ultrafast lasers. By synchronizing excitation and recording, laser-induced multiphoton fluorescence can be discriminated from background light levels with each laser pulse. We demonstrate the ability of our method to - in real-time - remove image artifacts that in a conventional imaging setup lead to clipping of the signal. In other words, our method enables imaging under conditions that in a conventional setup would yield corrupted data from which no accurate information can be extracted. This is advantageous in experimental setups requiring additional light sources for applications such as optogenetic stimulation.


E4BP4-mediated inhibition of T follicular helper cell differentiation is compromised in autoimmune diseases.
T follicular helper (Tfh) cells are indispensable for the formation of germinal center (GC) reactions, whereas T follicular regulatory (Tfr) cells inhibit Tfh-mediated GC responses. Aberrant activation of Tfh cells contributes substantially to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). Nonetheless, the molecular mechanisms mitigating excessive Tfh cell differentiation are not fully understood. Herein we demonstrate that the adenovirus E4 promoter-binding protein (E4BP4) mediates a feedback loop and acts as a transcriptional brake to inhibit Tfh cell differentiation. Furthermore, we show that such an immunological mechanism is compromised in patients with SLE. Establishing mice with either conditional knockout (cKO) or knockin (cKI) of the E4bp4 gene in T cells reveals that E4BP4 strongly inhibits Tfh cell differentiation. Mechanistically, E4BP4 regulates Bcl6 transcription by recruiting the repressive epigenetic modifiers HDAC1 and EZH2. E4BP4 phosphorylation site mutants have limited capability with regard to inhibiting Tfh cell differentiation. In SLE, we detected impaired phosphorylation of E4BP4, finding that this compromised transcription factor is positively correlated with disease activity. These findings unveiled molecular mechanisms by which E4BP4 restrains Tfh cell differentiation, whose compromised function is associated with uncontrolled autoimmune reactions in SLE.


Prostanoid FP and EP2 Receptor Agonists Induce Epithelial and Subepithelial Fibrogenetic Changes in Human Conjunctival Fibroblasts in Different Manners.
Purpose: To examine the effects of prostanoid FP and EP2 receptor agonists, PGF2α and Omidenepag (OMD), respectively, on the transforming growth factor beta (TGF-β2) induced conjunctival fibrogenesis. Methods: Two-dimension (2D) and three-dimension (3D) cultures of these fibroblasts were subjected to following analyses: (1) planar proliferation evaluated by transendothelial electron resistance (TEER) measurements, (2) real-time metabolic analyses, (3) subepithelial proliferation evaluated by 3D spheroid' size and stiffness measurements, and (4) the mRNA expression of extracellular matrix (ECM) molecules and their modulators. Results: TGF-β2 induced increase in the planar proliferation was significantly decreased or enhanced by PGF2α or OMD, respectively. The proportion of oxygen consumption required to drive ATP synthesis compared with that driving proton leakage was increased by PGF2α and OMD independently with TGF-β2. In contrast, maximal mitochondrial respiration was decreased by PGF2α and OMD, and the OMD-induced effect was further enhanced by the presence of TGF-β2. In addition, the TGF-β2 dependent increase in the glycolytic capacity was cancelled by PGF2α and/or OMD. Alternatively, subepithelial proliferation, as evidenced by the stiffness of the 3D spheroids, was substantially increased by both PGF2α and OMD, and these were differently modulated by TGF-β2. The expression of several related factors as above fluctuated among the conditions for both 2D and 3D and TGF-β2 untreated or treated cultures. Conclusion: The present findings indicate that the prostanoid FP or the EP2 receptor agonist may solely and differently induce the planar and subepithelial proliferation of HconF cells and these were also modulated by TGF-β2.


