Diapause: delaying the developmental clock in response to a changing environment.
Seasonal changes can induce organisms to modify their developmental growth. Many holometabolous insects, especially Lepidoptera, trigger diapause, an "actively induced" dormancy, for overwintering. Diapause is an alternative developmental pathway that reversibly blocks developmental growth during specific transitions and enhances the hibernating potential of the organism. Changes in environmental cues, such as light and temperature, trigger modifications in the levels, or in the timing, of developmental hormones. These in turn switch the developmental trajectory (diapause or direct development), strongly altering larval/pupal growth and inducing the appearance of diapause-bound seasonal morphs (polyphenism). We also discuss an example of vertebrate diapause using the killifish embryo as an example where diapause is an environmentally determined developmental switch analogous to that observed in lepidopteran dormancy. Based on the examples discussed here, we propose that the complex physiological responses leading to diapause might evolve quickly by relatively limited genetic changes in the regulation of hormonal signals that program normal developmental transitions.


Nutritional support for neonatal foals.
In recent years, equine neonatal medicine has made significant advances. The importance of nutritional support for the sick neonatal foal has been recognized, and methods of providing that sup-port have been developed. Today, the clinician has many options when designing a nutritional plan for the neonatal foal. When the foal's gut permits, enteral diets are an inexpensive source of nutrients. Under conditions where the gut requires rest, methods for delivering nutrients by the parenteral route have also been developed. In this article, the nutrition of the normal and sick foal is described. Guidelines for designing a nutritional plan are also reviewed.


Efficient inhibition of multidrug-resistant human tumors with a recombinant bispecific anti-P-glycoprotein x anti-CD3 diabody.
Overexpressing of P-glycoprotein (Pgp) has been shown to be responsible for cancer resistance to multiple chemotherapeutic agents. Immunotherapy with biological agents, such as bispecific antibodies (BsAbs), may represent a promising approach to overcome the emergence of drug resistance. Here we constructed a recombinant BsAb, a diabody, with specificities to both CD3 on human T-lymphocyte and Pgp on cancer cells. The diabody was produced in Escherichia coli in a soluble functional form and purified by an affinity chromatography with a yield of >4 mg/l culture medium in shaker flask. The diabody binds to both CD3 on T-lymphocytes and Pgp on multidrug-resistant (MDR) tumor cells with affinities that are comparable to its respective parental single chain Fv molecules. In the presence of activated human peripheral blood lymphocytes (PBLs), the diabody mediates effectively the lysis of the Pgp-overexpressing human leukemia K562/A02 and epidermoid carcinoma KBv(200) cells, but is much less potent in mediating the lysis of the parent K562 and KB cells. Further, the diabody localized selectively within the K562/A02 xenografts in mice. When combined with activated PBL, the diabody significantly inhibited the growth of K562/A02 and KBv(200), but had no effect on K562 and KB xenografts. In contrast, treatment with doxorubicin, a standard chemotherapeutic agent, only inhibited the growth of K562 and KB, but had no effect on K562/A02 and KBv(200) xenografts. Taken together, our results suggest that the anti-Pgp x anti-CD3 diabody may have a great potential in the treatment of various MDR cancers.


Endoscopically assisted buttocks augmentation.
Body-contouring aesthetic surgery focused on the gluteal region has been increasingly in demand. This article aims to describe the surgical technique, the results, and the complications for 28 women who underwent endoscopically assisted gluteoplasty using high-profile, high-cohesion round silicone implants between 1996 and 2006. The procedure involves precise dissection of the area for implant inclusion under endoscopic visualization, allowing optimization of the aesthetic gain, while minimizing the risks of sciatic nerve injury. Complications requiring surgical reintervention occurred for 7% of the patients. The technique demonstrated itself to be safe, dependable, and easy to learn.


NMR-based metabonomics for detection of Helicobacter pylori infection in gerbils: which is more descriptive.
Helicobacter pylori, the human pathogenic gram-negative microaerophilic bacterium, causes chronic gastric infection in more than half of the human population regardless of race. The infection of microbe is not yet controllable to pose a substantial public health impact and a growing social burden. The management of H. pylori infection primarily necessitates accurate and timely diagnosis at case level, on-demand supervision of pathologic progression, and reliable evaluation of the impact of pharmacologic interventions on the patients' population. The characterization of H. pylori infection on gerbils model was performed by metabolic profiling, employing 1H NMR spectroscopy compounding multivariate pattern recognition strategies. In the same manner, urine samples were individually collected from 10 gerbils infected with H. pylori GS13, and from 10 uninfected control animals equally accessible to feed and water. The resultant metabolic profiles indicate that H. pylori infection disturbs carbohydrate metabolism to elevate the levels of alpha- and beta-glucose, and cis-aconitate (a TCA cycle intermediate). In addition to the energy metabolism alteration, the colonization of H. pylori in gerbil stomach generates a remarkable deviation of amino acid metabolism as indicated by depletion of taurine and arginine, and elevation of proline and glutamine in the animal urine. Moreover, the H. pylori infection modifies the gut microbiota as highlighted by a range of microbial-related metabolites such as indoxyl sulfate and hippurate. These findings demonstrate that the (1)H NMR-based urine metabolic profiling is a promising technique capable of providing an accurate, noninvasive, and rapid diagnosis of H. pylori infection.


