Interventions for idiopathic toe walking.
Idiopathic toe walking (ITW) is an exclusionary diagnosis given to healthy children who persist in walking on their toes after they should typically have achieved a heel-toe gait. The literature discusses conservative and surgical interventions using a variety of treatment modalities. Young children and children without a limitation in ankle dorsiflexion (the upwards movement of the foot towards the shin of the leg) are commonly treated with conservative interventions. Older children who continue toe walking and present with limitations in ankle dorsiflexion are sometimes treated with surgical procedures. This systematic review is needed to evaluate the evidence for any intervention for the treatment of ITW. The conclusions of this review may support decision making by clinicians caring for children with ITW. It may also assist families when deciding on treatment options for their children with ITW. Many of the treatments employed have financial implications for parents or healthcare services. This review also aims to highlight any deficits in the current research base. To assess the effects of conservative and surgical interventions in children with ITW, specifically effects on gait normalisation, ankle range of motion, pain, frequency of recurrence, and any adverse effects. On 29 April 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL Plus, and PEDro. We searched the following registers of clinical trials for ongoing and recently completed trials: the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP, apps.who.int/trialsearch), and ClinicalTrials.gov (clinicaltrials.gov). We searched conference proceedings and other grey literature in the BIOSIS databases and System for Information on Grey Literature in Europe (OpenGrey, opengrey.eu). We searched guidelines via the Turning Research Into Practice database (TRIP, tripdatabase.com) and National Guideline Clearinghouse (guideline.gov). We did not apply language restrictions. We considered randomised or quasi-randomised trials for inclusion in the review if they involved participants diagnosed with ITW gait in the absence of a medical condition known to cause toe walking, or associated with toe walking. As there is no universally accepted age group for ITW, this review includes ITW at any age, who have been toe walking for more than six months, who can or cannot walk with a heel-toe gait, and who may or may not have limited dorsiflexion of the ankle joint. We used standard Cochrane methodological procedures. The primary outcome was improvement in toe walking (defined as greater than 50% of time spent heel-toe walking). Secondary outcomes were active and passive range of motion of the ankle joint, pain, recurrence of ITW after treatment, and adverse events. We assessed the certainty of the evidence using the GRADE framework. Four studies, comprising 104 participants, met the inclusion criteria. One study did not report data within the appropriate follow-up timeframe and data from two studies were insufficient for analysis. The single study from which we extracted data had 47 participants and was a randomised, controlled, parallel-group trial conducted in Sweden. It tested the hypothesis that combined treatment with serial casting and botulinum toxin type A (BTX) was more effective than serial casting alone in reducing ITW gait.This study found that more participants treated with BTX improved (defined as toe walking less than 50% of the time, as reported by parents) (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.57 to 2.55; 1 trial, 46 participants; very low-certainty evidence). However, there was little or no difference between groups in passive ankle joint dorsiflexion range of movement on the right with the knee extended (mean difference (MD) -1.48º, 95% CI -4.13 to 1.16; 1 trial, 47 participants), on the right with the knee flexed (MD -0.04º, 95% CI -1.80 to 1.73; 1 trial, 46 participants), on the left with the knee flexed (MD 1.07, 95% CI -1.22 to 3.37), or on the left with the knee extended (MD 0.05, 95% CI -0.91 to 1.91). Nor was there a clear difference between the groups in recurrence of toe-walking gait (assessed via severity of toe walking (graded 1 (mild), 2 (moderate), or 3 (severe)) on gait analysis, analysed as continuous data: MD 0.34 points, 95% CI -0.09 to 0.78; 46 participants). In principle, MDs greater than zero (i.e.) positive values) would favour BTX and casting and negative values would favour casting alone. We have not reported effects as better or worse because all results were from evidence of very low certainty. We downgraded the certainty of evidence because of study limitations (outcome assessment was not blinded) and imprecision. Outcomes of pain and active range of motion were not reported in the included study.In terms of adverse events, calf pain was reported twice in the casting-only group and three times in the BTX group. There were three minor skin problems in each group and one reported case of pain directly after BTX injection. The report did not state if calf pain and skin irritation were from the same or different participants. The study authors reported that adverse events did not alter treatment adherence. The certainty of evidence from one study, which compared serial casting with serial casting with BTX for ITW in children, was too low for conclusions to be drawn. A further three studies reported outcomes relating to BTX, footwear, exercises, and different types of orthoses as interventions, however the outcome data were too limited to assess their effects.


Protein kinase B: emerging mechanisms of isoform-specific regulation of cellular signaling in cancer.
The serine/threonine protein kinase B (PKB), also known as Akt, is one of the multifaceted kinases in the human kinome, existing in three isoforms. PKB plays a vital role in phosphoinositide 3-kinase (PI3K)-mediated oncogenesis in various malignancies and is one of the attractive targets for cancer drug discovery. Recent studies have shown that the functional significance of an individual isoform of PKB is not redundant in cancer. It has been found that PKB isoforms play distinct roles in the regulation of cellular invasion and migration during tumorigenesis. PKB activation plays a central role during epithelial-mesenchymal transition, a cellular program required for the cancer cell invasion and migration. However, the differential behavior of each PKB isoform has been shown in the regulation of epithelial-mesenchymal transition. Recent studies have suggested that PKBα (Akt1) plays a conflicting role in tumorigenesis by acting either as a pro-oncogenic factor by suppressing the apoptotic machinery or by restricting tumor invasion. PKBβ (Akt2) promotes cell migration and invasion and similarly PKBγ (Akt3) has been reported to promote tumor migration. As PKB is known for its pro-oncogenic properties, it needs to be unraveled how three isoforms of PKB compensate during tumor progression. In this review, we attempted to sum up how different isoforms of PKB play a role in cancer progression, metastasis, and drug resistance.


A social path to functioning in schizophrenia: From social self-efficacy through negative symptoms to social functional capacity.
Self-efficacy is important to functioning in schizophrenia. The exact pathway is less clear, possibly because most studies used composite rather than domain-specific self-efficacy scores. We examined if a specific measure of social self-efficacy is more important to a social (from negative symptoms to social functional capacity) compared to a non-social (from neurocognition to non-social functional capacity) path to functioning. Associations between social self-efficacy and negative symptoms, neurocognition and social and non-social functional capacity were examined in a cross-sectional study of schizophrenia (n=51). Two models were investigated using bootstrapping methods to test for mediation. In Model I, social self-efficacy was entered as a mediator; in Model II as a predictor. Social self-efficacy was unrelated to neurocognition and non-social functional capacity. Associations with negative symptoms and social functional capacity were significant. Negative symptoms were found to mediate between social self-efficacy and social functional capacity. Support was found for a social path to functioning in schizophrenia, going from social self-efficacy through negative symptoms to social functional capacity. Our results are consistent with the idea that negative symptoms can develop as a reaction to self-defeatist beliefs. Future studies should use domain-specific self-efficacy to further understand predictors of functioning in schizophrenia.


Congenital atresia of the ear.
Congenital atresia of the ear requires prompt diagnosis and an early assessment of hearing. In bilateral atresia, aural rehabilitation should be started early in life to avoid late sequelae of speech problems. In unilateral atresia, the need is not urgent if the child hears normally in the other ear. Polytomography and audiometric testing are the two most important parts of the patient's evaluation. Precise audiometric testing may be difficult, or even impossible, in these children. The indications for surgery are presented. The risk of injuring an abnormally placed facial nerve remains a deterrent to many otologic surgeons who would otherwise operate on atresia. Surgery for correction of atresia was performed on 20 ears in 18 patients. A method of fascia graft overlay in conjunction with a center-hole skin graft was used. In 14 or 17 ears where an attempt was made at hearing rehabilitation the average preoperative air conduction threshold was 59 db and the average postoperative air conduction threshold was 24 db. Two unique cases are discussed in detail. One is a primary cholesteatoma in association with atresia, and the other is a finding of primitive and embryonic subepithelial tissue in the mastoid air cell system.


Temperature-dependence of mitochondrial function and production of reactive oxygen species in the intertidal mud clam Mya arenaria.
Mitochondrial respiration, energetic coupling to phosphorylation and the production of reactive oxygen species (ROS) were studied in mitochondria isolated from the eurythermal bivalve Mya arenaria (Myoidea) from a low-shore intertidal population of the German Wadden Sea. Measurements were conducted both within the range of the habitat temperatures (5-15 degrees C) and when subjected to heat exposure at 20 degrees C and 25 degrees C. Experimental warming resulted in an increase in the rate of state 3 and state 4 respiration in isolated mitochondria. The highest respiratory coupling ratios (RCR) were found at 15 degrees C; at higher temperatures mitochondrial coupling decreased, and release of ROS doubled between 15 and 25 degrees C. ROS production was 2-3% of total oxygen consumption in state 3 (0.3-0.5 nmol ROS mg(-1) protein min(-1)) at the habitat temperature, reaching a maximum of 4.3 % of state 3 respiration and 7 % of oligomycin-induced state 4+ respiration under heat stress. Thus, state 4 respiration, previously interpreted exclusively as a measure of proton leakage, included a significant contribution from ROS formation in this animal, especially under conditions of heat stress. Oxygen radical formation was directly dependent on temperature-controlled respiration rates in states 3 and 4 and inversely related to mitochondrial coupling (RCR+) in state 4. Mitochondrial ROS formation is therefore involved in cellular heat stress in this eurythermal marine ectotherm.


Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel.
New information warrants updated recommendations for the 4 central issues in antiretroviral therapy: when to start, what drugs to start with, when to change, and what to change to. These updated recommendations are intended to guide practicing physicians actively involved in human immunodeficiency virus (HIV)- and acquired immunodeficiency syndrome (AIDS)-related care. In 1995, physicians with specific expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care were invited by the International AIDS Society-USA to serve on a volunteer panel. In 1999, others were invited to broaden international representation. The 17-member panel met regularly in closed meetings between its last report in 2000 and April 2002 to review current data. The effort was sponsored and funded by the International AIDS Society-USA, a not-for-profit physician education organization. The full panel was convened in late 2000 and assigned 7 section committees. A section writer and 3 to 5 section committee members (each panel member served on numerous sections) identified relevant evidence and prepared draft recommendations. Basic science, clinical research, and epidemiologic data from the published literature and abstracts from recent (within 2 years) scientific conferences were considered by strength of evidence. Extrapolations from basic science data and expert opinion of the panel members were included as evidence. Draft sections were combined and circulated to the entire panel and discussed in a series of full-panel conference calls until consensus was reached. Final recommendations represent full consensus agreement of the panel. Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease. However, the optimal time to initiate therapy remains imprecisely defined. Availability of new drugs has broadened options for therapy initiation and management of treatment failure, which remains a difficult challenge.