Vitamin E ameliorates the decremental effect of paraquat on cardiomyocyte contractility in rats.
Exposure to pesticides and industrial toxins are implicated in cardiovascular disease. Paraquat (PAR) is a toxic chemical widely used as an herbicide in developing countries and described as a major suicide agent. The hypothesis tested here is that PAR induced myocardial dysfunction may be attributed to altered mechanisms of Ca(2+) transport which are in turn possibly linked to oxidative stress. The mechanisms of PAR induced myocardial dysfunction and the impact of antioxidant protection was investigated in rat ventricular myocytes. Forty adult male Wistar rats were divided into 4 groups receiving the following daily intraperitoneal injections for 3 weeks: Group 1 PAR (10 mg/kg), Control Group 2 saline, Group 3 vitamin E (100 mg/kg) and Group 4 PAR (10 mg/kg) and vitamin E (100 mg/kg). Ventricular action potentials were measured in isolated perfused heart, shortening and intracellular Ca(2+) in electrically stimulated ventricular myocytes by video edge detection and fluorescence photometry techniques, and superoxide dismutase (SOD) and catalase (CAT) levels in heart tissue. Spontaneous heart rate, resting cell length, time to peak (TPK) and time to half (THALF) relaxation of myocyte shortening were unaltered. Amplitude of shortening was significantly reduced in PAR treated rats (4.99±0.26%) and was normalized by vitamin E (7.46±0.44%) compared to controls (7.87±0.52%). PAR significantly increased myocytes resting intracellular Ca(2+) whilst TPK and THALF decay and amplitude of the Ca(2+) transient were unaltered. The fura-2-cell length trajectory during the relaxation of the twitch contraction was significantly altered in myocytes from PAR treated rats compared to controls suggesting altered myofilament sensitivity to Ca(2+) as it was normalized by vitamin E treatment. A significant increase in SOD and CAT activities was observed in both PAR and vitamin E plus PAR groups. PAR exposure compromised rats heart function and ameliorated by vitamin E treatment.


Blood pressure control in Hispanics in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.
Historically, blood pressure control in Hispanics has been considerably less than that of non-Hispanic whites and blacks. We compared determinants of blood pressure control among Hispanic white, Hispanic black, non-Hispanic white, and non-Hispanic black participants (N=32 642) during follow-up in a randomized, practice-based, active-controlled trial. Hispanic blacks and whites represented 3% and 16% of the cohort, respectively; 33% were non-Hispanic black and 48% were non-Hispanic white. Hispanics were less likely to be controlled (<140/90 mm Hg) at enrollment, but within 6 to 12 months of follow-up, Hispanics had a greater proportion <140/90 mm Hg compared with non-Hispanics. At 4 years of follow-up, blood pressure was controlled in 72% of Hispanic whites, 69% of Hispanic blacks, 67% of non-Hispanic whites, and 59% of non-Hispanic blacks. Compared with non-Hispanic whites, Hispanic whites had a 20% greater odds of achieving BP control by 2 years of follow-up (odds ratio: 1.20; 95% CI: 1.10 to 1.31) after controlling for demographic variables and comorbidities, Hispanic blacks had a similar odds of achieving BP control (odds ratio: 1.04; 95% CI: 0.86 to 1.25), and non-Hispanic blacks had a 27% lower odds (odds ratio: 0.73; 95% CI: 0.69 to 0.78). We conclude that in all patients high levels of blood pressure control can be achieved with commonly available medications and that Hispanic ethnicity is not associated with inferior control in the setting of a clinical trial in which hypertensive patients had equal access to medical care, and medication was provided at no cost.


Altered Expression of Fas (APO-1, CD95) and Fas Ligand in the Liver of Mice Infected with Schistosoma Japonicum and Schistosoma Mansoni: Implications for Liver Carcinogenesis.
Epidemiological studies have associated infection with Schistosoma japonicum and S. mansoni with increased risk of cancers of the liver and colon, although the mechanism of carcinogenesis remains unestablished. The livers of mice experimentally infected with S. japonicum or S. mansoni were analysed for expression of Fas (CD95/APO-1) and Fas ligand immunohistochemically and for apoptotic cell death by the TUNEL method. Fas expression was significantly decreased in hepatocytes around the inflammatory area of egg granulomas; this decrease was most prominent during the chronic phase of infection. Fas ligand was expressed in hepatocytes inside and outside granulomas, especially from mice at the early stage of infection, but not in hepatocytes from uninfected mice. Abnormal proliferation and Fas ligand expression were also observed in capillary bile ducts inside egg granulomas. Apoptotic cell death of inflammatory cells and, less frequently, of hepatocytes was found both inside and around granulomas. The rate of apoptotic cell death was high during the early stage of infection with S. mansoni, but decreased during the chronic phase of infection. Our results suggest that schistosome infection causes alterations of the Fas-Fas ligand system, one of the major apoptotic pathways, in mouse liver.


