Using behaviour change theory to inform an innovative digital recruitment strategy in a mental health research setting.
Recruitment in mental health research is challenging, as some disorders such as depression or schizophrenia may involve vulnerable participants that lack motivation as part of their illness. A mental health diagnosis can be stigmatising, so privacy and access to hospital-based patient cohorts is carefully controlled. Our team describe a pragmatic portal recruitment process for facilitating timely recruitment into multiple research studies focusing on mental health. Three factors were analysed; evaluating the success and impact of this novel recruitment process; identification of patterns in recruitment to better target participants; and provision of metrics of the different media formats engaged. A web-based recruitment portal was developed by the research team in collaboration with the South Australian Health and Medical Research Institute (SAHMRI) Consumer & Carer Research Advisory Group. A comprehensive marketing campaign was then undertaken to direct participants towards the portal. Recruitment insights from the dates and times of registration across a two-year period is provided. In total, 933 potential participants registered with the recruitment portal across a two-year period at a cost of approximately $10,000. The advertisement campaign linked to the portal page enabled 506 participants to register in just one week. The area of research was self-selected by the potential participants, then eligibility was followed up with telephone and face to face interviews. Of the total 933 people who registered 706 (76%) expressed an interest in the target clinical depression study, 119 (13%) opted to be clinical controls, and the remainder chose one of the alternative studies. 240 (26%) of those who registered were excluded through telephone interviews because they fell outside of the strict eligibility criterion. We learnt that 77% (n = 723/933) of participants were recruited within seven days of promotional events, providing an interesting pattern of recruitment that may assist future recruitment design.


Access to End-of Life Parkinson's Disease Patients Through Patient-Centered Integrated Healthcare.
Background: Palliative care in Parkinson's Disease (PD) patients considerably differs from palliative care in oncology patients. Integrated care models are a concept to support patients and improve management of PD symptoms. However, it is not known if the access to PD patients at the end of life can be achieved through integrated care models. Aim: To analyze an integrated model of care for PD patients with the aim to identify if this integrated model of care has access to PD patients at the end of life. Material and Methods: The Cologne Parkinson's network was designed as a randomized, controlled prospective clinical trial in order to increase quality of life of PD patients. This innovative model of care integrated a neurologist in private practice, a movement disorder specialist of the University Hospital and a PD nurse. Mortality rates of PD patients during the study period of 6 months were registered and compared with mortality rates of the general population of Germany according to the Federal Statistical Office of Germany. The retrospective post-hoc analysis was conducted after completion of the initial study at the University Hospital and neurologists' practices in the greater area of Cologne, Germany. Eligible patients had a diagnosis of idiopathic PD and were aged 25-85 years. Results: Parkinson's Disease patients in this trial had an even slightly lower mortality rate as the general population (1.66 v. 2.1%). These results are contradictory and speak for a substantial proportion of late-stage disease patients, who have not been adequately included in this study or have been better treated within this trial. The mean disease duration of patients in this study was around 6 years which resembles the lower range of the mean disease duration at death of PD patients in general. Conclusions: The results of our post-hoc analysis show, that accessing PD patients in the last phase of their disease is extremely difficult and nearly fails in spite of an integrated care approach. Reasons for poor access and loss of follow-up at the end of life have to be identified and care models for PD patients until the end of life should be developed urgently.


Estrogen sulfotransferase regulates body fat and glucose homeostasis in female mice.
Estrogen regulates fat mass and distribution and glucose metabolism. We have previously found that estrogen sulfotransferase (EST), which inactivates estrogen through sulfoconjugation, was highly expressed in adipose tissue of male mice and induced by testosterone in female mice. To determine whether inhibition of estrogen in female adipose tissue affects adipose mass and metabolism, we generated transgenic mice expressing EST via the aP2 promoter. As expected, EST expression was increased in adipose tissue as well as macrophages. Parametrial and subcutaneous inguinal adipose mass and adipocyte size were significantly reduced in EST transgenic mice, but there was no change in retroperitoneal or brown adipose tissue. EST overexpression decreased the differentiation of primary adipocytes, and this was associated with reductions in the expression of peroxisome proliferator-activated receptor-γ, fatty acid synthase, hormone-sensitive lipase, lipoprotein lipase, and leptin. Serum leptin levels were significantly lower in EST transgenic mice, whereas total and high-molecular-weight adiponectin levels were not different in transgenic and wild-type mice. Glucose uptake was blunted in parametrial adipose tissue during hyperinsulinemic-euglycemic clamp in EST transgenic mice. In contrast, hepatic insulin sensitivity was improved but muscle insulin sensitivity did not change in EST transgenic mice. These results reveal novel effects of EST on adipose tissue and glucose homeostasis in female mice.


Wayfinding for people with dementia: a review of the role of architectural design.
This paper provides an overview of the available literature on architectural wayfinding design for people with dementia in nursing homes. The results were to be summarized and substantiated through an interdisciplinary interpretation, taking into account changes in the orientation process of people with dementia. Spatial disorientation and declining wayfinding abilities are among the early symptoms of dementia, limiting a person's ability to perform activities of daily living (ADLs) independently and ultimately, perhaps leading to institutionalization. A prerequisite to maintaining residents' quality of life in a nursing home is their ability to orient themselves within their new environment. The available literature on wayfinding design for people with dementia in nursing homes was reviewed. Two aspects of interventions for residents' wayfinding abilities were identified: the design of the floor plan typology and environmental cues. The design of the physical environment plays a major role in supporting the wayfinding abilities of people with dementia. The floor plan design of a nursing home in particular has a significant influence on residents' spatial orientation and wayfinding. Additional interventions such as signage, furnishing, lighting, and colors are additional supporting features but they cannot compensate for an adverse architectural design. For the creation of a supportive, dementia-friendly environment, both aspects of architectural design must be considered. Design guidelines to support the wayfinding abilities of people with dementia were developed to synthesize both.


The multidimensional role of the Wnt/β-catenin signaling pathway in human malignancies.
Several signaling pathways have been identified as important for developmental processes. One of such important cascades is the Wnt/β-catenin signaling pathway, which can regulate various physiological processes such as embryonic development, tissue homeostasis, and tissue regeneration; while its dysregulation is implicated in several pathological conditions especially cancers. Interestingly, deregulation of the Wnt/β-catenin pathway has been reported to be closely associated with initiation, progression, metastasis, maintenance of cancer stem cells, and drug resistance in human malignancies. Moreover, several genetic and experimental models support the inhibition of the Wnt/β-catenin pathway to answer the key issues related to cancer development. The present review focuses on different regulators of Wnt pathway and how distinct mutations, deletion, and amplification in these regulators could possibly play an essential role in the development of several cancers such as colorectal, melanoma, breast, lung, and leukemia. Additionally, we also provide insights on diverse classes of inhibitors of the Wnt/β-catenin pathway, which are currently in preclinical and clinical trial against different cancers.


Degradation of nitrobenzene by a Pseudomonas pseudoalcaligenes.
A Pseudomonas pseudoalcaligenes able to use nitrobenzene as the sole source of carbon, nitrogen, and energy was isolated from soil and groundwater contaminated with nitrobenzene. The range of aromatic substrates able to support growth was limited to nitrobenzene, hydroxylaminobenzene, and 2-aminophenol. Washed suspensions of nitrobenzene-grown cells removed nitrobenzene from culture fluids with the concomitant release of ammonia. Nitrobenzene, nitrosobenzene, hydroxylaminobenzene, and 2-aminophenol stimulated oxygen uptake in resting cells and in extracts of nitrobenzene-grown cells. Under aerobic and anaerobic conditions, crude extracts converted nitrobenzene to 2-aminophenol with oxidation of 2 mol of NADPH. Ring cleavage, which required ferrous iron, produced a transient yellow product with a maximum A380. In the presence of NAD, the product disappeared and NADH was produced. In the absence of NAD, the ring fission product was spontaneously converted to picolinic acid, which was not further metabolized. These results indicate that the catabolic pathway involves the reduction of nitrobenzene to nitrosobenzene and then to hydroxylaminobenzene; each of these steps requires 1 mol of NADPH. An enzyme-mediated Bamberger-like rearrangement converts hydroxylaminobenzene to 2-aminophenol, which then undergoes meta ring cleavage to 2-aminomuconic semialdehyde. The mechanism for release of ammonia and subsequent metabolism are under investigation.


Nonstrangulated colonic displacement in horses.
Nonstrangulated colonic displacement was diagnosed by exploratory celiotomy in 32 horses with acute abdominal pain. Clinical signs progressed slowly and included evidence of mild to moderate abdominal pain, good cardiovascular status, reduced intestinal sounds, and normal peritoneal fluid, and resembled those of colonic impaction. In most horses, rectal palpation supported a diagnosis of colonic obstruction but not a diagnosis of colonic impaction.


Determinants of human papillomavirus vaccine hesitancy among Lebanese parents.
Human papillomavirus (HPV) is the most common sexually transmitted infection. HPV is responsible for cancer of cervix uteri. Despite its safety and immunogenicity, HPV vaccine hesitancy is one of the most challenging topics that pediatricians face. We aimed to describe the impact of knowledge, attitude, and practice towards vaccines in general, on practice related to HPV vaccination in Lebanon. A questionnaire addressed to parents of students (3-18 years of age) was distributed in 2 public and 2 private schools randomly selected from the greater Beirut area during the school year 2017-2018. Questionnaires covered knowledge, attitude, and practices of vaccination in general and HPV vaccine in particular. Out of 400 distributed questionnaires, 306 (76.5%) were returned. Of the 185 parents aware of HPV vaccine, 60% hadn't given or were not planning to give the HPV vaccine to their children. Of parents not in favor of HPV vaccine, 7.5 thought that vaccines aren't necessary versus none among those in favor of HPV vaccine(p = 0.02). Thirteen percent of those not in favor of HPV vaccine thought that vaccines are not safe versus 2.7% in the group in favor (p = 0.02). An effect of gender on vaccine acceptance was noted: mothers vs fathers and daughters vs sons. Lack of recommendation by pediatricians and the thought that too little is known about the vaccine were the most selected reasons for parents not wanting to vaccinate their children against HPV, whereas cost and religious and cultural beliefs seemed to have no impact. Most parents in our study did not vaccinate or weren't willing to vaccinate their children against HPV even when they were in favor of vaccines in general. Physician recommendation was shown to be one of the most important predictors of vaccination. Effort should be put into educating parents about the importance of the vaccine and its well-established safety and efficacy regardless of gender. Lebanese physicians should also be educated and empowered to recommend HPV vaccine more strongly and consistently.