Therapy of Canine Hyperlipidemia with Bezafibrate.
Bezafibrate (BZF) is effective in the treatment of hypertriglyceridemia in human patients, but there are no data on its use in dogs. To assess the safety of BZF in hyperlipidemic dogs and its efficacy in decreasing serum triglyceride (TG) and cholesterol (CHO) concentrations. Forty-six dogs, 26 females and 20 males, mean (±SD) age of 9 (±3) years, with TG ≥150 mg/dL (33 dogs also were hypercholesterolemic [>300 mg/dL]). Prospective, uncontrolled clinical trial. Dogs were treated with bezafibrate once daily, using 200 mg tablets at a dosage of 4-10 mg/kg (depending on body weight). Serum TG and CHO concentrations and alanine aminotransferase (ALT) and creatine kinase (CK) activity before and after 30 days of treatment were compared. Sixteen dogs (34.8%) had primary hyperlipidemia, and 30 dogs (65.2%) had secondary hyperlipidemia (including spontaneous hyperadrenocorticism [41.3%, n = 19/46], chronic treatment with glucocorticoids [10.8%, n = 5/46], and hypothyroidism [15.2%, n = 7/46]). After 30 days, serum TG concentration normalized (<150 mg/dL) in 42 dogs (91.3%) and CHO concentration normalized (<270 mg/dL) in 22 of 33 dogs (66.7%). There was no difference in baseline TG concentration between the primary and secondary hyperlipidemia subgroups, but the decrease in TG concentration after treatment was greater in the primary hyperlipidemia subgroup. No adverse effects were observed, but ALT activity decreased significantly after 30 days of treatment. Over 30 days, BZF was safe and effective in treatment of primary and secondary hyperlipidemia in dogs.


[Construction and identification of primary open angle glaucoma disease MYOC Pro356Leu mutant plasmid in mouse].
To construct and identify the plasmid of mutant MYOC Pro356Leu in mouse. 1.Transfering Red recombinantinase- expressing plasmid pKD46 was transferred to RP23-180F15 BAC clone by electroporation.2.Amplifying tThe pStart-K vector was amplified by PCR and electroporating the PCR product was electroporated into the bacteria containing the mMYOC. 3.PCR amplification of the mMyoc AfeI fragment and Subcloningand then subcloned it into pBluescript vector.4.Designing two oligonucleotides was designed and introducingthe Pro356Leu (C to T at codon 356) was introduced into the pBS_mMyoc AfeI clone. 5. the Introducing pBS_mMyoc AfeI mut clone was introduced to pStart-K_mMyoc by digestion and ligation reaction. Identifying correct the final clones were identified by restriction enzyme digestion and sequenceing. pStart-K_mMyoc mut clone,the mouse MYOC Pro356Leu mutant plasmid was constructed and identified well by restriction enzyme digest and sequenceing. It is a good method to construct a long DNA fragment clone by red recombinase and pStart-K vector. The constructed Mouse MYOC Pro356Leu plasmidwill be very helpful for the studies on the function and biologic effects of MYOC gene in primary open angle glaucoma.


Improving Mood with Physical ACTivity (IMPACT) trial: a cluster randomised controlled trial to determine the effectiveness of a brief physical activity behaviour change intervention on depressive symptoms in young people, compared with psychoeducation, in addition to routine clinical care within youth mental health services-a protocol study.
Depression is highly prevalent and the leading contributor to the burden of disease in young people worldwide, making it an ongoing priority for early intervention. As the current evidence-based interventions of medication and psychological therapy are only modestly effective, there is an urgent need for additional treatment strategies. This paper describes the rationale of the Improving Mood with Physical ACTivity (IMPACT) trial. The primary aim of the IMPACT trial is to determine the effectiveness of a physical activity intervention compared with psychoeducation, in addition to routine clinical care, on depressive symptoms in young people. Additional aims are to evaluate the intervention effects on anxiety and functional outcomes and examine whether changes in physical activity mediate improvements in depressive symptoms. The study is being conducted in six youth mental health services across Australia and is using a parallel-group, two-arm, cluster randomised controlled trial design, with randomisation occurring at the clinician level. Participants aged between 12 years and 25 years with moderate to severe levels of depression are randomised to receive, in addition to routine clinical care, either: (1) a physical activity behaviour change intervention or (2) psychoeducation about physical activity. The primary outcome will be change in the Quick Inventory of Depressive Symptomatology, with assessments occurring at baseline, postintervention (end-point) and 6-month follow-up from end-point. Secondary outcome measures will address additional clinical outcomes, functioning and quality of life. IMPACT is to be conducted between May 2014 and December 2019. Ethical approval was obtained from the University of Melbourne Human Research Ethics Committee on 8 June 2014 (HREC 1442228). Trial findings will be published in peer-reviewed journals and presented at conferences. Key messages will also be disseminated by the youth mental health services organisation (headspace National Youth Mental Health Foundation). ACTRN12614000772640.


STAT2 is a primary target for measles virus V protein-mediated alpha/beta interferon signaling inhibition.
Measles virus, a member of the Morbillivirus family, infects millions of people each year despite the availability of effective vaccines. The V protein of measles virus is an important virulence factor that can interfere with host innate immunity by inactivating alpha/beta interferon (IFN-alpha/beta) and IFN-gamma signaling through protein interactions with signal transducer and activator of transcription proteins STAT1 and STAT2. Here we demonstrate that although STAT1 interference results from protein interactions within a V protein N-terminal region encompassed by amino acids 110 to 130, detection of STAT1 interaction and IFN-gamma signaling inhibition requires the presence of cellular STAT2. Cell-specific variability in STAT1 interference was observed to correlate with V protein expression level. A more direct target for measles virus V protein-mediated IFN-alpha/beta evasion is STAT2. Results indicate that the widely conserved C-terminal zinc finger domain of measles virus V protein is both necessary and sufficient to bind STAT2 and disrupt IFN-alpha/beta signal transduction. Mutagenesis and molecular modeling define a contact surface for STAT2 association that includes aspartic acid residue 248 as critical for STAT2 interference and IFN antiviral immune suppression. These findings clearly define the molecular determinants for measles virus IFN evasion and validate specific targets as candidates for therapeutic intervention.


Cannabinoid as Beneficial Replacement Therapy for Psychotropics to Treat Neuropsychiatric Symptoms in Severe Alzheimer's Dementia: A Clinical Case Report.
Alzheimer's Dementia (AD) is a devastating neurodegenerative disease that affects approximately 17% of people aged 75-84. Neuropsychiatric symptoms (NPS) such as delusions, agitation, anxiety, and hallucinations are present in up to 95% of patients in all stages of dementia. To date, any approved and effective pharmacological interventions for the treatment of NPS are still not available. We describe a clinical case of a female patient diagnosed with AD with continuous cognitive decline and dementia-related behavioral symptoms. Between 2008 and 2019, the patient was examined half-yearly at the memory clinic of the Medical University of Innsbruck. At each visit, cognitive state and pharmacological treatment were evaluated. In addition, NPs were assessed by using the neuropsychiatric inventory (NPI). In 2018, the patient progressed to severe AD stage and presented with progressive NPs (anxiety, suspected delusions, agitation, aggressive behavior, and suspected pain due to long immobility). Consequently, off-label treatment with low-dose dronabinol was initiated, which facilitated a reduction of psychopharmacological treatment from six to three psychotropics. At the same time, the patient's emotional state improved, while disruptive behavior, aggression, and sedation decreased significantly. This case report underpins the need for randomized, controlled trials to explore the effect of cannabinoid receptor agonists on behavioral and psychological symptoms in patients with severe AD.


Comparison between ST-cut quartz 25 degrees and -60 degrees NSPUDT propagation directions.
This paper discusses directivity and other propagation properties of natural single phase unidirectional transducer (NSPUDT) propagation directions on ST-cut quartz. The work focuses on the comparison of surface acoustic wave (SAW) directivity and propagation properties between the ST-cut quartz -60 degrees, Euler angles: (0 degrees, 132.75 degrees, -60 degrees), and the ST-cut quartz 25 degrees, Euler angles: (0 degrees, 132.75 degrees, 25 degrees), NSPUDT propagation directions, including predicted and measured directivity responses for both propagation directions. The well-known SAW 25 degrees propagation direction is used for low loss, high performance SAW filter designs for consumer products and communications applications. The ST-cut quartz -60 degrees propagation direction has been predicted to have a reflection coefficient 2.5 times larger than ST-cut quartz 25 degrees. In addition the ST-cut quartz -60 degrees satisfied the NSPUDT 90 degrees reflection coefficient phase condition much more closely, resulting in an improved directivity response. For the delay line structures used in the experiments, the measured directivity is 10.1 dB for the -60 degrees propagation direction. For the same structures, the measured directivity along the 25 degrees propagation direction is about 5.0 dB. The experimental results given in this paper verify that indeed ST-cut quartz -60 degrees has a higher directivity than ST-cut quartz 25 degrees, confirming the theoretical predictions. In addition, this work compares other propagation properties for both directions, namely, phase velocities, electromechanical couplings, temperature coefficients of delay, power flow angles, and metallic strip reflection coefficient amplitudes and phases.