Blunt thoracic aortic injury: a single institution comparison of open and endovascular management.
To review the treatment of blunt thoracic aortic injuries (BAI) at a single institution over the past 12 years and compare pre-, peri-, and postoperative variables and outcomes of both open (OR) and thoracic endovascular (TEVAR) repair of these injuries. All cases of confirmed BAI from 1994 to present were included in this retrospective review. Data collected included demographic data, injury severity score, Glasgow coma score, arrival hemodynamic variables, and associated injuries. Operative data included: type of procedure (OR or TEVAR), duration of procedure, need for and amount of blood transfused, use of anticoagulation, type of anesthesia, and service performing the procedure. Outcomes evaluated were: death, paraplegia, length of stay, days ventilated, and procedure related complications. Specific to EVAR; access, stent graft type and number, presence of endoleak and long-term clinical and radiologic follow-up were evaluated. Thirty cases of blunt thoracic aortic injury were identified. Two patients received no treatment and died, 28 patients were treated (OR 16, TEVAR 12) and included for comparison. There were no significant differences between groups with respect to preoperative variables with the exception of significantly more associated intra-abdominal injuries in the TEVAR group (P = .03). Five patients in the OR group (31.2%) died in the perioperative period. There were no deaths in the TEVAR group (P =.05). One OR patient (6.25%) suffered postoperative paraplegia. No paraplegia occurred in the TEVAR group. Intraoperative variables were similar between groups with the exception of mean units of blood transfused (OR 8.5 units, vs TEVAR 0.2 units, P = .002). Ten patients in the OR group either died or had a procedure related complication compared with none in the TEVAR group (P = .001). There was no difference in length of stay or length of mechanical ventilation between the groups. There were no procedure or device related complications in the TEVAR group during follow-up (mean 15.3 months, range 1 to 53.5 months). Endovascular repair of BAI results in significantly less combined mortality and morbidity when compared to OR. Significantly less blood is needed intraoperatively in the TEVAR group. No complications from stent graft insertion have been observed during follow-up. Endovascular repair is replacing open repair as the treatment of choice for BAI at our institution.


Overexpression of the apple alcohol acyltransferase gene alters the profile of volatile blends in transgenic tobacco leaves.
Alcohol acyltransferases (AATs) are key enzymes in ester biosynthesis. Previous studies have found that AAT may be a stress-related gene. To investigate further the function of the apple alcohol acyltransferase gene (MdAAT2), transgenic tobacco plants overexpressing MdAAT2 were generated. Gas chromatography-mass spectroscopy analysis showed that the volatile blends were altered in these transgenic tobacco leaves. Although no apple-fruity volatile esters were detected in transgenic tobacco leaves, methyl caprylate, methyl caprate, and methyl dodecanoate were newly generated, and the concentrations of methyl benzoate and methyl tetradecanoate were significantly increased, suggesting that MdAAT2 may use medium-chain fatty acyl CoA and benzoyl-CoA as acyl donors together with methanol acceptors as substrates. Surprisingly, the concentrations of linalool were significantly increased in transgenic tobacco leaves, which may mediate the repellent effect on Myzus persicae (Sulzer) aphids. Using methyl jasmonate (MeJA) and wounding treatments, we found that MdAAT2 may substitute for the partial ability of MeJA to induce the production of linalool in transgenic plants. These data suggest that MdAAT2 may be involved in the response to the MeJA signal and may play a role in the response to biotic and abiotic stress.


Metamitron-resistant Chenopodium album from sugar beet: cross-resistance profile.
In recent years, in several of the Belgian sugar beet growing regions, farmers have been confronted with unsatisfactory control of fat hen (Chenopodium album L.). Greenhouse bioassays conducted on reference C. album populations and on "suspected" populations from sugar beet fields where poor fat hen control had been observed, revealed that all "suspected" populations were resistant to metamitron, a key herbicide in the modern low rate weed control programs in sugar beet. These metamitron-resistant biotypes were all cross-resistant to atrazine. Since cross-resistance, particularly negative cross-resistance or reversed resistance, is known to play a major role in resistance management, other herbicides used in sugar beet and/or in rotational crops were tested to determine the cross-resistance profile of metamitron-resistant biotypes. Greenhouse bioassays were conducted using herbicides from different chemical families representing different modes of action. Cross-resistance was found for metribuzin, lenacil and chloridazon, all HRAC Group C1 herbicides that inhibit photosynthesis at PS II. The metamitron-resistant C. album populations examined showed negative cross-resistance to S-metolachlor (HRAC Group K3: inhibition of cell division), prosuifocarb (Group N: lipid synthesis, not AC-Case, inhibition), aclonifen and clomazone (both Group F3: inhibition of carotenoid biosynthesis).