User perspectives of digital manufacturing for lower-limb prosthetic sockets.
There is growing interest to use digital technology (DT) for manufacturing lower-limb prosthetic sockets to improve efficiency and clinical outcomes. However, little is known about how lower-limb prosthesis users perceive DTs, such as 3D scanning and 3D printing. This study aimed to provide an understanding of perceptions and experiences with DT for prosthetic socket manufacturing from the perspective of prosthesis users. A qualitative descriptive research study. Nine lower-limb prosthesis users (mean age 56; 5 female; 4 male) participated in one-on-one semistructured telephone interviews. Inductive thematic analysis was performed to identify a codebook and emerging themes from the interview transcripts. Two major themes were identified: (1) expectations and prioritization of 3D printed socket usability and (2) facilitators and barriers to uptake of DT among patients. DT methods were found to be acceptable and feasible from a patient perspective, although technological advancements are still required, and real-time communication about the process may be vital for ensuring patient engagement. Consideration of these findings may improve patient satisfaction to emerging prosthesis treatment plans and ultimately support widespread adoption of DT as an additional tool for fabricating prosthetic sockets.


Glucose insulin potassium infusion improves systolic function in patients with chronic ischemic cardiomyopathy.
We assessed the effects of glucose-insulin-potassium (GIK) by echocardiography in stable patients with ischemic dysfunction. Twelve male patients with stable coronary disease (SCD) and ejection fraction (EF) <45% were studied for systolic function. GIK (glucose 30%, 300 insulin units and KCl 6 g/l) was infused at 1 ml/kg per h over 20 min. Hemodynamic and echocardiographic measurements were recorded at rest (T(0)), at the end (20 min) of GIK infusion (T+20), 20 and 40 min after the end of the infusion (T+40 and T+60). At T+20, a significant decrease in WMSI (wall motion score index) was observed compared with T(0) (2.16+/-0.14 vs. 2.30+/-0.16: P<0.05). An increase in EF was reported at T+40 and T+60 compared with T(0) (44.1+/-7.8% and 53.3+/-11.6% vs. 35.6+/-4.5%, respectively: P<0.01). A decrease in WMSI was observed at T+40 and T+60 compared with rest (2.02+/-0.17 and 1.93+/-0.11 vs. 2.30+/-0.16, respectively: P<0.01). Our present work suggests that GIK infusion improves systolic function in patients with SCD and ejection fraction <45%. Further studies are needed to determine if short-term GIK infusion could be useful for therapeutic or diagnostic strategies in these patients.


Erratum to "Evaluation of updated Feed Saved breeding values developed in Australian Holstein dairy cattle" (JDS Commun. 3:114-119).
[This corrects the article DOI: 10.3168/jdsc.2021-0150.].


Reflex activity caused by laryngoscopy and intubation is obtunded differently by meptazinol, nalbuphine and fentanyl.
To evaluate the different potencies of several opioids in obtunding reflex mechanisms of laryngoscopy and intubation. Three groups of patients (each n = 25, ASA 1-2) undergoing elective plastic surgery were randomly given meptazinol (2.5 mg kg-1), nalbuphine (0.3 mg kg-1) or fentanyl (5 microg kg-1) in a blinded fashion prior to laryngoscopy and intubation. This was followed by a standardized bolus induction of a barbiturate and a muscle relaxant. The response to laryngoscopy and intubation was studied, using blood pressure, heart rate and bispectral index. With fentanyl, there was an increase of heart rate by 17%, and systolic blood pressure by 7% when compared to control. Bispectral index dropped an additional 8% when compared to 1 min after barbiturate induction. In the nalbuphine group there was a 16% increase in systolic blood pressure, and a 16% increase in heart rate when compared to control. Also, bispectral index increased by 18% when compared to 1 min after barbiturate injection. The group receiving meptazinol demonstrated no cardiovascular changes although bispectral index dropped by an additional 19% when compared to 1 min after barbiturate injection. Meptazinol, appears to depress cardiovascular stimulatory effects and electroencephalogram arousal induced by laryngoscopy and intubation better than nalbuphine or fentanyl.