Experimental blowgun injuries, ballistic aspects of modern blowguns.
Slender thin arrows blown through modern blowguns can cause serious injuries. In this paper we present some data regarding the terminal ballistics of such an arrow when blown by a young male who had no previous experience with the weapon. The penetration depth into wood was similar to that of an arrow fired from a pistol-crossbow. Further, the blowgun arrow could pass through more than 7 mm of porcine bone. The velocities at a distance of 2 m from the blowgun of three different types of arrows having weights of 1-1.6 g and diameters between 1 and 5 mm were between 22 and 32 m/s, giving an energy of 0.3 to 0.6 J. When blown from a blowgun, these slender modern arrows can thus penetrate human skin and even the cranial bone of a child and cause serious injury.


Asenapine for the Control of Physical Aggression: A Prospective Naturalist Pilot Study.
It has been previously purported that higher relative affinity to the dopamine D4 receptor compared to D2 (i.e., D4/D2 affinity ratio > 1) may underlie unique antiaggression potency. Asenapine is a newer antipsychotic that also has D4/D2 affinity ratio > 1. It has demonstrated efficacy in reducing acute agitation in a placebo-controlled study. We performed a prospective naturalistic, pilot, proof of concept study on an inpatient psychiatric unit. Among patients with aggression at time of admission (≥ 12 on Refined Aggression Questionnaire [RAQ], or ≥ 2 on Modified Overt Aggression Scale [MOAS]), asenapine treatment was associated with a significant reduction in total aggression as measured by the MOAS (-14.7 ± 11.59 vs. -5.4 ± 10.12, P = 0.045), and particularly physical aggression (-8.0 ± 5.06 vs. -0.78 ± 2.40, P < 0.0001) compared to treatment that did not include asenapine. These data suggest that asenapine may be useful in the targeted treatment of aggression, and provide some support for the D4/D2 affinity ratio hypothesis.


The role of prophylactic brain irradiation in small cell lung cancer treatment.
To review the effectiveness and safety of prophylactic cranial irradiation (PCI) in patients with small-cell lung cancer (SCLC). Brain metastases are frequent in SCLC with a cumulative incidence of 25% among 1,202 in 17 trials, and a 3-5 months median survival from first occurrence. The 5-year cumulative rate of brain metastases as isolated first site of relapse was 37% among 260 patients without PCI compared to 20% among 245 with PCI in two randomised trials (p < 0.001). A meta-analysis on seven randomised trials of PCI versus no PCI including 987 patients in complete remission without brain metastases or prior brain irradiation showed statistically significant effect in favour of PCI on survival, disease free survival, and risk of brain metastases (relative risks being 0.84, 0.75, and 0.46, and p-values being 0.01, < 0.001, and < 0.001, respectively). Two randomised trials evaluated neurotoxicity in totally 350 patients before PCI and found abnormalities in 24-60%. Repeated examination during the following years revealed no differences on cerebral CT-scans or neuropsychological testing between PCI patients or controls. A review including 42 PCI trials with 4,749 patients revealed the optimal total radiotherapy dose to be 30-35 Gy given as 2 Gy fractions. Also 24 Gy in 3 Gy fractions appear safe based on data from a large randomised study. Both the former study and the meta-analysis suggested early PCI to be better than late. PCI improves both overall and disease free survival and decreases the risk for brain relapse in SCLC patients in complete remission. PCI should be applied early, and useful and safe doses may be 30-36 GY in 2-3 Gy fractions, though future studies may further illuminate the optimal dose, fractionation and timing.


Cellular components and signals required for the cardiac outflow tract assembly in Drosophila.
Specification of cardiac primordia and formation of the Drosophila heart tube is highly reminiscent of the early steps of vertebrate heart development. We previously reported that the final morphogenesis of the Drosophila heart involves a group of nonmesodermal cells called heart-anchoring cells and a pair of derived from the pharyngeal mesoderm cardiac outflow muscles. Like the vertebrate cardiac neural crest cells, heart-anchoring cells migrate, interact with the tip of the heart, and participate in shaping the cardiac outflow tract. To better understand this process, we performed an in-depth analysis of how the Drosophila outflow tract is formed. We found that the most anterior cardioblasts that form a central outflow tract component, the funnel-shaped heart tip, do not originate from the cardiac primordium. They are initially associated with the pharyngeal cardiac outflow muscles and join the anterior aorta during outflow tract assembly. The particular morphology of the heart tip is disrupted in embryos in which heart-anchoring cells were ablated, revealing their critical role in outflow tract morphogenesis. We also demonstrate that Slit and Robo are required for directed movements of heart-anchoring cells toward the heart tip and that the cell-cell contact between the heart-anchoring cells and the ladybird-expressing cardioblasts is critically dependent on DE-cadherin Shotgun. Our observations suggest that the similarities between Drosophila and vertebrate cardiogenesis extend beyond the early developmental events.


[Factors associated with the use of clinical guidelines by health plan operators and their inpatient care providers].
This paper is aimed at identifying factors related to the use of clinical guidelines by health plan operators and their inpatient care providers in the supplementary care sector in Brazil from the viewpoint of managers. The study is based on two national surveys: one involving 90 health plan operators randomly selected from a universe of 1573, oriented towards characterizing the implementation of clinical guidelines and other tools of clinical governance; and another involving 74 hospitals, selected from a universe of 3817 inpatient care providers, aimed at capturing micro-regulation mechanisms applied by health plan operators and their repercussions on hospital practices. Use of clinical guidelines was reported by 32.3% of the health plan operators, and 51.6% of the hospitals interviewed. Among the first, geographical location, type and size of the organization were independently associated with use of clinical guidelines while among the hospitals size, complexity and use of other tools of clinical governance were independently associated with the dependent variable. The results show how incipient and unsatisfactory the intervention of the health plan and hospital managements still is with regard to the quality of health services offered to the beneficiaries.


Alcohol dehydrogenase: an autoantibody target in patients with alcoholic liver disease.
The link between alcohol consumption and liver disease is not direct and several factors including autoimmunity to hepatocyte components have been implicated. We have previously identified alcohol dehydrogenase (ADH) as an autoantigen in autoimmune liver disease and in a proportion of patients with alcoholic liver disease. The aim of the present study is to investigate the association between the presence of anti-ADH antibodies, alcohol consumption and severity of liver damage in alcoholic patients. The presence of antibodies to human ADH beta2 and horse ADH was investigated in 108 patients with documented history of alcohol consumption and alcohol related liver disease, 86 being active alcohol abusers and 22 on sustained alcohol withdrawal, 39 with non-alcohol related disease and 22 normal subjects. Antibodies to either ADH form were more frequently detected in active alcohol abusers (55/86, 64%) than in patients on sustained alcohol withdrawal longer than 6 months (1/8, 13 %, P < 0.005), HBV infection (2/8, 25 %, P=0.03), non-alcohol related disease (9/29, 23 %, P < 0.0001) and in normal controls (3/22, 14 %, P < 0.0001); were more frequent in patients with cirrhosis than in those with steatosis (26/34, 76 % vs 34/64, 53 %, P=0.02); and were associated with elevated levels of ALT (anti-ADH beta2, P < 0.05), immunoglobulin A (P < 0.05) and gamma-glutamyl transpeptidase (P=0.01). Anti-ADH antibody positive serum samples were able to inhibit the enzymatic activity of ADH. These findings suggest that anti-ADH antibodies may be triggered by alcohol consumption and act as a disease activity marker in alcoholic liver disease.


The treatment of locally advanced pancreatic cancer: a practice guideline.
Pancreatic adenocarcinoma is the fourth most common cause of adult cancer death. About 50% of patients present with metastatic disease, 20% with resectable disease and the remaining 30% of patients are diagnosed with incurable, locally advanced unresectable but nonmetastatic pancreatic cancer. To evaluate the current evidence regarding treatment of incurable, locally advanced, unresectable but nonmetastatic pancreatic cancer and produce an evidence-based practice guideline. A systematic review of the literature was performed. The MEDLINE, CANCERLIT, and Cochrane Library databases were searched using the following medical subject heading search terms: 'pancreatic neoplasms', 'chemotherapy, adjuvant', 'radiotherapy', 'immunotherapy', combined with the text words: 'chemotherapy', 'radiotherapy', 'radiation', 'immunotherapy', combined with terms for the following study designs or publication types: practice guidelines, meta-analyses and randomized controlled trials. The Physician Data Query clinical trials database and the proceedings of the annual meetings of the American Society of Clinical Oncology (1996 to 2001) and the American Society for Therapeutic Radiology and Oncology (1999 to 2001) were searched for reports of new or ongoing trials. Relevant literature was selected and reviewed independently, and the reference lists from these sources were searched for additional trials. Interpretation of evidence was resolved by consensus. Eight randomized trials were obtained that met the inclusion criteria. Recommendations are to offer combined chemotherapy and radiotherapy to suitable patients. The preferred chemotherapeutic agent to combine with radiotherapy is bolus or infusional 5-fluorouracil, but the optimal mode and duration of 5-fluorouracil delivery is unclear. Chemotherapy alone with gem-citabine is an acceptable alternative.


Appropriate terminology for the alcohol, eating, and physical activity relationship.
"Drunkorexia" merges prior literature identifying positive relationships between (a) alcohol use/abuse and disordered eating/eating disorders, (b) alcohol use/abuse and physical activity, and (c) disordered eating/eating disorders and physical activity. The term, highlighting an individual's proactive and/or reactive weight management behaviors (ie, disordered eating, physical activity) in relation to alcohol consumption, originated in news editorials and has recently gained recognition via use in scholarly publications. The purpose of this commentary is to recommend discontinuing use of the term "drunkorexia" due to (a) inconsistent definitions of drunkorexia across investigations, (b) drunkorexia being a misnomer, and (c) the medical community's lack of recognition/acceptance of drunkorexia. Because the behaviors encompassed by drunkorexia are of concern to researchers and health professionals, future investigations are still warranted. However, until a medically recognized term/phrase is accepted, scholars should utilize more appropriate characterizations such as "weight-conscious drinkers," "weight management behaviors of drinkers," or "Eating Disorders Not Otherwise Specified" (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision).