PTCA update: is your patient now a candidate? Even complex multivessel lesions may succumb to balloon dilation.
Indications for PTCA continue to grow. In complex multivessel lesions, PTCA now has high primary success and low complication rates. Dilation of chronic total occlusions is less successful than in subtotal occlusions but may relieve angina in some patients. Occluded saphenous vein grafts can be dilated and long-term patency achieved--particularly in grafts implanted for less than 36 months. Restenosis remains a major drawback; antithrombotic therapy (with heparin during PTCA and aspirin thereafter) is recommended. PTCA is a useful adjunct in acute myocardial infarction when thrombolytic therapy fails or is contraindicated, or when significant luminal narrowing remains after thrombolysis. Investigational devices--atherectomy catheters, lasers or laser balloons, and intracoronary stents--may further expand the role of PTCA.


Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study.
Background: Spontaneous simultaneous multiple intra-cerebral hemorrhages (SMICHs) and its occurrences in different territories of arterial disposition has been viewed as uncommon clinical occurrences, since the pathophysiological and predisposing factors as mechanisms aren't vividly defined. This research primarily aims for demographic stratification and dichotomization pertaining to risk factors, etiological classifications, anatomical distributions and outcome analysis by focusing on management strategies and pertinent stroke care. Methods: 40 patients presenting to the College of Medical Sciences, Chitwan, Nepal in the last two years were included in the study. The patients with two or more spontaneous SMICHs with affected arterial territories with similar tomographic density based profiling were chosen as samples. Regression analysis was chosen to test three hypotheses. Results: Among our study cohorts, cortical and cortical territory (60%) was the major anatomical patterns of involvement. A conservative approach was undertaken in nine patients (22.5%), whereas surgical intervention was needed in five others (12.5%). A total of 14(35%) patients leaving against medical advice and a further seven (17.5%) patients were referred for adjuvant oncologic care. Mortality was observed among five (12.5%) patients. Hypertension was seen as a significant variable in its pathogenesis. Male patients were more affected. Age groups comprising 36-45years and 56-65 years were involved in 32.5% and 30% of cases respectively. Conclusion: This study proves the need for a national stroke data bank pertaining to spontaneous SMICHs. This will help foster effective patient education during preoperative counseling; as well as formatting a management algorithm combating them.


Spontaneous Biliary Perforations: An Uncommon yet Important Entity in Children.
Spontaneous or idiopathic biliary perforations are an infrequently encountered but an important cause of surgical jaundice in paediatric patients and one of the most common causes of surgical jaundice in infancy. A pre-operative diagnosis with a clinical history and physical findings may not be possible in most of the cases. The exact cause of the perforation remains unclear and the diagnosis is made at the time of laparotomy for an acute abdomen. An early, efficient and an effective surgical management is associated with a good prognosis; however, a delay in the correct diagnosis or an inappropriate management may result in bacterial contamination of the biliary ascites, with an unfavourable outcome. The relative rarity of this condition is reflected by the very few case reports, limited case studies and scarcity of published literature.


Feasibility and efficacy of endoscopic reintervention after covered metal stent placement for EUS-guided hepaticogastrostomy: A multicenter experience.
Although the use of a long metal stent is favored for EUS-guided hepaticogastrostomy (EUS-HGS) for the relief of malignant biliary obstruction (MBO), endoscopic reintervention (E-RI) at the time of recurrent biliary obstruction (RBO) is challenging due to a long intragastric portion. This study evaluated the feasibility and safety of E-RI after a long partially covered metal stent (L-PCMS) placement during EUS-HGS. We performed a multicenter retrospective study between January 2015 and December 2019 examining patients with MBO who underwent E-RI for RBO through the EUS-HGS route after the L-PCMS placement. Technical and clinical success rates, details of E-RI, adverse events (AEs), stent patency, and survival time were evaluated. Thirty-three patients at eight referral centers in Japan who underwent E-RI through the EUS-HGS route were enrolled. The location of MBO was distal in 54.5%. The median intragastric length of the L-PCMS was 5 cm. As the first E-RI attempt, E-RI via the distal end of the existing L-PCMS was successful in 60.6%. The overall technical and clinical success rates of E-RI were 100% and 81.8%, respectively. Liver abscess was noted in one patient. A proximal biliary stricture was associated with the clinical ineffectiveness of E-RI in multivariable analysis (odds ratio, 12.5, P = 0.04). The median survival and stent patency duration after E-RI were 140 and 394 days, respectively. Our study findings suggest that E-RI for RBO after EUS-HGS with a L-PCMS is technically feasible and clinically effective, without any severe AEs, especially for patients with distal MBO.


A single tube PCR assay for simultaneous amplification of HSV-1/-2, VZV, CMV, HHV-6A/-6B, and EBV DNAs in cerebrospinal fluid from patients with virus-related neurological diseases.
Cerebrospinal fluid (CSF) specimens from 27 patients with encephalitis, meningitis, and other neurological diseases were studied for the presence of herpes simplex virus types 1 and 2 (HSV-1/-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), human herpesviruses 6A and 6B (HHV-6A/-6B) and Epstein-Barr virus (EBV) DNA using the polymerase chain reaction (PCR) method. The DNAs were amplified using two sets of consensus primer pairs in a single tube, bringing simultaneous amplification of the herpesviruses. The PCR products were analyzed by agarose gel electrophoresis, and Southern blot hybridization with virus-type specific probes, thus allowing discrimination between the different types of herpesviruses to be made. Each virus-specific probe was highly specific for identifying the PCR product. Thirty CSF specimens from 13 patients with encephalitis and 10 specimens from 10 patients with meningitis, respectively, were examined using this method. Eight patients with encephalitis and six with meningitis were positive for different herpesviruses, including patients with coinfections (HSV-1/-2 and VZV, VZV and CMV). Among four CSF specimens from four patients with other neurological disorders, dual amplification of CMV and EBV was present. Since identification of the types of herpesviruses in this system requires a very small amount of CSF, and is completed with one PCR, it is useful for routine diagnosis of herpesvirus infections in diagnostic laboratories. The viruses responsible for central nervous system infection are easily detected with various coinfection and serial patterns of herpesviruses, by this consensus primer-based PCR method. This may give an insight into the relationship between virus-related neurological diseases (VRNDS) and herpesvirus infections.


High risks adverse events associated with usage of aspirin in chronic obstructive pulmonary disease.
Despite potential benefits and widespread prescription of aspirin among chronic obstructive pulmonary disease (COPD) patients, limited research has investigated its adverse effects in COPD population. We conducted a retrospective analysis of adverse drug events (ADEs) reported in the US Food and Drug Administration Adverse Event Reporting System (FAERS) between Q1 2013 and Q2 2022. COPD patients were categorized into two groups based on aspirin use. ADEs related to aspirin use were identified using combined reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC) methods. A total of 56,660 ADEs reports associated with COPD patients were included in the study. Among these reports, 144 adverse events (AEs) were linked to aspirin use in COPD patients, including fatigue (4.12%), diarrhea (3.13%), dyspnea exertional (2.03%), rhinorrhea (1.99%), weight increased (1.89%) and vomiting (1.84%), muscle spasms (1.79%), cardiac disorder (1.74%), heart rate increased (1.69%) and peripheral swelling (1.59%). Subgroup analysis indicates that age and gender might affect the AEs frequency in COPD patients using aspirin. Our findings identify ten most frequently reported ADEs associated with aspirin use in COPD patients, thus offer valuable insights into the AEs of aspirin for safer clinical utilization in COPD management.


A minimalistic 3D pharmacophore model for cyclopentapeptide CXCR4 antagonists.
Because of its involvement in HIV entry, the chemokine receptor CXCR4 is an attractive target for antiretroviral drugs. Despite the large number of CXCR4 inhibitors studied, the 3D pharmacophore for binding to CXCR4 remains elusive, mainly as a result of conformational flexibility inherent in the identified ligands. In the present study, an exhaustive systematic exploration of the conformational space for a series of analogs of FC131, a cyclopentapeptide CXCR4 antagonist, has been performed. By comparing the resulting low-energy conformations using different sets of atoms, specific conformational features common only to the high/medium affinity compounds were identified. These features included the spatial arrangement of three pharmacophoric side chains as well as the orientation of a specific backbone amide bond. Together these features represent a minimalistic 3D pharmacophore model for binding of the cyclopentapeptide antagonists to CXCR4. The model enables rationalization of the experimental affinity data for this class of compounds as well as for the peptidomimetic KRH-1636.


The Cannabis Use Problems Identification Test (CUPIT): development, reliability, concurrent and predictive validity among adolescents and adults.
To describe the empirical construction and initial validation of the Cannabis Use Problems Identification Test (CUPIT), a brief self-report screening instrument for detection of currently and potentially problematic cannabis use. In a three-phase prospective design an item pool of candidate questions was generated from a literature review and extensive expert consultation. The CUPIT internal structure, cross-sectional and longitudinal psychometric properties were then systematically tested among heterogeneous past-year users. Volunteer participants were 212 high-risk adolescents (n = 138) and adults (n = 74) aged 13-61 years from multiple community settings. The comprehensive assessment battery included several established measures of cannabis-related pathology for CUPIT validation, with DSM-IV/ICD-10 diagnoses of cannabis use disorders as criterion standard. Sixteen items loading highly on two subscales derived from principal components analysis exhibited good to excellent test-retest (0.89-0.99) and internal consistency reliability (0.92, 0.83), and highly significant ability to discriminate diagnostic subgroups along the severity continuum (non-problematic, risky, problematic use). Twelve months later, baseline CUPIT scores demonstrated highly significant longitudinal predictive utility for respondents' follow-up diagnostic group membership. Receiver operating characteristic (ROC) analysis identified a CUPIT score of 12 to be the optimal cut-point for maximizing sensitivity for both currently diagnosable cannabis use disorder and those at risk of meeting diagnostic criteria in the following 12 months. The CUPIT is a brief cannabis screener that is reliable, valid and acceptable for use across diverse community settings and consumers of all ages. The CUPIT has clear potential to assist with achievement of public health goals to reduce cannabis-related harms in the community.