Postconcussional disorder and PTSD symptoms of military-related traumatic brain injury associated with compromised neurocircuitry.
Traumatic brain injury (TBI) is a common combat injury, often through explosive blast, and produces heterogeneous brain changes due to various mechanisms of injury. It is unclear whether the vulnerability of white matter differs between blast and impact injury, and the consequences of microstructural changes on neuropsychological function are poorly understood in military TBI patients. Diffusion tensor imaging (DTI) techniques were used to assess the neurocircuitry in 37 U.S. service members (29 mild, 7 moderate, 1 severe; 17 blast and 20 nonblast), who sustained a TBI while deployed, compared to 14 nondeployed, military controls. High-dimensional deformable registration of MRI diffusion tensor data was followed by fiber tracking and tract-specific analysis along with region-of-interest analysis. DTI results were examined in relation to post-concussion and post-traumatic stress disorder (PTSD) symptoms. The most prominent white matter microstructural injury for both blast and nonblast patients was in the frontal fibers within the fronto-striatal (corona radiata, internal capsule) and fronto-limbic circuits (fornix, cingulum), the fronto-parieto-occipital association fibers, in brainstem fibers, and in callosal fibers. Subcortical superior-inferiorly oriented tracts were more vulnerable to blast injury than nonblast injury, while direct impact force had more detrimental effects on anterior-posteriorly oriented tracts, which tended to cause heterogeneous left and right hemispheric asymmetries of white matter connectivity. The tractography using diffusion anisotropy deficits revealed the cortico-striatal-thalamic-cerebellar-cortical (CSTCC) networks, where increased post-concussion and PTSD symptoms were associated with low fractional anisotropy in the major nodes of compromised CSTCC neurocircuitry, and the consequences on cognitive function were explored as well.


Chronic actinic dermatitis/actinic reticuloid: a clinicopathologic and immunohistochemical analysis of 37 cases.
Chronic actinic dermatitis/actinic reticuloid (CAD/AR) is an eczematous hypersensitivity reaction to ultraviolet rays that can vary from mild eczematous cases to AR, the most severe cases which may resemble cutaneous T-cell lymphoma. Diagnosis is based on clinical, histopathologic, and photobiologic features. In this study, we characterize the histopathologic and immunohistochemical features of 40 biopsies from 37 patients with established CAD. The cohort included 30 men and 7 women, ranging in age from 38 to 84 years (median, 62 years) and with a median duration of symptoms at presentation of 3 years (range, 1 to 40 years). All patients presented with erythematous lichenified plaques on sun-exposed areas. Severe cases (12/37) had extension to non-exposed areas. Positive photo-testing (20/20) and patch-testing (10/10) results, and cases with a high peripheral blood eosinophila (7/24) and HIV positivity (4/37) were noted. Skin biopsies demonstrated eczematous features including parakeratosis, acanthosis, spongiosis, and prominent dermal fibroplasia. Dermal dendrocytes were prominent in all cases with frequent multinucleated giant cells positive for factor XIIIa and S100 protein. Most cases displayed a brisk lymphocytic infiltrate with subtle exocytosis, atypical lymphocytes, and increased numbers of Langerhans cells, eosinophils, and plasma cells. There was a predominance of CD8 T cells within the epidermis (20/25) and a low CD4:CD8 ratio was noted in 20 of 25 cases. T-cell clonality studies were negative in 10 of 10 cases. CAD/AR may be difficult to distinguish from eczematous variants of cutaneous T-cell lymphoma. Important clues to differentiate both conditions include the identification of prominent dermal dendrocytes with multinucleated giant cells, eosinophils, plasma cells, and a low CD4:CD8 ratio.


The CRF neurosecretory vesicle: vasopressin-dependent changes in vesicle size after adrenalectomy.
Neurosecretory vesicles of paraventricular corticotropin releasing factor (CRF) neurons increase in size after adrenalectomy (ADX) in parallel with an augmentation of their content in vasopressin (VP) immunoreactive sites. We have investigated in the Brattleboro rat model whether changes in vesicle size are related to elevated intravesicular concentrations of VP. Using quantitative immunoelectron microscopy, VP and CRF immunoreactive sites were assessed in the dense core vesicle compartment of CRF axon terminals in the median eminence. In heterozygous (control) rats, CRF was co-packaged with VP, and ADX induced a 3-fold increase in VP labeling intensity and produced a significant increase in the vesicle diameter. In homozygous rats lacking VP, only CRF immunoreactivity was detectable, and ADX was not accompanied by an increase in vesicle size. These observations suggest that the presence of VP is necessary for the ADX induced increase in vesicle size and that this increase might be needed to accommodate the excess of VP in the vesicle space.