Fluid flow mechanotransduction in vascular smooth muscle cells and fibroblasts.
Understanding how vascular wall endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts (FBs) sense and transduce the stimuli of hemodynamic forces (shear stress, cyclic strain, and hydrostatic pressure) into intracellular biochemical signals is critical to prevent vascular disease development and progression. ECs lining the vessel lumen directly sense alterations in blood flow shear stress and then communicate with medial SMCs and adventitial FBs to regulate vessel function and disease. Shear stress mechanotransduction in ECs has been extensively studied and reviewed. In the case of endothelial damage, blood flow shear stress may directly act on the superficial layer of SMCs and transmural interstitial flow may be elevated on medial SMCs and adventitial FBs. Therefore, it is also important to investigate direct shear effects on vascular SMCs as well as FBs. The work published in the last two decades has shown that shear stress and interstitial flow have significant influences on vascular SMCs and FBs. This review summarizes work that considered direct shear effects on SMCs and FBs and provides the first comprehensive overview of the underlying mechanisms that modulate SMC secretion, alignment, contraction, proliferation, apoptosis, differentiation, and migration in response to 2-dimensional (2D) laminar, pulsatile, and oscillating flow shear stresses and 3D interstitial flow. A mechanistic model of flow sensing by SMCs is also provided to elucidate possible mechanotransduction pathways through surface glycocalyx, integrins, membrane receptors, ion channels, and primary cilia. Understanding flow-mediated mechanotransduction in SMCs and FBs and the interplay with ECs should be helpful in exploring strategies to prevent flow-initiated atherosclerosis and neointima formation and has implications in vascular tissue engineering.


TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin.
The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. We previously showed that the pivotal effector of this pathway, YAP, is amplified in tumors and promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. Here, we report that overexpression of TAZ, a paralog of YAP, in human mammary epithelial cells promotes EMT and, in particular, some invasive structures in 3D cultures. TAZ also leads to cell migration and anchorage-independent growth in soft agar. Furthermore, we identified amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, as a target of TAZ. We show that AREG functions in a non-cell-autonomous manner to mediate EGF-independent growth and malignant behavior of mammary epithelial cells. In addition, ablation of TEAD binding completely abolishes the TAZ-induced phenotype. Last, analysis of breast cancer patient samples reveals a positive correlation between TAZ and AREG in vivo. In summary, TAZ-dependent secretion of AREG indicates that activation of the EGFR signaling is an important non-cell-autonomous effector of the Hippo pathway, and TAZ as well as its targets may play significant roles in breast tumorigenesis and metastasis.


Towards a concept of disorders of "higher vestibular function".
Vestibular disorders are commonly characterized by a combination of perceptual, ocular motor, postural, and vegetative manifestations, which cause the symptoms of vertigo, nystagmus, ataxia, and nausea. Multisensory convergence and numerous polysynaptic pathways link the bilaterally organized central vestibular network with limbic, hippocampal, cerebellar, and non-vestibular cortex structures to mediate "higher" cognitive functions. Anatomical classification of vestibular disorders: The traditional classification of vestibular disorders is based on the anatomical site of the lesion. While it distinguishes between the peripheral and the central vestibular systems, certain weaknesses become apparent when applied clinically. There are two reasons for this: first, peripheral and central vestibular disorders cannot always be separated by the clinical syndrome; second, a third category, namely disorders of "higher vestibular function", is missing. These disorders may be caused by peripheral as well as central vestibular lesions. Functional classification: Here we discuss a new concept of disorders of higher vestibular function which involve cognition and more than one sensory modality. Three conditions are described that exemplify such higher disorders: room tilt illusion, spatial hemineglect, and bilateral vestibulopathy all of which present with deficits of orientation and spatial memory. Further elaboration of such disorders of higher multisensory functions with respect to lesion site and symptomatology is desirable. The room tilt illusion and spatial hemineglect involve vestibular and visual function to the extent that both conditions can be classified as either disorders of higher vestibular or of higher visual functions. A possible way of separating these disorders in a first step is to determine whether the causative lesion site affects the vestibular or the visual system. For the vestibular system this lesion site may be peripheral or central. The criterion of "higher function" is fulfilled if cognition or senses other than the primarily affected one come into play.


Secondary hyperparathyroidism downregulates lipoprotein lipase expression in chronic renal failure.
In a recent study, we found marked downregulation of lipoprotein lipase (LPL) gene expression in fat, myocardium, and skeletal muscle of rats with chronic renal failure (CRF). Recently, hepatic lipase expression was shown to be depressed in CRF rats, and parathyroidectomy (PTX) was shown to reverse this abnormality. This study was undertaken to determine whether down-regulation of LPL expression in CRF is due to secondary hyperparathyroidism. Accordingly, LPL mRNA (Northern analysis), protein mass (Western analysis using mouse antibovine LPL monoclonal antibody, 5D2), and catalytic activity of the fat pad and soleus muscle were compared in five-sixths-nephrectomized male rats (CRF), parathyroidectomized CRF rats, and sham-operated control animals. The CRF animals exhibited marked hypertriglyceridemia and significant reductions of fat and skeletal muscle LPL mRNA abundance, protein mass, and catalytic activity (P < 0.05 vs. controls, for all parameters). PTX completely normalized the LPL mRNA, protein mass, and enzymatic activity and partially ameliorated the CRF hypertriglyceridemia (P < 0.05 vs. CRF group, for all parameters). Thus secondary hyperparathyroidism is responsible for impaired LPL expression in experimental CRF. This abnormality is completely corrected by PTX.


Levetiracetam Interaction with Direct Oral Anticoagulants: A Pharmacovigilance Study.
Levetiracetam is widely used in post-stroke epilepsy. However, it is suspected to possess P-glycoprotein (P-gp) induction properties, and therefore, a potentially significant interaction with direct oral anticoagulants (DOACs). We aimed to search for ischemic stroke signals with levetiracetam and the DOACs. In this retrospective pharmacovigilance study, we used the FAERS database to identify ischemic stroke events associated with DOACs and concomitant use of levetiracetam. We evaluated disproportionate reporting by the adjusted reporting odds ratio (adjROR) and the lower bound of the shrinkage 95% confidence interval. When shrinkage is positive, an increased risk of a specific adverse event occurrence is emphasized over the sum of the individual risks when these same drugs are used separately. We identified 1841 (1.5%), 3731 (5.3%), 338 (4.9%), and 1723 (1.3%) ischemic stroke reports with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. The adjROR of the interaction effect was 3.57 (95% CI 2.81-4.58) between DOACs and levetiracetam. The shrinkage analysis detected an interaction between each of the DOACs and levetiracetam. The logistic model and shrinkage analysis failed to detect an interaction when queried for hemorrhagic stroke. A significant signal in the classical enzyme inducer, carbamazepine, strengthened our results (adjROR; 8.47, 95% CI 5.37-13.36). Our study shows a strong signal for the levetiracetam interaction with the DOACs. Our findings suggest implementation of a drug monitoring strategy.


Predominantly fibrous malignant mesothelioma in a cat.
Malignant mesotheliomas are rare tumours in domestic cats. They occur within the abdominal or thoracic cavity and are regularly associated with pleural or peritoneal effusions. The histopathological diagnosis can be quite challenging, as these neoplasms may resemble other epithelial or mesenchymal neoplasms. However, differentiation can be achieved by immunohistochemistry in most cases. Here we describe the rare case of a malignant mesothelioma of the fibrous subtype in the thoracic cavity of a cat and discuss differential diagnoses and treatment options for this tumor type.


casanova plays an early and essential role in endoderm formation in zebrafish.
The cellular and molecular mechanisms that regulate endoderm development in vertebrates have only recently begun to be explored. Here we show that the zebrafish locus casanova plays an early and essential role in this process. casanova mutants lack a gut tube and do not express any molecular markers of endoderm differentiation. The early endodermal expression of genes such as axial, gata5, and fkd2 does not initiate in casanova mutants, indicating that the endoderm is defective from the onset of gastrulation. Mosaic analysis demonstrates that casanova functions cell autonomously within the endodermal progenitors. We also report the isolation of a zebrafish homologue of Mixer, a gene important for early endoderm formation in Xenopus. casanova does not encode zebrafish Mixer, and mixer expression is normal in casanova mutants, indicating that casanova acts downstream of, or parallel to, mixer to promote endoderm formation. We further find that the forerunner cells, a specialized group of noninvoluting dorsal mesendodermal cells, do not form in casanova mutants. Studies of casanova mutants do not support an important role for the forerunner cells in either dorsal axis or tail development, as has been previously proposed. In addition, although different populations of mesodermal precursors are generated normally in casanova mutants, morphogenetic defects in the heart, vasculature, blood, and kidney are apparent, suggesting a possible role for the endoderm in morphogenesis of these organs.