Down-regulation of RalBP1 expression reduces seizure threshold and synaptic inhibition in mice.
Idiopathic epilepsy is characterized by seizures without a clear etiology and is believed to have a strong genetic component but exhibits a complex inheritance pattern. Genetic factors seem to confer a low seizure threshold to susceptible individuals and thereby enhance epileptogenesis. However, the identity of susceptibility genes and the mechanisms regulating seizure threshold are still poorly understood. Here, we describe that reduced expression of RalBP1, a downstream effector of the small GTPases RalA and RalB, lowers the seizure threshold in mice. The intraperitoneal injection of the chemoconvulsant pentylenetetrazol induced more severe seizures in RalBP1 hypomorphic mice than in their wild-type littermates. The reduction of RalBP1 in the brain has no effect on neuronal excitability, but does decrease the inhibitory synaptic transmission onto CA1 pyramidal neurons. This impaired synaptic inhibition was associated with the loss of GABAergic interneurons in the CA1 subfield of the hippocampus. The present study identifies RalBP1 as a gene regulating the seizure threshold in mice and provides direct evidence for the role of RalBP1 in synaptic inhibition in vivo.


Fluid status and fluid responsiveness.
Fluid boluses are a key element of hemodynamic resuscitation, but overuse of fluids also can be harmful. It is thus important to understand how fluids actually improve clinical problems and how one can predict fluid responsiveness. It is also important to understand potential limitations of fluid therapy. Currently there is a lot of attention being paid to the assessment of fluid responsiveness, but there is a lack of studies evaluating indications for fluid treatment and the potential harm from excess fluid use. This review emphasizes the physiological factors that determine the response to fluids, the limitations of these responses, and the predictors of fluid responsiveness. A key principle is that fluid resuscitation improves clinical indicators by increasing cardiac output, and if the volume infusion does not increase cardiac output there will be no benefit. Assessment of changes in cardiac output, either directly or indirectly, is a key component of managing fluid therapy. Avoiding harm with the use of fluids requires understanding what is physiologically possible.


Prostaglandins and acid peptic disease.
Naturally occurring PGs are considered important in maintaining the integrity of the gastrointestinal mucosa. Evidence indicates that synthetic analogs of PGs heal gastroduodenal ulcers in doses that suppress gastric acid. No consistent benefit of this class of drugs compared with already available conventional agents has been demonstrated in the treatment of duodenal or gastric ulcer disease. Nonantisecretory doses of PGs, by maintaining mucosal integrity and preventing ulcer recurrence, may eventually have a role in the treatment of ulcer disease. The potential of PGs to prevent gastroduodenal mucosal injury caused by nonsteroidal antiinflammatory drugs, alcohol, aspirin, and stress, if supported by the results of ongoing clinical trials, may be a major therapeutic advance for the treatment of peptic ulcer and related acid peptic diseases.


Feed-derived iodine overrides environmental contribution to cow milk.
Diets worldwide are deficient in iodine, leading to a range of undesirable health effects at the population level. Dairy products are a primary source of iodine in diets for those populations in which iodized salt is not systematically used or available. However, the flows of iodine through dairy agroecosystems are not well understood. The aim of this research was to investigate iodine flows though the dairy agroecosystem, including the influence of atmospheric depositional inputs, environmental variables, season, husbandry, and diet. Three farm-based sampling campaigns were carried out in this investigation, with milk, soil, silage, grass, and feed iodine determined by inductively coupled plasma mass spectroscopy, and nonparametric statistical analysis tests were conducted on data sets obtained. Natural iodine inputs into the environment are dominated by atmospheric deposition, which mainly from sea spray, and thus the location of farms relative to the coast and prevailing wind direction. Herbage and silage produced from grass-based systems strongly correlated with soil iodine, yet there was a strong disconnect between soil, forage, and feed and the milk that results. This was due to the levels of iodine in supplemental feeds being approximately 10-fold higher than those in forage-derived feeds. The practice of feed supplementation, accentuated by summer housing of cows, led to elevated milk iodine.


Guidelines for Bystander First Aid 2016.
Cardiac life support is a form of first aid for cardiac emergencies. However, research and evidence in this field is lacking compared with other forms of first aid. Having identified the common emergencies that are encountered in the hospital, based on the available evidence, we have put together what could be an evidence-based approach to the first aid management of some of these common emergencies, viz. breathlessness, chest pain, allergies, stroke, heat injury, poisoning, unconsciousness, seizures, and trauma situations such as bleeding, wounds, contusions, head injury, burns and fractures. Educating the public is the key to developing a first responder bystander. These guidelines could become the basis for training of the public.


Mediator protein mutations that selectively abolish activated transcription.
Deletion of any one of three subunits of the yeast Mediator of transcriptional regulation, Med2, Pgd1 (Hrs1), and Sin4, abolished activation by Gal4-VP16 in vitro. By contrast, other Mediator functions, stimulation of basal transcription and of TFIIH kinase activity, were unaffected. A different but overlapping Mediator subunit dependence was found for activation by Gcn4. The genetic requirements for activation in vivo were closely coincident with those in vitro. A whole genome expression profile of a Deltamed2 strain showed diminished transcription of a subset of inducible genes but only minor effects on "basal" transcription. These findings make an important connection between transcriptional activation in vitro and in vivo, and identify Mediator as a "global" transcriptional coactivator.


Uric acid mediated the relationship between obesity and hypertension in children and adolescents: A population‑based cohort study.
Obesity and hyperuricemia (HUA) often coexist and have been widely accepted as risk factors for hypertension, but the role of uric acid (UA) in the relationship between obesity and hypertension remains unknown in children and adolescents. A total of 7525 subjects aged 6-16 years were from the School-based Cardiovascular and Bone Health Promotion Program (SCVBH) at baseline (2017) and followed up in 2019. Multivariable logistic regression with interaction terms, cross-lagged panel analysis, and causal mediation model were applied to delineate the joint impact of obesity and HUA on hypertension, including the interaction effect, the temporal association, and the mediating effect of UA in the relationship between obesity and hypertension. There were 10.8 % of the participants with normotension at baseline developed hypertension after two years of follow-up. Cross-lagged panel analysis showed that the two-time point association was significant only from baseline BMI to follow-up UA (β1 = 0.302, P < 0.001), but not from baseline UA to follow-up BMI (β2 = 0.002, P = 0.745). Multivariable logistic regression showed that both obesity and HUA increased the risk of hypertension, but no interaction effect between HUA and obesity. The causal mediation analysis found that UA partially mediated the association between BMI and SBP (mediate proportion: 20.3 %, 95 % CI: 17.4-22.9 %) or DBP (mediate proportion: 11.9 %, 95 % CI: 3.9-18.2 %). The results were consistent in the analysis of systolic hypertension rather than diastolic hypertension. It is mediating effect that UA played in the progress from obesity to hypertension, particularly systolic hypertension in children and adolescents.


Role of Effective Range in the Bulk Viscosity of Resonantly Interacting s- and p-Wave Fermi Gases.
We investigate the role of the effective range on the bulk viscosity of s- and p-wave Fermi gases. At resonance, the presence of the effective range breaks the scale invariance of the system, and hence results in a nonzero bulk viscosity. However, we show that the effective range plays a very different role in the two cases. In the s-wave case, the role of the effective range is perturbative, and its contribution to the bulk viscosity vanishes in the limit of zero effective range. On the other hand, the effective range in p-wave Fermi gases leads to a nonzero bulk viscosity, even in the zero-range limit. We employ a general diagrammatic approach to compute the bulk viscosity spectral function that includes the effects of the effective range. We then compute the analytic expressions for the spectral function in the high temperature limit, at low and high frequencies. We also derive the sum rules for the bulk viscosity spectral function for both s- and p-wave gases.


In vivo intra-articular negative pressure wound therapy effect on cartilage in a goat model.
This prospective, randomized, blinded pilot study determined if a difference was present in the histology and apoptotic rate of articular cartilage after application of a negative pressure wound therapy (NPWT) device to an uninjured joint surface compared to a control side using Capra hircus goats. The goats were euthanized at 3 or 7 days after surgery. The en bloc joint resection was divided into medial (direct sponge contact) and lateral compartments (no sponge contact; indirect NPWT). In the necropsied cartilage and menisci, there were no gross or histologic/morphometric differences identified by a blinded veterinary pathologist. The percentages of apoptotic and necrotic chondrocytes based on flow cytometry were not statistically different. This study demonstrated that there were no observable deleterious effects to uninjured cartilage from direct or indirect intra-articular NPWT placement. These data suggest that NPWT may be placed safely in an intra-articular position for up to 7 days. Further studies in humans are warranted.


A non-experimental study of oral anticoagulation therapy initiation before and after national patient safety goals.
The Joint Commission revised its National Patient Safety Goals (NPSGs) to include oral anticoagulation therapy (OAT) in 2008. We sought to examine the effect of including OAT in The Joint Commission's NPSGs on historically low rates of OAT initiation for individuals with incident atrial fibrillation (AF). Southeastern state in the USA. North Carolina State Health Plan claims data from 944 500 individuals enrolled between 1 January 2006 and 31 December 2010, supplemented with data from the Area Resource File and Online Survey, Certification and Reporting data network. We evaluated OAT initiation before and after the 2008 NPSGs revisions in a retrospective cohort new user design with an AF intervention group and two control groups: a positive control-patients estimated to be at very high risk of thromboembolism (mechanical heart valve and pulmonary embolism); and a negative control-patients with very low perceived risk of thromboembolism (paroxysmal AF). We developed multivariable models using a difference-in-difference parameterisation. Effects were estimated with generalised estimating equations. OAT initiation, a binary outcome defined as having a prescription drug claim for warfarin within 30 days of the index claim. OAT initiation was low (26.8%) for eligible individuals with incident AF in 2006-2008 but increased after NPSGs implementation (31.7%, p=0.022). OAT initiation was high but decreased in the positive control group (67.5% vs 62.0%, p=0.003). Multivariate analysis resulted in a relative 11% (95% CI (4% to 18%), p<0.01) increase in OAT initiation for incident AF patients. We document a substantial increase in guideline concordant OAT initiation in incident AF after the establishment of NPSGs, suggesting that regulatory healthcare agency initiatives can influence clinical practice.