Whole-exome sequencing: opportunities in pediatric endocrinology.
Pediatric endocrinology services see a wide variety of patients with diverse clinical symptoms, including disorders of growth, metabolism, bone and sexual development. Molecular diagnosis plays an important role in this branch of medicine. Traditional PCR-based Sanger sequencing is a mainstay format for molecular testing in pediatric cases despite its relatively high cost, but the large number of gene defects associated with the various endocrine disorders renders gene-by-gene testing increasingly unattractive. Using new high-throughput sequencing technologies, whole genomes, whole exomes or candidate-gene panels (targeted gene sequencing) can now be cost-effectively sequenced for endocrine patients. Based on our own recent experiences with exome sequencing in a research context, we describe the general clinical ascertainment of relevant pediatric endocrine patients, compare different formats for next-generation sequencing and provide examples. Our view is that protocols involving next-generation sequencing should now be considered as an appropriate component of routine clinical diagnosis for relevant patients.


[The clinical use of Amoxiclav in patients with suppurative meningoencephalitis].
Clinical use of Amoxiclav showed high therapeutic efficacy in patients with purulent meningoencephalitis both alone and in combination with cefalosporinum of the first generation. Against the background of treatment of patients with overt manifestations of meningoencephalitis and neurotoxicosis meningeal and encephalitic manifestations got attenuated during the first week, with liquorodynamics being stabilized, cerebrospinal fluid ameliorating by day 8-10 of the disease course. Bacteriologic assays showed that up to 83.4% of bacterial flora most common in Ukraine are sensitive to Amoxiclav, with such pathogenic organisms as Pneumococcus, Meningococcus, hemophilia bacillus that are actually main pathogens implicated in acute meningoencephalitis in Ukraine being sensitive to the above drug preparation in 100% of cases.


Continuous inferior mesenteric ganglion block for the control of abdominal pain.
A 71-year-old woman was referred for control of intractable left-sided abdominal pain and constipation caused by stage 2B rectosigmoid colon cancer. She was treated with an intravenous morphine sulfate infusion at 4 mg/h which made her drowsy and lethargic. Because the distal colon is innervated by the inferior mesenteric sympathetic ganglion, it was hypothesized that a continuous block of this ganglion would provide both pain control and increased intestinal motility. The patient was placed in a prone position, and a Tuohy needle was placed at an entry site 7 cm lateral to the L3 spinous process. The needle was advanced 2 cm anterior to the L3 vertebral body with fluoroscopic guidance. An 18-gauge indwelling catheter was placed through the needle and a continuous infusion with 0.1% bupivacaine was maintained for 4 days. The patient obtained immediate pain relief and bowel motility. She remained awake and comfortable throughout the duration of therapy. She was discharged home 3 days after stopping the infusion and required a minimal amount of opioids. Continuous inferior mesenteric ganglion block may be an option in providing relief for pain caused by distal colon pathology.


Impact of liver cirrhosis and portal hypertension on minimally invasive limited liver resection for primary liver malignancies in the posterosuperior segments: An international multicenter study.
To assess the impact of cirrhosis and portal hypertension (PHT) on technical difficulty and outcomes of minimally invasive liver resection (MILR) in the posterosuperior segments. This is a post-hoc analysis of patients with primary malignancy who underwent laparoscopic and robotic wedge resection and segmentectomy in the posterosuperior segments between 2004 and 2019 in 60 centers. Surrogates of difficulty (i.e, open conversion rate, operation time, blood loss, blood transfusion, and use of the Pringle maneuver) and outcomes were compared before and after propensity-score matching (PSM) and coarsened exact matching (CEM). Of the 1954 patients studied, 1290 (66%) had cirrhosis. Among the cirrhotic patients, 310 (24%) had PHT. After PSM, patients with cirrhosis had higher intraoperative blood transfusion (14% vs. 9.3%; p = 0.027) and overall morbidity rates (20% vs. 14.5%; p = 0.023) than those without cirrhosis. After coarsened exact matching (CEM), patients with cirrhosis tended to have higher intraoperative blood transfusion rate (12.1% vs. 6.7%; p = 0.059) and have higher overall morbidity rate (22.8% vs. 12.5%; p = 0.007) than those without cirrhosis. After PSM, Pringle maneuver was more frequently applied in cirrhotic patients with PHT (62.2% vs. 52.4%; p = 0.045) than those without PHT. MILR in the posterosuperior segments in cirrhotic patients is associated with higher intraoperative blood transfusion and postoperative morbidity. This parameter should be utilized in the difficulty assessment of MILR.


Dose reconstruction of a Brazilian industrial gamma radiography partial-body overexposure case.
In May 2000, an operator of a (60)Co industrial gamma radiography apparatus, during a routine service, was involved in a partial-body radiological accident, which caused serious injuries to his left hand. Dose reconstruction was started aiming to assess the radiation doses, in order to assist the medical staff in the evaluation and prescription of suitable medical procedures for the patient's treatment and follow-up. This work presents the dose reconstruction used for assessment of the distribution of doses on the patient's left hand, which was made using two methods: physical and computational techniques. For the first technique a physical hand simulator was built. The computational method was performed using microcomputer software for external dose calculations, named 'Visual Monte-Carlo-VMC', together with a hand voxel simulator. The values obtained through both methods for the distribution of absorbed doses on the operator's left hand were compared. About half of them were similar within a range of uncertainty of 20%.