Rat astroglial somatomedin/insulin-like growth factor binding proteins: characterization and evidence of biologic function.
Specific binding proteins (BPs) to somatomedin/insulin-like growth factors (Sm/IGFs) have been identified in conditioned media from a variety of cells in culture. By affinity cross-linking using disuccinimidyl suberate, we have covalently cross-linked radiolabeled somatomedin-C/insulin-like growth factor I (Sm-C/IGF I), insulin-like growth factor II (IGF II) and insulin to BPs in conditioned medium (CM) from cultured astroglial cells derived from cerebral cortices of neonatal rats. Two species of radiolabeled Sm/IGF BP complexes of 40,000 Da (40K) and 45K were identified. Competition with unlabeled Sm-C/IGF I and IGF II demonstrated that the BPs in each complex have similar affinities for Sm-C/IGF I and IGF II. The BP in the 45K complex was about 5-fold more sensitive to competition with unlabeled Sm/IGFs than the BP in the 40K complex, suggesting that it either has a higher affinity for Sm/IGFs or is less abundant. Evidence that the BPs in each complex are distinct includes the following findings: (1) insulin competed with Sm/IGF for binding to the 45K complex, but not the 40K complex, and (2) the BP in the 40K complex, but not the 45K complex, was recognized by antibodies raised against a BP purified from CM of buffalo rat liver (BRL) 3A cells. Growth hormone did not affect the apparent secretion of either BP. The binding activity of both BPs was retained after mild heat treatment, changes to extremes of pH (2-10), and prolonged storage at -20 degrees C, but was destroyed after heating to higher temperatures (80 degrees C and greater), reduction, and proteolytic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Multi-institutional analysis of radiation modality use and postoperative outcomes of neoadjuvant chemoradiation for esophageal cancer.
Relative radiation dose exposure to vital organs in the thorax could influence clinical outcomes in esophageal cancer (EC). We assessed whether the type of radiation therapy (RT) modality used was associated with postoperative outcomes after neoadjuvant chemoradiation (nCRT). Contemporary data from 580 EC patients treated with nCRT at 3 academic institutions from 2007 to 2013 were reviewed. 3D conformal RT (3D), intensity modulated RT (IMRT) and proton beam therapy (PBT) were used for 214 (37%), 255 (44%), and 111 (19%) patients, respectively. Postoperative outcomes included pulmonary, GI, cardiac, wound healing complications, length of in-hospital stay (LOS), and 90-day postoperative mortality. Cox model fits, and log-rank tests both with and without Inverse Probability of treatment Weighting (IPW) were used to correct for bias due to non-randomization. RT modality was significantly associated with the incidence of pulmonary, cardiac and wound complications, which also bore out on multivariate analysis. Mean LOS was also significantly associated with treatment modality (13.2days for 3D (95%CI 11.7-14.7), 11.6days for IMRT (95%CI 10.9-12.7), and 9.3days for PBT (95%CI 8.2-10.3) (p<0.0001)). The 90day postoperative mortality rates were 4.2%, 4.3%, and 0.9%, respectively, for 3D, IMRT and PBT (p=0.264). Advanced RT technologies (IMRT and PBT) were associated with significantly reduced rate of postoperative complications and LOS compared to 3D, with PBT displaying the greatest benefit in a number of clinical endpoints. Ongoing prospective randomized trial will be needed to validate these results.


Co-evolution of Enzymes Involved in Plant Cell Wall Metabolism in the Grasses.
There has been a dramatic evolutionary shift in the polysaccharide composition of cell walls in the grasses, with increases in arabinoxylans and (1,3;1,4)-β-glucans and decreases in pectic polysaccharides, mannans, and xyloglucans, compared with other angiosperms. Several enzymes are involved in the biosynthesis of arabinoxylans, but the overall process is not yet defined and whether their increased abundance in grasses results from active or reactive evolutionary forces is not clear. Phylogenetic analyses reveal that multiple independent evolution of genes encoding (1,3;1,4)-β-glucan synthases has probably occurred within the large cellulose synthase/cellulose synthase-like (CesA/Csl) gene family of angiosperms. The (1,3;1,4)-β-glucan synthases appear to be capable of inserting both (1,3)- and (1,4)-β-linkages in the elongating polysaccharide chain, although the precise mechanism through which this is achieved remains unclear. Nevertheless, these enzymes probably evolved from synthases that originally synthesized only (1,4)-β-linkages. Initially, (1,3;1,4)-β-glucans could be turned over through preexisting cellulases, but as the need for specific hydrolysis was required, the grasses evolved specific (1,3;1,4)-β-glucan endohydrolases. The corresponding genes evolved from genes for the more widely distributed (1,3)-β-glucan endohydrolases. Why the subgroups of CesA/Csl genes that mediate the synthesis of (1,3;1,4)-β-glucans have been retained by the highly successful grasses but by few other angiosperms or lower plants represents an intriguing biological question. In this review, we address this important aspect of cell wall polysaccharide evolution in the grasses, with a particular focus on the enzymes involved in noncellulosic polysaccharide biosynthesis, hydrolysis, and modification.


Use of state hospital discharge data to assess the morbidity from rotavirus diarrhea and to monitor the impact of a rotavirus immunization program: A pilot study in Connecticut.
Now that rotavirus vaccines have been licensed and recommended for routine immunization of US infants, there is an urgent need for data to assess the morbidity from rotavirus diarrhea and to monitor the impact of a rotavirus immunization program. In a pilot study, we have assessed the usefulness of state hospital discharge data on diarrhea in children to provide this information by examining data from Connecticut. Retrospective analysis of discharge records from acute care, nongovernmental hospitals in Connecticut. Patients. Children 1 month through 4 years of age with a diarrhea-associated diagnosis listed on the discharge record. Setting. Connecticut, 1987 through 1996. During the 10-year study period, a total of 11 324 diarrhea-associated hospitalizations (49.4 hospitalizations per 10,000 children) were reported. Diarrhea-associated hospitalizations peaked during February through April, especially among children 4 to 35 months of age. The seasonality and age distribution of diarrhea-associated hospitalizations of presumed noninfectious and viral etiologies resembled those of rotavirus-associated hospitalizations. During 1993 to 1996, rotavirus was coded for 10.4% of diarrhea-associated hospitalizations increasing from 8.6% in 1993 to 14.7% in 1996. The unadjusted median cost of a diarrhea-associated hospitalization during 1987 to 1996 and 1993 to 1996 was $1,941 and $2,428, respectively. Diarrhea causes substantial morbidity in children from Connecticut. The winter seasonal peak of diarrhea-associated hospitalizations in children 4 to 35 months of age coinciding with the peak of rotavirus-specific hospitalizations suggests that rotavirus is an important contributor to the overall morbidity. Although our findings suggest incomplete coding of rotavirus cases, state hospital discharge data should provide sensitive and timely information to monitor the impact of a rotavirus immunization program in Connecticut.


Cortical motor reorganization after a single clinical attack of multiple sclerosis.
In order to evaluate whether cortical motor reorganization occurs in the earliest phase of multiple sclerosis, we studied patients after a first clinical attack of hemiparesis. From a consecutive series of 70 patients enrolled in a study of patients with clinically isolated syndrome and serial MRI findings indicative of multiple sclerosis, we retrospectively selected 10 patients with hemiparesis as the onset symptom and no further clinical episode [mean age 32 +/- 9 years, disease duration 24 +/- 14 months, median Expanded Disability Status Score (EDSS) 1.25]. Ten age-matched, healthy subjects served as controls. Each subject was submitted to two functional MRI trials (one per hand) using a 1.5 T magnet during a sequential finger-to-thumb opposition task. Image analysis was performed using SPM99 software. Movements of both the 'affected' and the 'unaffected' hand activated significantly larger areas in patients than in controls in both the contralateral and ipsilateral cortical motor areas. Patients activated a greater number of foci than controls during both the right-hand and the left-hand movement. Most of these foci were located in cortical areas which were less or not at all activated in controls, such as the lateral premotor cortex [Brodmann area (BA) 6], the insula and the inferior parietal lobule (BA 40). Between-group analysis of patients versus controls showed significant (P < 0.001) foci in these areas, principally located in the ipsilateral hemisphere during right-hand movement and in both the cerebral hemispheres during left-hand movement. Time since clinical onset showed a significant positive correlation with the extent of activation in the ipsilateral motor areas (P = 0.006) during the right-hand movement and with the extent of activation in both the ipsilateral (P = 0.02) and contralateral (P = 0.006) motor areas during the left-hand movement. The T(1) lesion load along the motor pathway showed a significant positive correlation (P = 0.007) with the extent of activation in the contralateral motor areas during right-hand movement. Our study shows functional adaptive changes that involve both the symptomatic and asymptomatic hemisphere during a simple motor task in patients who had suffered a single clinical attack of hemiparesis. The extent of these changes increased with the time elapsed since disease onset and the severity of brain damage.


Sustained low peritoneal effluent CCL18 levels are associated with preservation of peritoneal membrane function in peritoneal dialysis.
Peritoneal membrane failure (PMF) and, ultimately, encapsulating peritoneal sclerosis (EPS) are the most serious peritoneal dialysis (PD) complications. Combining clinical and peritoneal transport data with the measurement of molecular biomarkers, such as the chemokine CCL18, would improve the complex diagnosis and management of PMF. We measured CCL18 levels in 43 patients' effluent and serum at baseline and after 1, 2, and 3 years of PD treatment by retrospective longitudinal study, and evaluated their association with PMF/EPS development and peritoneal risk factors. To confirm the trends observed in the longitudinal study, a cross-sectional study was performed on 61 isolated samples from long-term (more than 3 years) patients treated with PD. We observed that the patients with no membrane dysfunction showed sustained low CCL18 levels in peritoneal effluent over time. An increase in CCL18 levels at any time was predictive of PMF development (final CCL18 increase over baseline, p = .014; and maximum CCL18 increase, p = .039). At year 3 of PD, CCL18 values in effluent under 3.15 ng/ml showed an 89.5% negative predictive value, and higher levels were associated with later PMF (odds ratio 4.3; 95% CI 0.90-20.89; p = .067). Moreover, CCL18 levels in effluent at year 3 of PD were independently associated with a risk of PMF development, adjusted for the classical (water and creatinine) peritoneal transport parameters. These trends were confirmed in a cross-sectional study of 61 long-term patients treated with PD. In conclusion, our study shows the diagnostic capacity of chemokine CCL18 levels in peritoneal effluent to predict PMF and suggests CCL18 as a new marker and mediator of this serious condition as well as a new potential therapeutic target.


[Hand injuries in workers on the eastern shore of Marcaibo Lake in the state of Zulia, Venezuela, 1986-1993].
In order to analyze the frequency, injury rate and cause of on site accidents to the hands of workers on the east coast of lake of Maracaibo in Zulia State, data was obtained from the accident reports registered with the Venezuelan Institute of Social Security. An occupational hand injury was defined as a traumatic injury to the hands, fingers or wrists that occurred while the employee was at work; that resulted from a single exposure to a hazardous agent. The following variables were analyzed: age, severity, economic activity, material agent, mechanic cause, type of injury, type of accident and unsafe action. The frequency rate was used to analyze the annual accident rate. During the period under study 2.456 injuries to the hand were registered, representing 36% of the total injuries reported; 95% were light injuries, 5% incapacitating and two cases resulted in the death of the worker. 72% of the injuries were located in the fingers, 22% in the hands and 6% in the wrists. The greatest frequency of injuries were found in the economic activity in mines and quarries with a rate of 123.1 per thousand. The age group most affected was of 20-29 years (42%), Wounds or contusions and crushings were the injuries most commonly reported, in 39% and 36% of the cases respectively. The main type of injuries were caused by run over, running into or blow from objects. The principal agents causing injuries were materials, substances and radiations in 45% of the cases. It is concluded that the hand injury rate is very high in the exploitation of mines and quarries and represents the main cause of worker's disability.