SGK1 mediates the hypotonic protective effect against H2O2-induced apoptosis of rat basilar artery smooth muscle cells by inhibiting the FOXO3a/Bim signaling pathway.
Serum- and glucocorticoid-inducible kinease-1 (SGK1) is a serine/threonine kinase regulated by hypotonic stimuli, which is involved in regulation of cell cycle and apoptosis. Our previous study shows that activation of volume-regulated Cl- channels (VRCCs) protects rat basilar artery smooth muscle cells (BASMCs) against hydrogen peroxide (H2O2)-induced apoptosis. In the present study, we investigated whether SGK1 was involved in the protective effect of VRCCs in BASMCs. We showed that hypotonic challenge significantly reduced H2O2-induced apoptosis, and increased SGK1 phosphorylation, but did not affect SGK1 protein expression. The protective effect of hypotonic challenge against H2O2-induced apoptosis was mediated through inhibiting mitochondria-dependent apoptotic pathway, evidenced by increased Bcl-2/Bax ratio, stabilizing mitochondrial membrane potential (MMP), decreased cytochrome c release from the mitochondria to the cytoplasm, and inhibition of the activation of caspase-9 and caspase-3. These protective effects of hypotonic challenge against H2O2-induced apoptosis was diminished and enhanced, respectively, by SGK1 knockdown and overexpression. We further revealed that SGK1 activation significantly increased forkhead box O3a (FOXO3a) phosphorylation, and then inhibited the translocation of FOXO3a into nucleus and the subsequent expression of Bcl-2 interacting mediator of cell death (Bim). In conclusion, SGK1 mediates the protective effect of VRCCs against H2O2-induced apoptosis in BASMCs via inhibiting FOXO3a/Bim signaling pathway. Our results provide compelling evidences that SGK1 is a critical link between VRCCs and apoptosis, and shed a new light on the treatment of vascular apoptosis-associated diseases, such as vascular remodeling, angiogenesis, and atherosclerosis.


Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer.
Angiogenesis is essential for both primary and metastatic tumor growth. Tumor blood vessel formation is complex and regulated by many factors. Ovarian carcinomas have a poor prognosis, often associated with multifocal intraperitoneal dissemination accompanied by intense neovascularization. To examine tumor angiogenesis in the tumor microenvironment, we studied malignant ascites of patients with untreated ovarian carcinoma. We observed high numbers of plasmacytoid dendritic cells (PDCs) and significant stromal-derived factor (CXCL-12/SDF)-1 in their malignant ascites, attracting PDCs into the tumor environment. We now show that tumor-associated PDCs induced angiogenesis in vivo through production of tumor necrosis factor alpha and interleukin 8. By contrast, myeloid dendritic cells (MDCs) were absent from malignant ascites. MDCs derived in vitro suppressed angiogenesis in vivo through production of interleukin 12. Thus, the tumor may attract PDCs to augment angiogenesis while excluding MDCs to prevent angiogenesis inhibition, demonstrating a novel mechanism for modulating tumor neovascularization. Because dendritic cells (DCs) have long been known to affect tumor immunity, our data also implicate DCs in regulation of tumor neoangiogenesis, suggesting a novel role of DCs in tumor pathology.


Effect of acute exercise on low molecular weight thiols in plasma.
An important defence against free radicals is represented by plasma low molecular weight (LMW) thiols that compose a dynamic system of reduced and oxidized forms able to act as a buffer redox system. This study examined the effect of an acute graded exercise bout on LMW thiols in 16 young subjects (six sedentaries and 10 athletes). Blood analysis was performed before and immediately after the exercise and total and reduced thiols were measured in order to evaluate the thiol redox status. Findings suggested that the exercise test proposed was not enough to imbalance the redox status of all LMW thiols. However, when the redox status was evaluated for each thiol, it was evident that homocysteine (Hcy) redox status was significantly different after physical activity. In particular, we found a lower level of reduced Hcy after the exercise test both in sedentaries and in athletes. We concluded that duration and intensity of the proposed exercise were not enough to promote a reactive oxygen species production able to imbalance the redox thiols status and that the lowering of the reduced Hcy form may be due to the effect produced during the effort on the synthesis and/or removal processes of Hcy.


Using microbiological data to improve the use of antibiotics for respiratory tract infections: A protocol for an individual patient data meta-analysis.
Resistance to antibiotics is rising and threatens future antibiotic effectiveness. 'Antibiotic targeting' ensures patients who may benefit from antibiotics receive them, while being safely withheld from those who may not. Point-of-care tests may assist with antibiotic targeting by allowing primary care clinicians to establish if symptomatic patients have a viral, bacterial, combined, or no infection. However, because organisms can be harmlessly carried, it is important to know if the presence of the virus/bacteria is related to the illness for which the patient is being assessed. One way to do this is to look for associations with more severe/prolonged symptoms and test results. Previous research to answer this question for acute respiratory tract infections has given conflicting results with studies has not having enough participants to provide statistical confidence. To undertake a synthesis of IPD from both randomised controlled trials (RCTs) and observational cohort studies of respiratory tract infections (RTI) in order to investigate the prognostic value of microbiological data in addition to, or instead of, clinical symptoms and signs. A systematic search of Cochrane Central Register of Controlled Trials, Ovid Medline and Ovid Embase will be carried out for studies of acute respiratory infection in primary care settings. The outcomes of interest are duration of disease, severity of disease, repeated consultation with new/worsening illness and complications requiring hospitalisation. Authors of eligible studies will be contacted to provide anonymised individual participant data. The data will be harmonised and aggregated. Multilevel regression analysis will be conducted to determine key outcome measures for different potential pathogens and whether these offer any additional information on prognosis beyond clinical symptoms and signs. PROSPERO Registration number: CRD42023376769.


Engineering of molybdenum-cofactor-dependent nitrate assimilation in Yarrowia lipolytica.
Engineering a new metabolic function in a microbial host can be limited by the availability of the relevant cofactor. For instance, in Yarrowia lipolytica, the expression of a functional nitrate reductase is precluded by the absence of molybdenum cofactor (Moco) biosynthesis. In this study, we demonstrated that the Ogataea parapolymorpha Moco biosynthesis pathway combined with the expression of a high affinity molybdate transporter could lead to the synthesis of Moco in Y. lipolytica. The functionality of Moco was demonstrated by expression of an active Moco-dependent nitrate assimilation pathway from the same yeast donor, O. parapolymorpha. In addition to 11 heterologous genes, fast growth on nitrate required adaptive laboratory evolution which, resulted in up to 100-fold increase in nitrate reductase activity and in up to 4-fold increase in growth rate, reaching 0.13h-1. Genome sequencing of evolved isolates revealed the presence of a limited number of non-synonymous mutations or small insertions/deletions in annotated coding sequences. This study that builds up on a previous work establishing Moco synthesis in S. cerevisiae demonstrated that the Moco pathway could be successfully transferred in very distant yeasts and, potentially, to any other genera, which would enable the expression of new enzyme families and expand the nutrient range used by industrial yeasts.


Vat Photopolymerization of Reinforced Styrene-Butadiene Elastomers: A Degradable Scaffold Approach.
Vat photopolymerization (VP) is a high-throughput additive manufacturing modality that also offers exceptional feature resolution and surface finish; however, the process is constrained by a limited selection of processable photocurable resins. Low resin viscosity (<10 Pa·s) is one of the most stringent process-induced constraints on resin processability, which in turn limits the mechanical performance of printed resin systems. Recently, the authors created a VP-processable photosensitive latex resin, where compartmentalization of the high molecular weight polymer chains into discrete particles resulted in the decoupling of viscosity from molecular weight. However, the monomers used to form the hydrogel green body resulted in decreased ultimate material properties due to the high cross-link density. Herein, we report a novel scaffold that allows for facile UV-based AM and simultaneously enhances the final part's material properties. This is achieved with a chemically labile acetal-containing cross-linker in conjunction with N-vinylpyrrolidone, which forms a glassy polymer after photocuring. Subsequent reactive extraction cleaves the cross-links and liberates the glassy polymer, which provides mechanical reinforcement of the geometrically complex VP-printed elastomer. With only a 0.1 wt % loading of photoinitiator, G'/G'' crossover times of less than 1 s and green body plateau moduli nearing 105 Pa are obtained. In addition, removal of the hydrophilic and thermally labile scaffold results in decreased water uptake and increased thermal stability of the final printed part. Ultimate strain and stress values of over 650% and 8.5 MPa, respectively, are achieved, setting a new benchmark for styrene-butadiene VP elastomers.


Bulimia nervosa: the role of the family physician.
Bulimia nervosa is an eating disorder characterized by binge eating and purging. The disorder is estimated to occur in up to 5 percent of young women. Despite severe psychosocial impairment and potentially serious medical complications, patients do not usually reveal their bulimic behavior to a physician unless directly asked. Promising treatments include cognitive-behavioral psychotherapy and antidepressant medications.


Genome-wide analysis of effectors of peroxisome biogenesis.
Peroxisomes are intracellular organelles that house a number of diverse metabolic processes, notably those required for beta-oxidation of fatty acids. Peroxisomes biogenesis can be induced by the presence of peroxisome proliferators, including fatty acids, which activate complex cellular programs that underlie the induction process. Here, we used multi-parameter quantitative phenotype analyses of an arrayed mutant collection of yeast cells induced to proliferate peroxisomes, to establish a comprehensive inventory of genes required for peroxisome induction and function. The assays employed include growth in the presence of fatty acids, and confocal imaging and flow cytometry through the induction process. In addition to the classical phenotypes associated with loss of peroxisomal functions, these studies identified 169 genes required for robust signaling, transcription, normal peroxisomal development and morphologies, and transmission of peroxisomes to daughter cells. These gene products are localized throughout the cell, and many have indirect connections to peroxisome function. By integration with extant data sets, we present a total of 211 genes linked to peroxisome biogenesis and highlight the complex networks through which information flows during peroxisome biogenesis and function.