The organic contamination survey and health risk assessment of 16 source water reservoirs in Haihe River basin.
Although contamination by organic pollutants has previously been reported to occur in the Haihe River basin, few studies have been carried out on the levels of source water reservoir contamination and the health risk in the Haihe River basin. To understand the organic pollution status of the reservoirs in the Haihe River basin, samples were collected from 16 source water reservoirs. The samples were analyzed for the representative organic pollutants, which included benzene homologues, chlorobenzene compounds, organophosphorus pesticides, and nitrobenzene compounds, a total in all of 17 compounds. It was observed that the concentrations of the 17 compounds in the 16 reservoirs were all less than the limit laid down by Chinese surface water quality standards. In addition, benzene, toluene, nitrobenzene, p-nitrochlorobenzene, 2,4-dinitrotoluene and 2,4-dinitrochlorobenzene, dichlorvos, demeton, dimethoate methyl parathion, malathion and parathion were frequently detected in the 16 source water reservoirs, especially the organophosphorus pesticides; the detection rates of dichlorvos, dimethoate, methyl parathion, malathion and parathion were all 100% in the 16 source water reservoirs. The detection rate of target compounds suggested that organic pollution had been common in the source water of the Haihe River basin. The health risk assessment results suggested that the noncarcinogenic risk hazard quotient values of the target compounds were less than one, and the cancer risk values were all below 1 × 10(-6), which indicated that the heath risk produced by the target compounds in the 16 reservoirs was at an acceptable level.


The ghost sex-life of the paedogenetic beetle Micromalthus debilis.
Genetic and sexual systems can be evolutionarily dynamic within and among clades. However, identifying the processes responsible for switches between, for instance, sexual and asexual reproduction, or cyclic and non-cyclic life histories remains challenging. When animals evolve parthenogenetic reproduction, information about the sexual mating system becomes lost. Here we report an extraordinary case where we have been able to resurrect sexual adults in a species of beetle that reproduces by parthenogenetic paedogenesis, without the production of adults. Via heat treatment, we were able to artificially induce adult beetles of Micromalthus debilis in order to describe its pre-paedogenetic mating system. Adults showed a highly female biased sex ratio, out-breeding behaviour, and sex-role reversal. Paedogenetic larvae of Micromalthus are infected with the endosymbiotic bacteria Rickettsia and Wolbachia. Clear signs of vestigialization in adults are concurrent with the loss of adults. Our data suggest an ancient female sex ratio bias that predates the loss of adults, perhaps associated with endosymbionts. We propose a model for the transition from a haplodiploid cyclical parthenogenetic life history to parthenogenetic paedogenesis. Paedogenetic development induces a new mechanism of sex ratio bias in midges, wasps and beetles.


The neurophysiological correlates of motor tics following focal striatal disinhibition.
The cortico-basal ganglia pathway is involved in normal motor control and implicated in multiple movement disorders. Brief repetitive muscle contractions known as motor tics are a common symptom in several basal ganglia related motor disorders. We used focal micro-injections of the GABA-A antagonist bicuculline to the sensorimotor putamen of behaving primates to induce stereotyped tics similar to those observed in human disorders. This focal disruption of GABA transmission in the putamen led to motor tics confined to a single or a few muscles. The temporal and structural properties of the tics were identified using electromyogram and frame-by-frame analysis of multi-camera video recordings. During experimental sessions the tics would wax and wane, but their size and shape remained highly stereotyped within the session. Neuronal spiking activity and local field potentials were recorded simultaneously from multiple locations along the cortico-basal ganglia pathway: motor cortex, putamen and globus pallidus external and internal segments. The local field potentials displayed stereotyped tic-related voltage transients lasting several hundred milliseconds. These 'local field potential spikes', which appeared throughout the cortico-basal ganglia pathway, were consistently observed in close temporal association to the motor tics. During tic expression, neuronal activity was altered in most of the recorded neurons in a temporally focal manner, displaying phasic firing rate modulations time locked to the tics. Consistent with theoretical models of tic generation, transient inhibition of the basal ganglia output nucleus prior to and during tic expression was observed. The phasic reduction of basal ganglia output was correlated with a disinhibition of cortical activity, manifesting as short bursts of activity in motor cortex. The results demonstrate that the basal ganglia provide a finely timed disinhibition in the output nuclei of the basal ganglia. However, a large fraction of the neurons were simultaneously inhibited during tics, although tics were only manifested in a small confined muscle group. This suggests that rather than representing a specific action within the basal ganglia itself, these nuclei provide a temporally exact but spatially distributed release signal. The tics induced by striatal disinhibition bear a striking resemblance to motor tics recognized in human pathologies associated with basal ganglia dysfunction. The neuronal changes observed during tic formation may provide valuable insights into the underlying mechanism of tic disorders, as well as into basic information processing in the cortico-basal ganglia loop.