Estimation of the prevalence of uterine infertility and its different causes in France according to data from a literature review.
Uterine infertility (UI) is defined as the complete absence of a uterus (absolute uterine infertility or AUI) or the presence of a non functional uterus (non-absolute uterine infertility or NAUI). The exact prevalence of uterine infertility is currently unknown. Our aim was to assess the number of French women concerned by Uterine Infertility according to a recent literature review. We have previously conducted a systematic review of the literature on UI and its various causes in the world. Based on these study and demographic data of 2022 from INSEE (Institut National de la Statistique et des Études Économiques), we attempted to estimate the number of women under 40 years of age in France affected by potential UI using direct standardization. Based on the estimation from INSEE data, approximately 2066 women of childbearing age would have MRKH syndrome in France, 380 the Androgen Insensitivity Syndrome and 3700 had an haemostasis hysterectomy in France. We did not find data on the prevalence of hysterectomies before the age of 40 in France. For the following pathologies: uterine malformations, radiation uterus, synechiae, myomas and adenomyosis there was a huge amount of missing data, which does not allow us to estimate the number of potentially infertile patients. Prevalence of UI is poorly known. UI probably concerns several thousand patients in France. The creation of a UI registry would make enable to assess the number of patients potentially eligible for adoption, uterus transplantation or even surrogacy.


iPhone-based Pupillometry: A Novel Approach for Assessing the Pupillary Light Reflex.
The response of the pupil to a flash of light, the pupillary light reflex (PLR), is an important measure in optometry and in other fields of medicine that is typically evaluated by qualitative observation. Here we describe a simple, portable, iPhone-based pupillometer that quantifies the PLR in real time. The purposes of this study were to describe a novel application that records the PLR and to compare its technical capabilities with a laboratory-based infrared (IR) camera system. Pupil sizes were measured from 15 visually normal subjects (age, 19 to 65 years) using an IR camera system and the Sensitometer test. This test elicits pupillary constriction using the iPhone flash, records pupil size using the camera, and provides measurements in real time. Simultaneous recordings were obtained with the Sensitometer test and IR camera, and two measures were calculated: (1) dark-adapted steady-state pupil size and (2) minimum pupil size after the flash. The PLR was defined as the difference between these two measures. Pupil size was also recorded during the redilation phase after the flash. Bland-Altman analysis was used to assess the limits of agreement between the two methods. Statistically significant correlations between the IR and Sensitometer test measures were found for the PLR (r = 0.91, P < .001) and redilation size (r = 0.65, P = .03). Bland-Altman analysis indicated a mean PLR difference of 6% between these two methods. The PLR limit of agreement was 14%, indicating that 95% of subjects are expected to have IR and Sensitometer test measurements that differ by 14% or less. Bland-Altman analysis indicated a mean redilation size difference of 1% between the two methods; the limit of agreement was 5%. There is excellent agreement between pupil responses recorded using the Sensitometer test and IR camera. The Sensitometer test provides a highly promising approach for simple, portable, inexpensive pupillary measurements.


Differential gene expression of BMP2 and BMP receptors in chick retina & choroid induced by imposed optical defocus.
Recent studies have demonstrated the defocus sign-dependent, bidirectional gene expression regulation of bone morphogenetic proteins, BMP2, 4 and 7 in chick RPE. In this study, we examined the effects of imposed positive (+10 D) and negative (-10 D) lenses on the gene expression of these BMPs and BMP receptors (BMPR1A, BMPR1B, BMPR2) in chick retina and choroid after monocular lens treatment for 2 or 48 h, as indicators of the roles of retinal and choroidal BMPs and receptors in postnatal eye growth regulation. In retina, although all genes were expressed, neither +10 nor -10 D lenses, worn for either 2 or 48 h, significantly altered gene expression. In contrast, treatment-related differential gene expression was detected in the choroid for both BMPs and their receptors, although interestingly, with the +10 D lens, BMP2 was up-regulated by 156.7 ± 19.7% after 2 h, while BMPR1A was down-regulated to 82.3 ± 12.5% only after 48 h. With the -10 D lens, only the gene expression of BMPR1B was significantly altered, being up-regulated by 162.3 ± 21.2% after 48 h. Untreated birds showed no difference in expression between their two eyes, for any of the genes examined. The finding that retinal gene expression for BMP2, 4, 7 and their receptors are not affected by short-term optical defocus contrasts with previous observations of sign-dependent expression changes for the same genes in the RPE. The latter changes were also larger and more consistent in direction than the choroidal gene expression changes reported here. The interrelationship between these various changes and their biological significance for eye growth regulation are yet to be elucidated.


The post-mitotic state in neurons correlates with a stable nuclear higher-order structure.
Neurons become terminally differentiated (TD) post-mitotic cells very early during development yet they may remain alive and functional for decades. TD neurons preserve the molecular machinery necessary for DNA synthesis that may be reactivated by different stimuli but they never complete a successful mitosis. The non-reversible nature of the post-mitotic state in neurons suggests a non-genetic basis for it since no set of mutations has been able to revert it. Comparative studies of the nuclear higher-order structure in neurons and cells with proliferating potential suggest that the non-reversible nature of the post-mitotic state in neurons has a structural basis in the stability of the nuclear higher-order structure.


Lateral and vertical stiffness of the epitaxial h-BN monolayer on Rh(111).
The response to strain in covalently bound single layers has a large impact on the growth and properties. We investigate the quasi-two-dimensional hexagonal boron nitride on Rh(111), which is interesting due to its high intrinsic corrugation. We use combined atomic force and scanning tunneling microscopy to measure the response of this monolayer to probing forces. Three-dimensional force maps and the atomic resolution of the layer enable us to determine lateral and vertical stiffness of this prototypical system with unprecedented spatial resolution. Extremely low stiffnesses ≈1 N/m are derived. Our experiments give insights into the mechanical properties of corrugated incommensurate layers that buckle into the third dimension to relieve strain.


Pharmacokinetics of the Novel Echinocandin CD101 in Multiple Animal Species.
CD101 is a novel semisynthetic echinocandin with antifungal activity against Candida and Aspergillus spp. The pharmacokinetics (PK) of CD101 administered intravenously to mice, rats, dogs, cynomolgus monkeys, and chimpanzees are presented. CD101 consistently exhibited very low clearance, a modest volume of distribution at steady state (Vss), and a long half-life (t1/2) across all species tested. In mouse, rat, dog, cynomolgus monkey, and chimpanzee, CD101 clearance was 0.10, 0.47, 0.30, 0.41, and 0.06 ml/min/kg, respectively; Vss was 206, 1,390, not determined, 597, and 400 ml/kg, respectively; and t1/2 was 25, 39, 53, 40, and 81 h, respectively. CD101 demonstrated a lower clearance and correspondingly longer half-life than those of anidulafungin, with more pronounced differences in higher species (anidulafungin t1/2, 8 h in cynomolgus monkey and 30 h in chimpanzee). In the rat, tissue/plasma area under the concentration-time curve (AUC) ratios, in descending order, were 4.62 (kidney), 4.33 (lung), 4.14 (liver), 3.87 (spleen), 1.09 (heart), and 0.609 (brain), indicating that CD101 exposure relative to plasma levels was comparable for major organs (approximately 4-fold higher in tissue than in plasma), with the exception of the heart and brain. Biliary elimination of intact CD101 was the predominant route of excretion; the mean cumulative amount of CD101 excreted into the bile and feces over the course of 5 days accounted for 22.6% and 27.7% of the total dose administered, respectively. There were no sex differences in the pharmacokinetics of CD101. Given its low clearance, long half-life, and wide tissue distribution, CD101 once weekly is expected to provide appropriate systemic levels for treatment and prevention of invasive fungal infections.


Synergistic neutralization of rubella virus by monoclonal antibodies to viral haemagglutinin.
Using murine monoclonal antibodies (MAbs) to rubella virus haemagglutinin, five epitopes were identified in competitive ELISA binding assays: A, B, D and E by haemagglutination-inhibiting (HI) MAbs with no neutralizing (Nt) activity, and C by a MAb with neither activity. However, when HI and Nt activities were determined in the presence of anti-mouse immunoglobulins, epitopes A, B and D were defined by both HI and Nt MAbs, whereas epitopes C and E were identified by HI MAbs without Nt activity. A synergistic Nt activity, in the absence of anti-mouse immunoglobulins, was displayed by mixtures of antibodies of different epitope groups. Analysis of mixtures of MAb pairs each belonging to a different epitope class, showed that synergistic Nt activity was elicited primarily by the group A epitope, secondarily by groups B and D and only minimally by groups C and E.


Proteomes of hard and soft near-isogenic wheat lines reveal that kernel hardness is related to the amplification of a stress response during endosperm development.
Wheat kernel texture, a major trait determining the end-use quality of wheat flour, is mainly influenced by puroindolines. These small basic proteins display in vitro lipid binding and antimicrobial properties, but their cellular functions during grain development remain unknown. To gain an insight into their biological function, a comparative proteome analysis of two near-isogenic lines (NILs) of bread wheat Triticum aestivum L. cv. Falcon differing in the presence or absence of the puroindoline-a gene (Pina) and kernel hardness, was performed. Proteomes of the two NILs were compared at four developmental stages of the grain for the metabolic albumin/globulin fraction and the Triton-extracted amphiphilic fraction. Proteome variations showed that, during grain development, folding proteins and stress-related proteins were more abundant in the hard line compared with the soft one. These results, taken together with ultrastructural observations showing that the formation of the protein matrix occurred earlier in the hard line, suggested that a stress response, possibly the unfolded protein response, is induced earlier in the hard NIL than in the soft one leading to earlier endosperm cell death. Quantification of the albumin/globulin fraction and amphiphilic proteins at each developmental stage strengthened this hypothesis as a plateau was revealed from the 500 °Cd stage in the hard NIL whereas synthesis continued in the soft one. These results open new avenues concerning the function of puroindolines which could be involved in the storage protein folding machinery, consequently affecting the development of wheat endosperm and the formation of the protein matrix.