The Role of Personal Accomplishment in General Surgery Resident Well-being.
To investigate the association of personal accomplishment (PA) with the other subscales, assess its association with well-being outcomes, and evaluate drivers of PA by resident level. Most studies investigating physician burnout focus on the emotional exhaustion (EE) and depersonalization (DP) subscales, neglecting PA. Therefore, the role of PA is not well understood. General surgery residents were surveyed following the 2019 American Board of Surgery In-Training Examination regarding their learning environment. Pearson correlations of PA with EE and DP were assessed. Multivariable logistic regression models assessed the association of PA with attrition, job satisfaction, and suicidality and identified factors associated with PA by PGY. Residents from 301 programs were surveyed (85.6% response rate, N = 6956). Overall, 89.4% reported high PA, which varied by PGY-level (PGY1: 91.0%, PGY2/3: 87.7%, PGY4/5: 90.2%; P = 0.02). PA was not significantly correlated with EE (r = -0.01) or DP (r = -0.08). After adjusting for EE and DP, PA was associated with attrition (OR 0.60, 95%CI 0.46-0.78) and job satisfaction (OR 3.04, 95%CI 2.45-3.76) but not suicidality (OR 0.72, 95%CI 0.48-1.09). Although the only factor significantly associated with PA for interns was resident cooperation, time in operating room and clinical autonomy were significantly associated with PA for PGY2/3. For PGY4/5s, PA was associated with time for patient care, resident cooperation, and mentorship. PA is a distinct metric of resident well-being, associated with job satisfaction and attrition. Drivers of PA differ by PGY level and may be targets for intervention to promote resident wellness and engagement.


Induction of lysosomal biogenesis in atherosclerotic macrophages can rescue lipid-induced lysosomal dysfunction and downstream sequelae.
Recent reports of a proatherogenic phenotype in mice with macrophage-specific autophagy deficiency have renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique ability to process both exogenous material, including lipids and autophagy-derived cargo such as dysfunctional proteins/organelles. We aimed to understand the effects of an atherogenic lipid environment on macrophage lysosomes and to evaluate novel ways to modulate this system. Using a variety of complementary techniques, we show that oxidized low-density lipoproteins and cholesterol crystals, commonly encountered lipid species in atherosclerosis, lead to profound lysosomal dysfunction in cultured macrophages. Disruptions in lysosomal pH, proteolytic capacity, membrane integrity, and morphology are readily seen. Using flow cytometry, we find that macrophages isolated from atherosclerotic plaques also display features of lysosome dysfunction. We then investigated whether enhancing lysosomal function can be beneficial. Transcription factor EB (TFEB) is the only known transcription factor that is a master regulator of lysosomal biogenesis although its role in macrophages has not been studied. Lysosomal stress induced by chloroquine or atherogenic lipids leads to TFEB nuclear translocation and activation of lysosomal and autophagy genes. TFEB overexpression in macrophages further augments this prodegradative response and rescues several deleterious effects seen with atherogenic lipid loading as evidenced by blunted lysosomal dysfunction, reduced secretion of the proinflammatory cytokine interleukin-1β, enhanced cholesterol efflux, and decreased polyubiquitinated protein aggregation. Taken together, these data demonstrate that lysosomal function is markedly impaired in atherosclerosis and suggest that induction of a lysosomal biogenesis program in macrophages has antiatherogenic effects.


The evolutionary pathway from a biologically inactive polypeptide sequence to a folded, active structural mimic of DNA.
The protein Ocr (overcome classical restriction) from bacteriophage T7 acts as a mimic of DNA and inhibits all Type I restriction/modification (RM) enzymes. Ocr is a homodimer of 116 amino acids and adopts an elongated structure that resembles the shape of a bent 24 bp DNA molecule. Each monomer includes 34 acidic residues and only six basic residues. We have delineated the mimicry of Ocr by focusing on the electrostatic contribution of its negatively charged amino acids using directed evolution of a synthetic form of Ocr, termed pocr, in which all of the 34 acidic residues were substituted for a neutral amino acid. In vivo analyses confirmed that pocr did not display any antirestriction activity. Here, we have subjected the gene encoding pocr to several rounds of directed evolution in which codons for the corresponding acidic residues found in Ocr were specifically re-introduced. An in vivo selection assay was used to detect antirestriction activity after each round of mutation. Our results demonstrate the variation in importance of the acidic residues in regions of Ocr corresponding to different parts of the DNA target which it is mimicking and for the avoidance of deleterious effects on the growth of the host.


Image Segmentation and Analysis of Flexion-Extension Radiographs of Cervical Spines.
We present a new analysis tool for cervical flexion-extension radiographs based on machine vision and computerized image processing. The method is based on semiautomatic image segmentation leading to detection of common landmarks such as the spinolaminar (SL) line or contour lines of the implanted anterior cervical plates. The technique allows for visualization of the local curvature of these landmarks during flexion-extension experiments. In addition to changes in the curvature of the SL line, it has been found that the cervical plates also deform during flexion-extension examination. While extension radiographs reveal larger curvature changes in the SL line, flexion radiographs on the other hand tend to generate larger curvature changes in the implanted cervical plates. Furthermore, while some lordosis is always present in the cervical plates by design, it actually decreases during extension and increases during flexion. Possible causes of this unexpected finding are also discussed. The described analysis may lead to a more precise interpretation of flexion-extension radiographs, allowing diagnosis of spinal instability and/or pseudoarthrosis in already seemingly fused spines.


Francisella tularensis SchuS4 and SchuS4 lipids inhibit IL-12p40 in primary human dendritic cells by inhibition of IRF1 and IRF8.
Induction of innate immunity is essential for host survival of infection. Evasion and inhibition of innate immunity constitute a strategy used by pathogens, such as the highly virulent bacterium Francisella tularensis, to ensure their replication and transmission. The mechanism and bacterial components responsible for this suppression of innate immunity by F. tularensis are not defined. In this article, we demonstrate that lipids enriched from virulent F. tularensis strain SchuS4, but not attenuated live vaccine strain, inhibit inflammatory responses in vitro and in vivo. Suppression of inflammatory responses is associated with IκBα-independent inhibition of NF-κBp65 activation and selective inhibition of activation of IFN regulatory factors. Interference with NF-κBp65 and IFN regulatory factors is also observed following infection with viable SchuS4. Together these data provide novel insight into how highly virulent bacteria selectively modulate the host to interfere with innate immune responses required for survival of infection.


Cellular analysis by in situ hybridization and immunoperoxidase of alpha-fetoprotein and albumin gene expression in rat liver during the perinatal period.
To analyze at the cellular level the decrease in alpha-fetoprotein (AFP) gene expression during the early postnatal growth, we searched for AFP gene transcripts by in situ hybridization using a specific cDNA probe, and for the corresponding protein by immunocytochemistry, on rat liver sections at various times of the perinatal period. The relative number of mRNA sequences was evaluated by Northern blot analysis. Albumin (ALB) gene expression was studied simultaneously with the same techniques. In 17-19-d-old fetuses all hepatocytes express simultaneously, for both genes, the mRNAs and the corresponding proteins. During the first postnatal weeks, at a time when the global number of AFP mRNA molecules decreases, all hepatocytes still contain cytoplasmic transcripts and protein. A zonal heterogeneity in the level of AFP gene expression develops around the first week, a higher number of gene products being detected in perivenous than in periportal hepatocytes. This heterogeneity persists until the fourth week when AFP mRNA sequences and protein are barely detectable. All hepatocytes express the ALB gene after birth, but at around the second week, a periportal intensification of the in situ hybridization signal and immunostaining becomes apparent. Our data indicate that co-expression of the AFP and ALB genes by all hepatocytes is a normal step in liver ontogeny; the diminution of AFP gene expression after birth is not the result of the disappearance of specialized cell clones; and zonal quantitative differences in the level of AFP and ALB gene expression are observed within the maturing liver lobule.


Intraosseous Angiolipoma of the Rib.
Angiolipomas are a subgroup of lipomas and are rarely observed benign tumours in which mature fat tissue and angiomatous elements exist jointly. Costa-induced angiolipomas are rarer. A male patient aged 46 years consulted our clinic due to severe pain in his left side. The patient's X-ray showed a lobulated area with increased density (bone mass) in the left upper zone of the lung. A lesion in the fourth rib was excised with a left thoracotomy. Pathological diagnosis was reported as angiolipoma.


Diagnosis and treatment of autoimmune pancreatitis.
To summarize the existing knowledge of autoimmune pancreatitis (AIP) and to review the progress made in the diagnosis and treatment of AIP in the past year. The term 'AIP' appears to encompass at least two distinct subtypes, type 1 and type 2. Type 1 AIP is the pancreatic manifestation of a systemic fibroinflammatory disease called immunoglobulin G4-associated systemic disease. Type 2 AIP affects younger patients, does not have a gender predilection and is associated with normal serum immunoglobulin G4 levels. Existing criteria are geared toward diagnosis of type 1; type 2 AIP can be definitively diagnosed only on pancreatic histology. Both subtypes respond to corticosteroid therapy. However, there are no standardized protocols for initial treatment or management and prevention of relapses in AIP. A novel antibody for AIP has recently been identified and its performance needs validation from other centers. Newly published strategies for differentiating AIP from pancreatic cancer are available. AIP is a rare disease whose recognition and understanding are evolving. Much needs to be elucidated with regard to its cause, pathogenesis, treatment of relapse and long-term outcomes. A multidisciplinary team, familiar with the disease, is critical in making the correct diagnosis.


Aspergillus myosin-V supports polarized growth in the absence of microtubule-based transport.
In the filamentous fungus Aspergillus nidulans, both microtubules and actin filaments are important for polarized growth at the hyphal tip. Less clear is how different microtubule-based and actin-based motors work together to support this growth. Here we examined the role of myosin-V (MYOV) in hyphal growth. MYOV-depleted cells form elongated hyphae, but the rate of hyphal elongation is significantly reduced. In addition, although wild type cells without microtubules still undergo polarized growth, microtubule disassembly abolishes polarized growth in MYOV-depleted cells. Thus, MYOV is essential for polarized growth in the absence of microtubules. Moreover, while a triple kinesin null mutant lacking kinesin-1 (KINA) and two kinesin-3s (UNCA and UNCB) undergoes hyphal elongation and forms a colony, depleting MYOV in this triple mutant results in lethality due to a severe defect in polarized growth. These results argue that MYOV, through its ability to transport secretory cargo, can support a significant amount of polarized hyphal tip growth in the absence of any microtubule-based transport. Finally, our genetic analyses also indicate that KINA (kinesin-1) rather than UNCA (kinesin-3) is the major kinesin motor that supports polarized growth in the absence of MYOV.