Conditional Poisson Regression with Random Effects for the Analysis of Multi-site Time Series Studies.
The analysis of time series studies linking daily counts of a health indicator with environmental variables (e.g., mortality or hospital admissions with air pollution concentrations or temperature; or motor vehicle crashes with temperature) is usually conducted with Poisson regression models controlling for long-term and seasonal trends using temporal strata. When the study includes multiple zones, analysts usually apply a two-stage approach: first, each zone is analyzed separately, and the resulting zone-specific estimates are then combined using meta-analysis. This approach allows zone-specific control for trends. A one-stage approach uses spatio-temporal strata and could be seen as a particular case of the case-time series framework recently proposed. However, the number of strata can escalate very rapidly in a long time series with many zones. A computationally efficient alternative is to fit a conditional Poisson regression model, avoiding the estimation of the nuisance strata. To allow for zone-specific effects, we propose a conditional Poisson regression model with a random slope, although available frequentist software does not implement this model. Here, we implement our approach in the Bayesian paradigm, which also facilitates the inclusion of spatial patterns in the effect of interest. We also provide a possible extension to deal with overdispersed data. We first introduce the equations of the framework and then illustrate their application to data from a previously published study on the effects of temperature on the risk of motor vehicle crashes. We provide R code and a semi-synthetic dataset to reproduce all analyses presented.


Self-limiting corneal edema with multiple parallel lines on the endothelium (SCEMPLE).
The purpose of this study was to report the natural course and in vivo confocal microscopy (IVCM) findings of five cases with unilateral self-limiting corneal edema and multiple parallel lines on the endothelium (SCEMPLE). This study is an observational case series. Five patients, who experienced a blurred vision due to SCEMPLE, were studied using slit-lamp examination and white-light IVCM (Confoscan 4; Nidek Technologies, Padova, Italy). IVCM of the linear deposits revealed characteristic hyperreflective material protruding between the endothelial cells. The lines also displayed spot-like holes and polygonal precipitates, which resembled dislodged endothelial cells. Because other signs of corneal inflammation, such as stromal infiltration and ciliary injection, were lacking, the condition was left untreated. After 1 day, slit-lamp examination and IVCM revealed only a small residual of the lines. Spontaneous, complete resolution occurred in all five cases within 1 week, leaving a lower endothelial cell density of the affected eyes as only sequela. SCEMPLE requires no treatment but may result in endothelial cell loss. The self-limiting character and IVCM appearance dispute SCEMPLE being a form of endotheliitis and suggest a different etiology.


The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling.
Alternative splicing of pre-mRNAs is an important means of regulating developmental processes, yet the molecular mechanisms governing alternative splicing in embryonic contexts are just beginning to emerge. Polyglutamine-binding protein 1 (PQBP1) is an RNA-splicing factor that, when mutated, in humans causes Renpenning syndrome, an X-linked intellectual disability disease characterized by severe cognitive impairment, but also by physical defects that suggest PQBP1 has broader functions in embryonic development. Here, we reveal essential roles for PQBP1 and a binding partner, WBP11, in early development of Xenopus embryos. Both genes are expressed in the nascent mesoderm and neurectoderm, and morpholino knockdown of either causes defects in differentiation and morphogenesis of the mesoderm and neural plate. At the molecular level, knockdown of PQBP1 in Xenopus animal cap explants inhibits target gene induction by FGF but not by BMP, Nodal or Wnt ligands, and knockdown of either PQBP1 or WBP11 in embryos inhibits expression of fgf4 and FGF4-responsive cdx4 genes. Furthermore, PQBP1 knockdown changes the alternative splicing of FGF receptor-2 (FGFR2) transcripts, altering the incorporation of cassette exons that generate receptor variants (FGFR2 IIIb or IIIc) with different ligand specificities. Our findings may inform studies into the mechanisms underlying Renpenning syndrome.