[Assessment of vitamins and minerals intake with supplements in pregnant women].
The aim of the work was to assess the application of diet supplements in pregnant women, as well as the intake of vitamins and minerals with pharmaceuticals. Sixty women in age 19 - 40 years coming from the Mazowsze district were examined. The information about applying supplements was obtained using questionnaire method. The intake of vitamin and mineral supplements before and during pregnancy was declared on the level of 55% and 98.3% respectively. The average intake of vitamin D (157%), folic acid (128%), vitamin B2 (125%), vitamin C (121%), iron (120%), iodine and zinc (113%) from supplements was above recommended values. The average intake of vitamin B1, B12 and B6 from supplements was about 95-105% of RDA. The lowest average consumption was noted for vitamin A (60%) as well as calcium and magnesium (10-12% of recommended value). Pregnant women who have lived in country consumed less vitamins and minerals from supplements, however differences were statistically significant in case vitamin A, E, magnesium, cooper, iodine and manganese.


Exercise physiology in the 1990's: mechanistically defining the exercise model.
Definition of the exercise model via a mechanistic approach is a goal which should be of high priority among sport researchers in the 1990's, in an attempt to further qualify previous phenomenological observations of exercising man. Prolonged argument on the "theory-versus-practice" issue is one which is counter-productive in the advancement of knowledge in our discipline, and must be addressed and resolved. With specific emphasis on the neuromuscular control of movement, current research literature suggests that the components limiting to human performance may reside in the muscle, motoneurone and in the supraspinal of movement. Mechanistically defining the limits in each component, related to patterns of movement during exercise, may soon herald a reclassification of exercise types and their limits, defined by the particular system involved. Similarly, new evidence on adaptations throughout the neuromuscular system calls for a systematic study of these adaptations, how they influence structure and function of cell and organ systems, and their effects on the performance of the voluntarily exercising human. A mechanistic approach to these problems, using "simple" experimental models to more precisely define cause-effect, are justifiable and necessary in our field on the basis of the potential applicability of such information in the fields of design of exercise programmes, and the evaluation of their effectiveness, for normal and special populations. The problems associated with increased academic specialization and the communication gap which might result, are not inevitable. An enhancement of the proliferation of this knowledge and its interpretation in practical terms will result through our own awareness of the necessity of doing this, and through sensitization of our students to this issue.


Optimum Sowing Date and Genotype Testing for Upland Rice Production in Brazil.
A better understanding of widespread agricultural practices adopted in the region of Ribeira Valley, São Paulo, Brazil for upland rice (Oryza sativa L.) production is needed. The objectives of this study were to determine the optimum sowing date and highest yielding genotypes for rice production. Treatments included four upland rice genotypes (ANA 5011, AN-Cambará, Moti-Amarelo, and Moti-Branco) and four sowing dates (October, November, December, and January) in 2011 and 2012. The results of the study showed that genotype ANA 5011 had the earliest maturity, while the Moti genotypes had the latest maturity in all sowing dates. The Moti genotypes were found to have greater plant height and 1,000-grain weight than the other two genotypes. In contrast, the Moti genotypes had fewer panicles m-2, fewer total filled and total numbers of spikelets panicle-1, and lower final yield. The genotype AN-Cambará had the highest number of tillers, filled and total number of spikelets panicle-1, panicle m-2, and the highest yield. Sowing in either November or December was found to be the most suitable dates for rice cultivation for all genotypes. In conclusion, the AN-Cambará genotype was found to have the highest yield potential for the region among all genotypes studied.


The US/Mexico border: a binational approach to framing challenges and constructing solutions for improving farmworkers' lives.
Mexican migrant and seasonal farmworkers in the US-Mexico border region face health hazards and occupational risks and are becoming commonly known in the public health literature. According to several studies, farmworkers have high levels of chronic diseases such as diabetes and respiratory problems, are at risk for infectious diseases, and experience among the highest incidences of work-related injuries of any profession. The findings from two studies are considered and presented with the objective of contributing to an overall understanding of migrant farmworkers as a workforce moving across national boundaries and affected by the work environments and health stressors both shared and unique to each context. We propose a binational approach to comprehensively address the health problems and socioeconomic challenges faced by migrant and seasonal farmworkers. In this paper we present the results of two distinct but complementary studies of farmworker health on the Arizona-Sonora border.


Nicotinamide restores phosphaturic effect of PTH and calcitonin in phosphate deprivation.
Results of previous studies suggest a potentially important role for nicotinamide adenine dinucleotide (NAD) in the cellular regulation of phosphate transport by the renal proximal tubules. The present clearance studies were performed to evaluate whether intraperitoneal administration of nicotinamide, a precursor of NAD and inhibitor of NAD catabolism, would not only increase phosphate excretion but also restore the phosphaturic response to parathyroid hormone (PTH) in rats fed a low phosphate diet. Rats fed a low phosphate diet were resistant to the phosphaturic effect of PTH, calcitonin, and dibutyryl cAMP (DBcAMP) in spite of the fact that all three agents elicited an increase in the urinary excretion of cAMP. Administration of nicotinamide to rats fed a low phosphate diet increased renal cortical NAD levels, increased phosphate excretion, partially restored the phosphaturic effect of PTH and DBcAMP, and completely restored the phosphaturic response to calcitonin. We conclude that nicotinamide restores the phosphaturic effect of PTH and calcitonin in rats fed a low phosphate diet by acting at a cellular step subsequent to cAMP generation to inhibit tubular reabsorption of phosphate.


Human posterior parietal cortex plans where to reach and what to avoid.
In this time-resolved functional magnetic resonance imaging (fMRI) study, we aimed to trace the neuronal correlates of covert planning processes that precede visually guided motor behavior. Specifically, we asked whether human posterior parietal cortex has prospective planning activity that can be distinguished from activity related to retrospective visual memory and attention. Although various electrophysiological studies in monkeys have demonstrated such motor planning at the level of parietal neurons, comparatively little support is provided by recent human imaging experiments. Rather, a majority of experiments highlights a role of human posterior parietal cortex in visual working memory and attention. We thus sought to establish a clear separation of visual memory and attention from processes related to the planning of goal-directed motor behaviors. To this end, we compared delayed-response tasks with identical mnemonic and attentional demands but varying degrees of motor planning. Subjects memorized multiple target locations, and in a random subset of trials targets additionally instructed (1) desired goals or (2) undesired goals for upcoming finger reaches. Compared with the memory/attention-only conditions, both latter situations led to a specific increase of preparatory fMRI activity in posterior parietal and dorsal premotor cortex. Thus, posterior parietal cortex has prospective plans for upcoming behaviors while considering both types of targets relevant for action: those to be acquired and those to be avoided.


Effectiveness of link workers providing social prescribing on health outcomes and costs for adult patients in primary care and community settings. A protocol for a systematic review of the literature.
Introduction: The use of link workers for social prescribing and health and social care coordination is increasing, but there is insufficient data to demonstrate their effectiveness or for whom they work best. Multimorbidity is increasing in prevalence and affects those living in deprived areas ten years earlier than affluent areas. This systematic review aims to examine the evidence for the effectiveness and costs of link workers in improving health outcomes. We will also look for evidence for the use of link workers specifically for people living with multimorbidity and in deprived areas. Methods: Databases of published and grey literature will be searched for randomised and non-randomised controlled trials examining use of link workers based in primary care for community dwelling adults compared to usual care. Primary outcomes will be health related quality of life and mental health. Data on costs will be extracted. Studies will be selected for inclusion by title and abstract review by two reviewers. A Preferred Reporting Items for Systematic Reviews (PRISMA) flow diagram will document the selection process. A standardised form will be used to extract data. Data quality will be assessed using the Cochrane Risk of Bias tool for randomised controlled trials, a narrative synthesis will be completed and the GRADE assessment tool used to comment on evidence quality. A meta-analysis of effect size of primary outcomes and subgroup analysis for multimorbidity and social deprivation will be performed if there are sufficient comparable data. Conclusion: This systematic review will give an important overview of the evidence for the use of link workers providing social prescribing and health and social care coordination in primary care. This will help inform intervention development and guide policy makers on whether these interventions are cost effective and which groups stand to benefit most. Prospero registration: CRD42019134737 (04/07/2019).


Can I have a beer, please? A study of alcohol service to young adults on licensed premises in Stockholm.
This study evaluated the effects of a community alcohol prevention program on the frequency of alcohol service to young adults at licensed premises in Stockholm, Sweden. We used a pretest (1996)-posttests (1998 and 2001) design with intervention and control areas. The multicomponent intervention combines training of serving staff in responsible beverage service, policy initiatives, and enforcement of existing alcohol regulations. Adolescents 18 years old (the legal drinking age on licensed premises in Sweden), but younger looking according to an expert panel, visited licensed premises in pairs, where each adolescent ordered a beer. At baseline in 1996, the adolescents made 600 attempts to order. At follow-up in 1998, the number of attempts to order was 252, and at the second follow-up in 2001, the adolescents made 238 attempts. We found no statistically significant differences between the intervention and control areas. Overall, the frequency of alcohol service to adolescents on licensed premises in these areas of Stockholm decreased significantly over time, from 45 to 41 and to 32%, in 1996, 1998, and 2001, respectively. The decrease in alcohol service in 2001 was statistically significant compared to the baseline in 1996. One explanation for this improvement could be more effective enforcement of existing alcohol laws in both the intervention and control areas. We also found that licensed premises that used doormen to screen potential customers were less likely to sell to minors.