Secretion systems and signal exchange between nitrogen-fixing rhizobia and legumes.
The formation of symbiotic nitrogen-fixing nodules on the roots and/or stem of leguminous plants involves a complex signal exchange between both partners. Since many microorganisms are present in the soil, legumes and rhizobia must recognize and initiate communication with each other to establish symbioses. This results in the formation of nodules. Rhizobia within nodules exchange fixed nitrogen for carbon from the legume. Symbiotic relationships can become non-beneficial if one partner ceases to provide support to the other. As a result, complex signal exchange mechanisms have evolved to ensure continued, beneficial symbioses. Proper recognition and signal exchange is also the basis for host specificity. Nodule formation always provides a fitness benefit to rhizobia, but does not always provide a fitness benefit to legumes. Therefore, legumes have evolved a mechanism to regulate the number of nodules that are formed, this is called autoregulation of nodulation. Sequencing of many different rhizobia have revealed the presence of several secretion systems - and the Type III, Type IV, and Type VI secretion systems are known to be used by pathogens to transport effector proteins. These secretion systems are also known to have an effect on host specificity and are a determinant of overall nodule number on legumes. This review focuses on signal exchange between rhizobia and legumes, particularly focusing on the role of secretion systems involved in nodule formation and host specificity.


New entries toward 3,3-difluoropiperidines.
Difluoropiperidines attract considerable interest from organic and medicinal chemists, but their synthesis is often problematic. This paper describes a new synthetic pathway toward valuable 3,3-difluoropiperidines starting from suitable delta-chloro-alpha,alpha-difluoroimines. The latter imines can be synthesized via electrophilic fluorination of the corresponding delta-chloroimines using NFSI (N-fluorodibenzenesulfonimide) in acetonitrile. After hydride reduction of the imino bond and subsequent intramolecular substitution of the chloride atom, new 3,3-difluoropiperidines were obtained in good yields. In addition, this methodology was applied to establish the first synthesis of N-protected 3,3-difluoropipecolic acid, a new fluorinated amino acid.


Temporal resolution and spectral sensitivity of the visual system of three coastal shark species from different light environments.
Visual temporal resolution and scotopic spectral sensitivity of three coastal shark species (bonnethead Sphyrna tiburo, scalloped hammerhead Sphyrna lewini, and blacknose shark Carcharhinus acronotus) were investigated by electroretinogram. Temporal resolution was quantified under photopic and scotopic conditions using response waveform dynamics and maximum critical flicker-fusion frequency (CFF). Photopic CFF(max) was significantly higher than scotopic CFF(max) in all species. The bonnethead had the shortest photoreceptor response latency time (23.5 ms) and the highest CFF(max) (31 Hz), suggesting that its eyes are adapted for a bright photic environment. In contrast, the blacknose had the longest response latency time (34.8 ms) and lowest CFF(max) (16 Hz), indicating its eyes are adapted for a dimmer environment or nocturnal lifestyle. Scotopic spectral sensitivity revealed maximum peaks (480 nm) in the bonnethead and blacknose sharks that correlated with environmental spectra measured during twilight, which is a biologically relevant period of heightened predation.


Agreement between electronic and paper Epworth Sleepiness Scale responses in obstructive sleep apnoea: secondary analysis of a randomised controlled trial undertaken in a specialised tertiary care clinic.
Originally developed as a paper questionnaire, the electronic Epworth Sleepiness Scale (ESS) is widely used in sleep clinics and sleep population research. Despite potential differences between computer-based and conventional questionnaire delivery, studies have not evaluated the agreement between electronic and paper versions of the ESS. Given the widespread use of the ESS, a bias between results would present considerable data concerns. Thus, the aim of this study was to examine agreement between electronic and paper ESS responses in obstructive sleep apnoea (OSA). We undertook a secondary analysis of baseline data from a randomised controlled trial (ANZCTR: ACTRN12611000847910). Data were collected in a tertiary sleep research laboratory located in Sydney, Australia. Data were analysed from 112 adult patients with OSA. Patients were given the English version of the ESS as part of a battery of sleep laboratory questionnaires. They completed electronic and subsequently paper ESS questionnaires on the same day. We found no significant difference between electronic and paper ESS questionnaires (mean=0.1, SD=2.1, 95% CI -0.3 to 0.5, P=0.57) or heteroscedasticity. There was no evidence of bias along the range of the measure. 95% limits of agreement at 4.3 and -4.1 were comparable with previous data. We found no evidence of bias between electronic and paper ESS questionnaires in this sample of patients with OSA, as the two formats displayed sufficient agreement to be clinically comparable. Regardless of severity, patients reported the same level of daytime sleepiness with the same level of accuracy across both measures. ACTRN12611000847910; Pre-results.


Arrhythmogenecity and thrombogenicity of the residual left atrial appendage stump following surgical exclusion of the appendage in patients with atrial fibrillation.
It is common to find residual stump after the amputation or clip exclusion of the left atrial appendage (LAA). We evaluated the arrhythmogenic and thrombogenic potential of LAA stumps in atrial fibrillation (AF) patients. Consecutive patients undergoing catheter ablation for AF recurrence with LAA stump detected at baseline transesophageal echocardiogram (TEE) were included in the analysis. Nonpulmonary vein (non-PV) triggers were ablated based on operator's discretion. A total of 213 patients with LAA stump were included in the analysis. Firing from the LAA stump was detected in 186 cases, of which 145 received stump isolation (group I) and the stump was not targeted for isolation in 41 (group II) patients. In 27 patients with no firing from the stump (group III) only non-PV triggers from sites other than the LAA stump were targeted for ablation. At 16.7 ± 8.5 months of follow-up, 126 (86.9%) patients from group I, eight (19.5%) from group II, and eight (33.3%) from group III remained arrhythmia-free off antiarrhythmic drugs (AAD) (P < 0.001). Sixty out of 70 patients underwent redo procedure; electrical isolation of the stump and ablation of other non-PV triggers was done in all 60 cases. At 1 year after the repeat procedure, 55 (91.7%) patients remained arrhythmia-free off-AAD. A total of four (1.88%) thromboembolic (TE) events reported, three of which were transient ischemic attacks and all three patients had "smoke" detected in the left atrium. LAA stump is arrhythmogenic and electrical isolation improves clinical outcome. TE events are rare and mostly associated with left atrial smoke in this subset of AF population.


Copper(II) Complexes with Carnosine Conjugates of Hyaluronic Acids at Different Dipeptide Loading Percentages Behave as Multiple SOD Mimics and Stimulate Nrf2 Translocation and Antioxidant Response in In Vitro Inflammatory Model.
A series of copper(II) complexes with the formula [Cu2+Hy(x)Car%] varying the molecular weight (MW) of Hyaluronic acid (Hy, x = 200 or 700 kDa) conjugated with carnosine (Car) present at different loading were synthesized and characterized via different spectroscopic techniques. The metal complexes behaved as Cu, Zn-superoxide dismutase (SOD1) mimics and showed some of the most efficient reaction rate values produced using a synthetic and water-soluble copper(II)-based SOD mimic reported to date. The increase in the percentage of Car moieties parallels the enhancement of the I50 value determined via the indirect method of Fridovich. The presence of the non-functionalized Hy OH groups favors the scavenger activity of the copper(II) complexes with HyCar, recalling similar behavior previously found for the copper(II) complexes with Car conjugated using β-cyclodextrin or trehalose. In keeping with the new abilities of SOD1 to activate protective agents against oxidative stress in rheumatoid arthritis and osteoarthritis diseases, Cu2+ interaction with HyCar promotes the nuclear translocation of erythroid 2-related factor that regulates the expressions of target genes, including Heme-Oxigenase-1, thus stimulating an antioxidant response in osteoblasts subjected to an inflammatory/oxidative insult.


RVG peptide as transfection reagent for specific cdk4 gene silencing in vitro and in vivo.
The rabies virus glycoprotein (RVG) peptide is known as a transfection reagent for systemic delivery of small interfering RNA (siRNA) into the brain. However, selective transfection of neuronal cells or specific brain regions remains a problem. In the present study, we show that the RVG peptide can efficiently be used as shuttle system to transfect neuronal cells with cdk4 siRNA leading to selective knockdown of cdk4 expression in vitro and in vivo. After transfection, cdk4 expression was reduced up to 75% in Neuro2A cells. Stereotactically injected RVG peptide delivered cdk4 siRNA specifically to neurons in the hippocampus, resulting in a specific knockdown of cdk4 expression up to 400 µm from the injection site. Further complexation studies of RVG peptide with larger molecules such as plasmid vectors or DNA fragments were also successfully performed and improved in vitro. Therefore, the peptide is not only a highly promising drug delivery system for siRNA and potentially other therapeutic molecules, but also a powerful tool to systematically analyze gene function in the brain under experimental settings in correlation to neurodegenerative disorders.


[Coronary artery bypass in octogenarians; how to reduce operative mortality and enhance long-term quality of life].
Octogenarians are at increased risk for perioperative morbidity and mortality after coronary artery bypass. This study is aimed to elucidate the suitable operative strategy and perioperative management. A retrospective analysis was conducted of 54 consecutive patients with 80-years of age or older, who underwent elective isolated coronary artery bypass between May 1999 and May 2008. Mean follow-up was 43.3 months and 96.3% complete. Operavive mortality was 3.7% and the incidence of stroke was 3.7%. The 7-year cardiac survival was 80.4% and the 7-year cardiac event free was 65.0%. The use of arterial graft to the right coronary artery was identified as independent predictor of late cardiac event. Neither total arterial revascularization nor bilateral internal thoracic artery grafting was a significant cardiac event factor. This retrospective study suggests a benefit of the less invasive strategy in terms of operative mortality and morbidity. Application of fast-track treatment in octogenarians appears to be an effective approach to reduce perioperative morbidity and enhance long-term quality of life.


An update on vitrectomy surgery and retinal detachment repair in sickle cell disease.
Eighteen patients (19 eyes) with sickling hemoglobinopathies underwent vitrectomy or scleral buckling operations. The indications for surgery were tractional or rhegmatogenous retinal detachment or vitreous hemorrhage. The retina was reattached in all four patients with rhegmatogenous detachments requiring scleral buckling surgery but no vitrectomy. All had excellent visual acuity postoperatively. Four of the five patients with vitreous hemorrhage requiring vitrectomy without buckling had substantial improvement in visual acuity. In ten patients with vitreous hemorrhage with either preexisting or iatrogenic retinal breaks, rhegmatogenous detachment, or tractional detachment, the rate of improvement in visual acuity was only 50%. Problems associated with vitreous or retinal surgery in patients with sickling hemoglobinopathies include iatrogenic retinal breaks, intraocular bleeding and secondary glaucoma, anterior segment ischemia, and systemic sickling.