The Management of Peri-implant Breakdown Around Functioning Osseointegrated Dental Implants.
Peri-implant tissue breakdown can be the result of microbial action as well as of biomechanical and occlusal overload. The long-term goal of the treatment of peri-implant breakdown is to arrest the progression of the disease and to achieve a maintainable site for the patient. Peri-implant bony defects around functioning implants can be treated with either non-surgical or surgical (resective or regenerative) techniques. Bone regeneration is possible in selected peri-implant bony defects of functioning implants if appropriate surgical techniques are utilized and the etiologic cause is eradicated. J Periodontol 1993; 64:1176-1183.


MELANOPHORE BANDS AND AREAS DUE TO NERVE CUTTING, IN RELATION TO THE PROTRACTED ACTIVITY OF NERVES.
1. When appropriate chromatic nerves are cut caudal bands, cephalic areas, and the pelvic fins of the catfish Ameiurus darken. In pale fishes all these areas will sooner or later blanch. By recutting their nerves all such blanched areas will darken again. 2. These observations show that the darkening of caudal bands, areas, and fins on cutting their nerves is not due to paralysis (Brücke), to the obstruction of central influences such as inhibition (Zoond and Eyre), nor to vasomotor disturbances (Hogben), but to activities emanating from the cut itself. 3. The chief agents concerned with the color changes in Ameiurus are three: intermedin from the pituitary gland, acetylcholine from the dispersing nerves (cholinergic fibers), and adrenalin from the concentrating nerves (adrenergic fibers). The first two darken the fish; the third blanches it. In darkening the dispersing nerves appear to initiate the process and to be followed and substantially supplemented by intermedin. 4. Caudal bands blanch by lateral invasion, cephalic areas by lateral invasion and internal disintegration, and pelvic fins by a uniform process of general loss of tint equivalent to internal disintegration. 5. Adrenalin may be carried in such an oil as olive oil and may therefore act as a lipohumor; it is soluble in water and hence may act as a hydrohumor. In lateral invasion (caudal bands, cephalic areas) it probably acts as a lipohumor and in internal disintegration (cephalic areas, pelvic fins) it probably plays the part of a hydrohumor. 6. The duration of the activity of dispersing nerves after they had been cut was tested by means of the oscillograph, by anesthetizing blocks, and by cold-blocks. The nerves of Ameiurus proved to be unsatisfactory for oscillograph tests. An anesthetizing block, magnesium sulfate, is only partly satisfactory. A cold-block, 0 degrees C., is successful to a limited degree. 7. By means of a cold-block it can be shown that dispersing autonomic nerve fibers in Ameiurus can continue in activity for at least 6(1/2) hours. It is not known how much longer they may remain active. So far as the duration of their activity is concerned dispersing nerve fibers in this fish are unlike other types of nerve fibers usually studied.


Shock-lithification of unconsolidated rock materials.
Loose quartz grains packed around chemical explosives are forced during cratering explosions into compacted, coherent masses resembling sand stone blocks found at certain meteorite craters. Sandstone-like lumps found at the Wabar (Arabia) meteorite craters are similar to these shock-lithified sands. Shock-lithification by impact may be effected on Moon as large meteorites strike surfaces covered with rubble from earlier collisions.


Reactive metabolites as a cause of hepatotoxicity.
Many compounds, including established drugs, cause liver damage through biotransformation to reactive cytotoxic metabolites which bind covalently to hepatic macromolecules. The forms of expression of such injury include acute necrosis, chronic hepatitis, cirrhosis and neoplasia. Hepatotoxicity depends on the balance between metabolic activation and inactivation and reduced glutathione protects against the toxicity of some agents by trapping their reactive electrophilic metabolites. Toxicity is usually increased by induction and decreased by inhibition of hepatic microsomal enzymes.


The Role of RUNX2 in Osteosarcoma Oncogenesis.
Osteosarcoma is an aggressive but ill-understood cancer of bone that predominantly affects adolescents. Its rarity and biological heterogeneity have limited studies of its molecular basis. In recent years, an important role has emerged for the RUNX2 "platform protein" in osteosarcoma oncogenesis. RUNX proteins are DNA-binding transcription factors that regulate the expression of multiple genes involved in cellular differentiation and cell-cycle progression. RUNX2 is genetically essential for developing bone and osteoblast maturation. Studies of osteosarcoma tumours have revealed that the RUNX2 DNA copy number together with RNA and protein levels are highly elevated in osteosarcoma tumors. The protein is also important for metastatic bone disease of prostate and breast cancers, while RUNX2 may have both tumor suppressive and oncogenic roles in bone morphogenesis. This paper provides a synopsis of the current understanding of the functions of RUNX2 and its potential role in osteosarcoma and suggests directions for future study.