The effect of platelet activating factor on pulmonary beta-adrenoceptors.
An intravenous infusion of platelet activating factor (Paf) in the guinea-pig elicits an increase in bronchial responsiveness to the spasmogens, histamine and bombesin. Airways obstruction induced by bombesin in Paf-treated animals is poorly reversed by isoprenaline compared to comparable airways obstruction induced by bombesin in vehicle-treated animals. Isoprenaline induced a comparable dose-related relaxation in vitro of tracheal smooth muscle isolated from Paf- and vehicle-treated animals. No change in beta-adrenoceptor numbers or binding affinity was observed in lungs removed from Paf-treated animals in comparison with those from vehicle-treated animals, or after direct incubation with Paf in vitro. The reduced bronchodilator responsiveness to isoprenaline in Paf-treated animals is not related to changes in pulmonary beta-adrenoceptor function. These results suggest that non-spasmogenic elements may contribute to airways obstruction induced in hyper-responsive animals.


Thiopurine S-methyltransferase pharmacogenetics: functional characterization of a novel rapidly degraded variant allozyme.
A novel human thiopurine S-methyltransferase (TPMT) variant allele, (319 T>G, 107Tyr>Asp, *27), was identified in a Thai renal transplantation recipient with reduced erythrocyte TPMT activity. The TPMT*27 variant allozyme showed a striking decrease in both immunoreactive protein level and enzyme activity after transient expression in a mammalian cell line. We set out to explore the mechanism(s) responsible for decreased expression of this novel variant of an important drug-metabolizing enzyme. We observed accelerated degradation of TPMT*27 protein in a rabbit reticulocyte lysate. TPMT*27 degradation was slowed by proteasome inhibition and involved chaperone proteins-similar to observations with regard to the degradation of the common TPMT*3A variant allozyme. TPMT*27 aggresome formation was also observed in transfected mammalian cells after proteasome inhibition. Inhibition of autophagy also decreased TPMT*27 degradation. Finally, structural analysis and molecular dynamics simulation indicated that TPMT*27 was less stable than was the wild type TPMT allozyme. In summary, TPMT*27 serves to illustrate the potential importance of protein degradation - both proteasome and autophagy-mediated degradation - for the pharmacogenetic effects of nonsynonymous SNPs.


Mast cells that reside at different locations in the jejunum of mice infected with Trichinella spiralis exhibit sequential changes in their granule ultrastructure and chymase phenotype.
Whether or not a nontransformed, mature mouse mast cell (MC) or its committed progenitor can change its granule protease phenotype during inflammatory responses, has not been determined. To address this issue, the granule morphology and protease content of the MC in the jejunum of BALB/c mice exposed to Trichinella spiralis were assessed during the course of the infection. Within 1 wk after helminth infection of the mice, increased numbers of MC appeared in the crypts at the base of the villi, and by wk 2 the number of MC throughout the villi increased by approximately 25-fold. Shortly after the peak of the mastocytosis, the intraepithelial population of MC disappeared, followed by a progressive loss of lamina propria MC. The presence of stellate-shaped granules containing crystalline structures in intraepithelial MC at the height of infection and the retention of such granules with fragmented crystals in lamina propria MC during resolution of the mastocytosis suggest that MC migrate during the various phases of the inflammation. As assessed by immunohistochemical analyses of serial sections, predominant chymase phenotypes were observed at the height of the infection in the muscle that expressed mouse MC protease (mMCP) 5 without mMCP-1 or mMCP-2 and in the epithelium that expressed mMCP-1 and mMCP-2 without mMCP-5. Accompanying these two MC populations were transitional forms in the submucosa that expressed mMCP-2 and mMCP-5 without mMCP-1 and in the lamina propria that expressed mMCP-2 alone. These data suggest that jejunal MC sequentially express mMCP-2, cease expressing mMCP-5, and finally express mMCP-1 as the cells progressively appear in the submucosa, lamina propria, and epithelium, respectively. In the recovery phase of the disease, MC sequentially cease expressing mMCP-1, express mMCP-5, and finally cease expressing mMCP-2 as they present at the tips of the villi, the base of the villi, and the submucosa, respectively. That MC can reversibly alter their protease phenotypes suggests that a static nomenclature with fixed functional implications is inadequate to describe MC populations during an inflammatory process within a particular tissue.


An association between a dopamine transporter gene (SLC6A3) haplotype and ADHD symptom measures in nonclinical adults.
Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self-reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3'UTR and intron 8 of DAT1, the 10-repeat and 6-repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7-repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS-G and CAARS-H (DSM-IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS-G was also found for the 7-repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults.


International survey of perceived barriers to admission and discharge from spinal cord injury rehabilitation units.
Survey. To describe and compare perceived barriers with patient flow in spinal rehabilitation units (SRUs). International. Ten SRUs (Australia, Canada, India, Ireland, Italy, Netherlands, Pakistan, Switzerland, UK and USA) that admit both traumatic and non-traumatic spinal cord injury patients. Survey completed between December 2010 and February 2013 on perception of barriers for admission into and discharge from SRUs. Opinion was sought from the participants regarding the utility of collecting data on the timeliness of access to SRUs and occurrence of discharge barriers for benchmarking and quality improvement purposes. The perceived barriers in accessing SRUs ranged from no access problem to a severe access problem (no access problems n=3; minor access problems n=3; moderate access problems n=2; severe access problem n=1 and extreme n=1). Most units (n=9/10) agreed that collecting data on timeliness of access to SRUs for acute hospital patients may help improve patient outcomes and health system processes by providing information for benchmarking and quality improvement purposes. All units reported perceived barriers to discharge from SRUs. Compared with admission barriers, a greater perception of barriers to discharge was reported (minor problem n=3; moderate problem n=3; severe problem n=3; and extreme n=1). All units agreed that collecting data on barriers to discharge from SRU may help improve patient outcomes and system processes. Perceived barriers to patient flow in SRUs are reported in many countries. Projects to identify and minimise the occurrence and impact of admission and discharge barriers could increase access to rehabilitation and improve the rehabilitation outcomes for patients.


Estrogen receptor beta as target for colorectal cancer prevention.
Colorectal cancer (CRC) is a leading cause of death in the United States. Despite its slow development and the capacity for early diagnosis, current preventive approaches are not sufficient. However, a role for estrogen has been demonstrated in multiple epidemiologic studies, which may benefit CRC prevention. A large body of evidence from preclinical studies indicates that expression of the estrogen receptor beta (ERβ/ESR2) demonstrates an inverse relationship with the presence of colorectal polyps and stage of tumors, and can mediate a protective response. Natural compounds, including phytoestrogens, or synthetic ERβ selective agonists, can activate or upregulate ERβ in the colon and promote apoptosis in preclinical models and in clinical experience. Importantly, this activity has been associated with a reduction in polyp formation and, in rodent models of CRC, has been shown to lower incidence of colon adenocarcinoma. Collectively, these findings indicate that targeted activation of ERβ may represent a novel clinical approach for management of colorectal adenomatous polyps and prevention of colorectal carcinoma in patients at risk for this condition. In this review, we discuss the potential of new chemopreventive or dietary approaches based on estrogen signaling.


Nitric oxide is involved in interleukin-1alpha-induced cytotoxicity in polarised human thyrocytes.
Nitric oxide (NO) is a well-known mediator of autoimmune processes. In the thyroid gland, it is produced in response to interleukin 1 (IL-1) and may mediate cytokine action at an early stage of autoimmune thyroiditis. In this study, we have investigated whether NO is involved in cytokine-induced cytotoxic effects and epithelial barrier alterations in thyrocytes. Human thyroid epithelial cells were cultured as tight polarised monolayers on a permeable support and exposed or not to IL-1alpha (100 U/ml), alone or in combination with interferon-gamma (IFN-gamma; 100 U/ml) added to the basal compartment. NO production was not detected in control thyrocytes, but was significantly induced by the combination of IL-1alpha with IFN-gamma, in a time-dependent fashion. Similarly, expression of the inducible isoform of nitric oxide synthase (NOSII), determined by immunoblot and immunofluorescence confocal microscopy, was not detected in control cells, but was markedly induced after 48-h exposure to both cytokines. This treatment significantly increased the release of cytosolic lactate dehydrogenase (LDH) in the apical and basolateral media and decreased transepithelial electrical resistance. Although IFN-gamma was not sufficient to induce NO production, it could by itself decrease transepithelial resistance and synergised the IL-1alpha effect on LDH release. The NOS inhibitor, L-nitro-arginine-methyl ester, suppressed the cytokine-induced NO production and decreased the LDH release, but failed to prevent the loss of transepithelial resistance. These results indicated that human thyrocytes express NOSII and produce NO in response to IL-1alpha+IFN-gamma and suggest that NO acts as a mediator of cytokine-induced cytotoxicity in the thyroid gland and may promote the exposure of autoantigens to the immune system. In contrast, NO does not appear to mediate the cytokine-induced disruption of the thyroid epithelial barrier.


[Effectiveness evaluation of health belief model-based health education intervention for patients with hypertension in community settings].
Objective: To evaluate the effectiveness of health belief model-based health education intervention in improving blood pressure control of patients with hypertension in community settings. Methods: From September 2016 to September 2017, 400 newly diagnosed patients with hypertension were recruited from 6 community healthcare centers with comparable population size and health services in the Shunyi District of Beijing. All community healthcare centers were randomly assigned to the intervention group (206 patients) and the control group (194 patients). Patients in the intervention group received 3 lectures (20-30 min for each) of health belief model-based health education. Patients in the control group received usual care. The basic characteristics, health beliefs, and health literacy were collected, and blood pressure was measured before and after the intervention, respectively. The difference-in-difference model was used to analyze the change of blood pressure and the influencing factors between two groups before and after the intervention. Results: A total of 134 patients in the intervention group and 129 patients in the control group completed the study. After adjusting for the age, gender, family income, medical insurance, chronic diseases and family history, the score of perceived barriers was increased by 1.65 (P=0.016), and perceived seriousness was decreased by 0.73 (P=0.018). The systolic blood pressure of patients was decreased by 7.37 mmHg (1 mmHg=0.133 kPa, P=0.001) and diastolic blood pressure was decreased by 4.07 mmHg (P=0.014), respectively. The β (95%CI) values were -7.37 (-11.88,-2.86) and -4.07 (-7.30, -0.84). The perceived susceptibility and self-efficacy had a significant influence on the blood pressure of patients (P<0.05). Conclusion: Health belief model-based health education intervention could significantly improve the blood pressure control of patients with hypertension in the community settings.