Epidemic trends, public health response and health system capacity: the Chilean experience in four months of the COVID-19 pandemic.
To report the surveillance of COVID-19 pandemic in Chile and analyse the response to public health interventions implemented from 3 March to 30 June 2020 and to assess the risks of collapse of the health care system. We analysed the effective reproductive number, underreporting of cases, burden of critical beds, case fatality ratio and number of diagnostic RT-PCR for SARS-CoV-2. After an accelerated onset, the COVID-19 pandemic seemed to be relatively controlled in Chile (late April 2020), with reproductive numbers close to 1.00. However, at this time, the load of infected patients was high, with an important number of underreported cases; the diagnostic effort was still limited and heterogeneous across regions. After 1 May up to 30 June a marked exponential increase in the number of cases was observed with a peak on June 14. In this last period the occupation of intensive care unit beds increased to saturation level (89% nationally; 95% in the Metropolitan Region). Our findings suggest that the implemented public health interventions have been initially effective in decreasing the spread of the pandemic. Premature decisions to relax these interventions may have resulted in a rebound in cases with a rapid saturation of the health care system.


The two-factor model of psychopathic personality: evidence from the psychopathic personality inventory.
Psychopathy or psychopathic personality disorder represents a constellation of traits characterized by superficial charm, egocentricity, irresponsibility, fearlessness, persistent violation of social norms, and a lack of empathy, guilt, and remorse. Factor analyses of the Psychopathic Personality Inventory (PPI)typically yield two factors: Fearless Dominance (FD) and Self-Centered Impulsivity (SCI). Additionally, the Coldheartedness (CH) subscale typically does not load on either factor. The current paper includes a meta-analysis of studies that have examined theoretically important correlates of the two PPI factors and CH. Results suggest that (a) FD and SCI are orthogonal or weakly correlated, (b) each factor predicts distinct (and sometimes opposite) correlates, and (c) the FD factor is not highly correlated with most other measures of psychopathy. This pattern of results raises important questions about the relation between FD and SCI and the role of FD in conceptualizations of psychopathy. Our findings also indicate the need for future studies using the two-factor model of the PPI to conduct moderational analyses to examine potential interactions between FD and SCI in the prediction of important criterion measures.


Carbon nanotube-directed polytetrafluoroethylene crystal growth via initiated chemical vapor deposition.
Initiated chemical vapor deposition (iCVD) has been shown to be suitable for blanketing surfaces with thin polymer coatings of ≈1-2 nm and greater. In this work, iCVD coatings of polytetrafluoroethylene (PTFE) deposited on carbon nanotube (CNT)-based surfaces show CNT-templated PTFE single crystal growth. While the coating forms disoriented agglomerates when deposited on an amorphous carbon background, "shish-kebab" structures are observed when grown on single-walled carbon nanotubes (SWCNT) as well as CNT buckypaper. It is shown that the shish-kebab structure is composed of PTFE lamellae arranged with the chain backbones running parallel to the SWCNT axis. This result allows one to control not only the surface chemistry using PTFE but also the coating surface topology.


Method for measuring jugular venous pulse with a miniature gyroscope sensor patch.
The right internal jugular vein is connected to the right atrium of the heart via the superior vena cava, and consequently its pressure, known as the jugular venous pressure or the jugular venous pulse (JVP), is an important indicator of cardiac function. The JVP can be estimated visually from the neck but it is rather difficult and imprecise. In this article we propose a method to measure the JVP using a motion sensor patch attached to the neck. The JVP signal was extracted from the sensor's 3-axes gyroscope signal and aligned with simultaneously measured ECG and seismocardiogram signals.The method was tested on 20 healthy subjects. The timings of the characteristic JVP waves were compared with the ECG R peaks and seismocardiogram heart sounds S1 and S2. The JVP was reliably measured from 18 subjects with all three waves identified. The timings of the waves were also physiologically plausible when compared to the ECG R peak and the heart sounds. Importantly, the JVP was also found to modulate with respiration, further indicating that the measured signal was indeed the JVP and not the carotid pulse.The results show that the JVP can be measured with a wearable patch-like device registering the delicate motions of the right internal jugular vein. The method has potential to be developed into a clinical tool to measure cardiac health in diseases such as heart failure and chronic obstructive pulmonary disease (COPD).Clinical relevance-The developed method could enable an affordable measurement of clinically important cardiac parameter, jugular venous pulse, as a part of a routine examination.


Neuroarthropathy of the extremities: magnetic resonance imaging features.
The objective of this article was to review the magnetic resonance imaging (MRI) findings of four different neuroarthropathic extremities, and discuss the role of MRI in establishing a correct diagnosis. The shoulder, ankle, and knee had predominantly atrophic neuroarthropathic changes, whereas both atrophic and productive changes could be seen in the elbow. Bone marrow edema, suggesting a recent stress fracture, was detected in the elbow and knee. Osteochondral defects, or "detritic" synovitis with effusion, were extensive in all joints but exceptionally profound in the shoulder with amputation-like osteolysis and a total loss of the humeral head. Radiologists may encounter the joint manifestations of neuropathy, which may be confused with various pathologies, including tumor and septic arthritis, before the neurological diagnosis is established. MRI is helpful in detecting the extension of the disease as well as to differentiate chronic Charcot's arthropathy from septic arthritis before radiographic findings suggest the diagnosis.


Cancer nutrition rehabilitation program: the role of social work.
The Cancer Nutrition Rehabilitation (cnr) program at the McGill University Health Centre is an interdisciplinary 8-week treatment program offering patients information, education, treatment, and support in areas such as diet, exercise, and rehabilitation, plus resources to address their psychosocial needs. The program social worker helps the patient and the patient's family to cope with the illness, to problem-solve, and to obtain needed resources. Here, we present a description of these patients-demographics, medical diagnoses, and psychosocial needs as assessed by the Person-in-Environment standardized instrument-derived from the social-work files of the 75 patients referred to social work in the period February 2007-December 2008. The reason most frequently reported for referral to social work was assistance with psychosocial problems. For 41.3% of the sample, these problems were assessed as high severity, and almost half the patients in the sample (47.8%) were assessed as having inadequate coping ability. Patient age was the most important demographic variable. Although seniors (63-94 years of age) were the least likely to have high-severity psychosocial problems, they were the most likely to have inadequate coping ability. That finding suggests that the cnr social worker, in addition to dealing with the instrumental, practical needs of cancer patients, is in a unique position to respond to their emotional difficulties in coping with their illness, and that health care professionals need to pay particular attention to the coping ability of elderly patients.


Responses of two scleractinian corals to cobalt pollution and ocean acidification.
The effects of ocean acidification alone or in combination with warming on coral metabolism have been extensively investigated, whereas none of these studies consider that most coral reefs near shore are already impacted by other natural anthropogenic inputs such as metal pollution. It is likely that projected ocean acidification levels will aggravate coral reef health. We first investigated how ocean acidification interacts with one near shore locally abundant metal on the physiology of two major reef-building corals: Stylophora pistillata and Acropora muricata. Two pH levels (pHT 8.02; pCO2 366 μatm and pHT 7.75; pCO2 1140 μatm) and two cobalt concentrations (natural, 0.03 μg L-1 and polluted, 0.2 μg L-1) were tested during five weeks in aquaria. We found that, for both species, cobalt input decreased significantly their growth rates by 28% while it stimulated their photosystem II, with higher values of rETRmax (relative Electron Transport Rate). Elevated pCO2 levels acted differently on the coral rETRmax values and did not affect their growth rates. No consistent interaction was found between pCO2 levels and cobalt concentrations. We also measured in situ the effect of higher cobalt concentrations (1.06 ± 0.16 μg L-1) on A. muricata using benthic chamber experiments. At this elevated concentration, cobalt decreased simultaneously coral growth and photosynthetic rates, indicating that the toxic threshold for this pollutant has been reached for both host cells and zooxanthellae. Our results from both aquaria and in situ experiments, suggest that these coral species are not particularly sensitive to high pCO2 conditions but they are to ecologically relevant cobalt concentrations. Our study reveals that some reefs may be yet subjected to deleterious pollution levels, and even if no interaction between pCO2 levels and cobalt concentration has been found, it is likely that coral metabolism will be weakened if they are subjected to additional threats such as temperature increase, other heavy metals, and eutrophication.


Multifunctional natural microneedles based methacrylated Bletilla striata polysaccharide for repairing chronic wounds with bacterial infections.
The expeditious healing of chronic wounds with bacterial infections poses a formidable challenge in clinical practice because of the persistent bacterial presence, excessive inflammation, and the accumulation of reactive oxygen species (ROS) in clinical practice. Thus, in this study, natural antimicrobial material microneedles (MNs) with multifunctional properties were prepared by adding peony leaf extract (PLE) into a matrix of methacrylated Bletilla striata polysaccharide (BSPMA) and methacrylated chitosan (CSMA) via cross-linking under ultra-violet light to accelerate the rapid healing of chronic wounds with bacterial infections. Results showed that BCP-MNs effectively inhibited the growth of Escherichia coli, Staphylococcus aureus, and methicillin-resistant S. aureus (MRSA) by disrupting bacterial cell membranes and accelerated the healing of infected wounds by enhancing cell migration, epidermal regeneration, pro-collagen deposition, and angiogenesis and reducing inflammation. Furthermore, BCP-MNs not only possessed good mechanical properties, stability, and biocompatibility but also showed potent antioxidant effects to eliminate excessive ROS accumulation in the wound bed. In conclusion, BCP-MNs possess multifunctional wound-healing properties and can serve as excellent wound dressing in to treat infected wounds.


Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections.
Human herpesvirus-6 (HHV-6), a ubiquitous beta-herpesvirus, is the causative agent of roseola infantum and has been associated with a number of neurologic disorders including seizures, encephalitis/meningitis, and multiple sclerosis. Although the role of HHV-6 in human CNS disease remains to be fully defined, a number of studies have suggested that the CNS can be a site for persistent HHV-6 infection. To characterize the extent and distribution of HHV-6 in human glial cells from surgical brain resections of patients with mesial temporal lobe epilepsy (MTLE). Brain samples from eight patients with MTLE and seven patients with neocortical epilepsy (NE) undergoing surgical resection were quantitatively analyzed for the presence of HHV-6 DNA using a virus-specific real-time PCR assay. HHV-6 expression was also characterized by western blot analysis and in situ immunohistochemistry (IHC). In addition, HHV-6-reactive cells were analyzed for expression of glial fibrillary acidic protein (GFAP) by double immunofluorescence. DNA obtained from four of eight patients with MTLE had significantly elevated levels of HHV-6 as quantified by real-time PCR. HHV-6 was not amplified in any of the seven patients with NE undergoing surgery. The highest levels of HHV-6 were demonstrated in hippocampal sections (up to 23,079 copies/10(6) cells) and subtyped as HHV-6B. Expression of HHV-6 was confirmed by western blot analysis and IHC. HHV-6 was co-localized to GFAP-positive cells that morphologically appeared to be astrocytes. HHV-6B is present in brain specimens from a subset of patients with MTLE and localized to astrocytes in the absence of inflammation. The amplification of HHV-6 from hippocampal and temporal lobe astrocytes of MTLE warrants further investigation into the possible role of HHV-6 in the development of MTLE.


Microbial water relations: features of the intracellular composition of sugar-tolerant yeasts.
Several factors contributed to differences in intracellular composition between sugar-tolerant (osmophilic) and nontolerant species of yeast. One such factor was the difference in accumulation of those nonelectrolytes whose uptake was not dominated by vigorous metabolism. In such cases (lactose and glycerol), the sugar-tolerant species had a much lower capacity for the solute than did the nontolerant species. Sucrose uptake was consistently different between all sugar-tolerant strains on the one hand and all nontolerant strains on the other. The difference was attributable in part to metabolism of sucrose by the nontolerant yeasts. The major difference between the two types of yeast, however, was the presence of one or more polyhydric alcohols at high concentrations within each of the sugar-tolerant strains but none of the nontolerant strains. In most cases the major polyol was arabitol. The solute concentration (and, hence, water availability) of the growth medium affected both the amount of arabitol produced by Saccharomyces rouxii and the proportion retained by the yeast after brief washing with water at 0 C. When the yeast was suspended in a buffer at 30 C, the polyol leaked out at a slow, constant, reproducible rate. The polyene antibiotic amphotericin B caused rapid release of polyol by the yeast, the rate being proportional to amphotericin concentration. Contact of the yeast with glucose (1 mM) caused an extremely rapid ejection of polyol which lasted less than 40 s. Some implications of these results are discussed, as is the role of the polyol as a compatible solute in determining the water relations of the yeast.


Collaboration between general practitioners and occupational physicians: a comparison of the results of two national surveys in France.
To study the perceptions that general practitioners (GPs) and occupational physicians (OPs) have of GPs' role in occupational health and their willingness to work together to prevent the exclusion of patients with disabilities from the workplace. Cross-sectional telephone survey of two randomly selected national samples of GPs and OPs was conducted. The majority of GPs and OPs are in favor of cooperation, especially to prevent exclusion from the workplace. However, some GPs lack trust in OPs' independence, an attitude associated negatively with the practice of GP referral to OPs to anticipate disability-related problems likely to occur when returning to work after a prolonged sick leave. There are some barriers to cooperation, on the part of both OPs and GPs. Initiatives are needed to encourage cooperation between these two types of physicians.


A specialist root herbivore exploits defensive metabolites to locate nutritious tissues.
The most valuable organs of plants are often particularly rich in essential elements, but also very well defended. This creates a dilemma for herbivores that need to maximise energy intake while minimising intoxication. We investigated how the specialist root herbivore Diabrotica virgifera solves this conundrum when feeding on wild and cultivated maize plants. We found that crown roots of maize seedlings were vital for plant development and, in accordance, were rich in nutritious primary metabolites and contained higher amounts of the insecticidal 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) and the phenolic compound chlorogenic acid. The generalist herbivores Diabrotica balteata and Spodoptera littoralis were deterred from feeding on crown roots, whereas the specialist D. virgifera preferred and grew best on these tissues. Using a 1,4-benzoxazin-3-one-deficient maize mutant, we found that D. virgifera is resistant to DIMBOA and other 1,4-benzoxazin-3-ones and that it even hijacks these compounds to optimally forage for nutritious roots.


Progressive visual loss following rupture of an intracranial dermoid cyst.
A 51-year-old man with several months of headache and progressive visual decline was found to have bilateral optic disc pallor with significant impairment of visual acuity. Despite a thorough ophthalmologic evaluation, the cause of visual loss could not be elucidated. MRI of the brain revealed a lesion in the left anterior Sylvian fissure as well as disseminated foci of subarachnoid fat consistent with a diagnosis of a ruptured dermoid cyst. The decision for open surgical resection was chosen to minimize the risk of cyst re-rupture and further visual or neurologic decline. The diagnosis of dermoid cyst was confirmed at the time of surgery. Vasospasm-induced ischemia of the optic nerves, optic chiasm or bilateral optic tracts secondary to the inflammatory reaction following cyst rupture is the most likely mechanism of visual loss in this patient. To the authors' knowledge, this report represents the first reported case of visual loss secondary to rupture of an intracranial dermoid cyst not related to mass effect of the tumor on the optic apparatus, visual pathways or visual cortex.


CD147 promotes breast cancer migration and invasion by inducing epithelial-mesenchymal transition via the MAPK/ERK signaling pathway.
CD147, a transmembrane glycoprotein, has been implicated in various cancer-related processes but its role in breast cancer remains poorly understood. Herein, we investigated the expression of CD147 in different breast cancer cell lines and explored its functional roles, including migration, invasion, drug resistance and modulation of key proteins associated with cancer progression. The expression of CD147 was assessed in MCF-10 A, BT549, MDA-MB-231 and MCF-7 breast cancer cell lines using qRT-PCR and Western blotting, following which lyposome transfections were performed, leading overexpression of CD147 in BT549 cells and knockdown of CD147 in MCF-7 cells. Scratch assays and Transwell invasion and were performed to evaluate the cells' migration and invasion abilities. Sensitivity to 5-FU was determined via CCK-8 assays, and the expression of Snail1, E-cadherin, Vimentin, MMP-9 and the MAPK/ERK pathway were analyzed by qRT-PCR and Western blotting. Compared with normal beast epithelial cells, CD147 was highly expressed in all breast cancer cell lines, with the highest overexpression observed in MCF-7 cells and the lowest overexpression observed in BT549 cells. Overexpression of CD147 in BT549 cells increased, migration, invasion, viability and resistance to 5-FU of BT549 cells, while CD147 knockdown in MCF-7 cells reduced these properties of MCF-7 cells. Furthermore, CD147 influenced the expression of Snail1, Vimentin, E-cadherin, and MMP-9, suggesting its involvement in epithelial-mesenchymal transition (EMT) regulation. The MAPK/ERK pathway was activated by CD147 in BT549 cells, as indicated by increased p-MEK/MEK ratio and p-ERK/ERK ratio. In contrast, CD147 silencing in MCF-7 cells resulted in reduced p-MEK/MEK ratio and p-ERK/ERK ratio. In summary, our findings suggest CD147 as a potential therapeutic target in breast cancer treatment, particularly in cases where drug resistance and metastasis are concerns, worthy of further explorations.


Undiagnosed systemic lupus erythematosus in the community.
Systemic lupus erythematosus (SLE) produces a wide range of symptoms, some of them mild; therefore it may be underdiagnosed. In a pilot study we tested the ability of a screening questionnaire to identify undiagnosed cases in the community. A 10-item questionnaire was mailed to 3500 women aged 18-65 randomly selected from a general practice list in Birmingham, UK. A random sample of 300 non-respondents were sent two further mailings. Women returning the questionnaire with three positive answers were to attend for an antinuclear antibody (ANA) test; and those testing positive were to be referred to a rheumatologist for standard clinical assessment. 1153 (30%) of the women responded, and 307 of these gave three or more positive answers on the questionnaire. The survey disclosed three women with previously undiagnosed SLE; and, in addition, it picked up all four of the women whose SLE had been diagnosed previously. The prevalence of SLE revealed by this survey in Birmingham women is 200/100,000 (95% confidence interval 80 to 412), whereas the prevalence of diagnosed SLE in this age group is 54/100,000 (95% CI 47-62). Thus, a substantial number of undiagnosed cases exist, and further work needs to focus on the prevalence in different ethnic groups and the benefits of early diagnosis and treatment.


Trade-offs in cervical cancer prevention: balancing benefits and risks.
New screening and vaccination technologies will provide women with more options for cervical cancer prevention. Because the risk of cervical cancer diminishes with effective routine screening, women may wish to consider additional attributes, such as the likelihood of false-positive results and diagnostic procedures for mild abnormalities likely to resolve without intervention in their screening choices. We used an empirically calibrated simulation model of cervical cancer in the United States to assess the benefits and potential risks associated with prevention strategies differing by primary screening test, triage test for abnormal results (cytologic testing, human papillomavirus [HPV] DNA test), and screening frequency. Outcomes included colposcopy referrals, cervical intraepithelial neoplasia (CIN) types 1 and 2 or 3, lifetime cancer risk, and quality-adjusted life expectancy. Across strategies, colposcopy referrals and diagnostic workups varied 3-fold, although diagnostic rates of CIN 2 or 3 were similar and 95% of positive screening test results were for mild abnormalities likely to resolve on their own. For a representative group of a thousand 20-year-old women undergoing triennial screening for 10 years, we expect 1038 colposcopy referrals (7 CIN 2 or 3 diagnoses) from combined cytologic and HPV DNA testing and fewer than 200 referrals (6-7 CIN 2 or 3 diagnoses) for strategies that use triage testing. Similarly, for a thousand 40-year-old women, combined cytologic and HPV DNA testing led to 489 referrals (9 CIN 2 or 3), whereas alternative strategies resulted in fewer than 150 referrals (7-8 CIN 2 or 3). Using cytologic testing followed by triage testing in younger women minimizes both diagnostic workups and positive HPV test results, whereas in older women diagnostic workups are minimized with HPV DNA testing followed by cytologic triage testing. Clinically relevant information highlighting trade-offs among cervical cancer prevention strategies allows for inclusion of personal preferences into women's decision making about screening and provides additional dimensions to the construction of clinical guidelines.