Pathology of the facial nerve.
A good examination in facial nerve imaging (CT or MR imaging) depends on a good knowledge of anatomy. Two clinical situations must be considered: imaging of patients with or without facial palsy. CT and MR imaging are very useful when the symptoms are atypical or progressive: MR imaging gives very good information about the facial nerve inflammation but may also discover a schwannoma, a hemangioma, a meningioma, or a primitive or secondary cholesteatoma. In malignant tumors of the parotid gland, a study of the fallopian canal must always be performed to delineate an extension in the mastoid, tympanic, or intrameatic parts. In some rare cases, a metastasis in the temporal bone may occur, especially in the region of the geniculate ganglion. Particular attention must be paid to children with facial palsy, considering the possibility of a histiocytosis or metastasis of a neuroblastoma.


Kawasaki Disease in Germany: A Prospective, Population-based Study Adjusted for Underreporting.
National estimates of Kawasaki disease (KD) incidence often do not include incomplete cases (diagnosed based on only laboratory or echocardiographic criteria), and/or they rely on retrospective case reports and data registries where underreporting is known to be a problem. We conducted a prospective nationwide KD surveillance study in children younger than 5 years through the hospital-based German Pediatric Surveillance Unit (ESPED). We accounted for underreporting through applying capture-recapture methodology in 2 federal states using hospital discharge records with KD International Statistical Classification of Diseases and Related Health Problems 10th revision code (ie, M30.3). KD diagnosis (complete and incomplete) was established according to the American Heart Association criteria, 2004. Incidence of KD, corrected for underreporting, was 7.2 of 100,000 in children younger than 5 years in Germany. Underreporting to ESPED was estimated at 37%-44%. Overall, 315 validated KD cases were reported. Of the 64 (20%) incomplete cases, 58% (37/64) were detected through echocardiographic findings and 42% (27/64) through laboratory criteria alone. Incomplete cases were younger than complete cases (1.2 vs. 2.0 years, P = 0.0001) and had more coronary aneurysms (43% vs. 11%, P = 0.0001). A substantial number of incomplete KD cases were diagnosed based on the laboratory and echocardiographic criteria only. This was particularly the case in relation to infants younger than 1 year-an age group known to have an increased risk of developing coronary aneurysms. In addition, we found a high rate of underreporting to national Pediatric Surveillance Units. We suggest that improved surveillance and development of better diagnostic tests remain a high priority.


Quetiapine-induced cervical dystonia.
Our objective was to report and describe a case of quetiapine-induced dystonia in an older lady with psychosis. Quetiapine is a second-generation antipsychotic and known to be rare in causing extrapyramidal side effects with rates similar to placebo. There have been few documented cases of quetiapine-induced dystonia. It is important to be vigilant and consider the development of dystonia in patients who may not fit the typical risk profile.


Intraperitoneal bupivacaine alone or with dexmedetomidine or tramadol for post-operative analgesia following laparoscopic cholecystectomy: A comparative evaluation.
Intraperitoneal instillation of local anaesthetics has been shown to minimise post-operative pain after laparoscopic surgeries. We compared the antinociceptive effects of intraperitoneal dexmedetomidine or tramadol combined with bupivacaine to intraperitoneal bupivacaine alone in patients undergoing laparoscopic cholecystectomy. A total of 120 patients were included in this prospective, double-blind, randomised study. Patients were randomly divided into three equal sized (n = 40) study groups. Patients received intraperitoneal bupivacaine 50 ml 0.25% +5 ml normal saline (NS) in Group B, bupivacaine 50 ml 0.25% + tramadol 1 mg/kg (diluted in 5 ml NS) in Group BT and bupivacaine 50 ml 0.25% + dexmedetomidine 1 μg/kg, (diluted in 5 ml NS) in Group BD before removal of trocar at the end of surgery. The quality of analgesia was assessed by visual analogue scale score (VAS). Time to the first request of analgesia, total dose of analgesic in the first 24 h and adverse effects were noted. Statistical analysis was performed using Microsoft (MS) Office Excel Software with the Student's t-test and Chi-square test (level of significance P = 0.05). VAS at different time intervals, overall VAS in 24 h was significantly lower (1.80 ± 0.36, 3.01 ± 0.48, 4.5 ± 0.92), time to first request of analgesia (min) was longest (128 ± 20, 118 ± 22, 55 ± 18) and total analgesic consumption (mg) was lowest (45 ± 15, 85 ± 35, 175 ± 75) in Group BD than Group BT and Group B. Intraperitoneal instillation of bupivacaine in combination with dexmedetomidine is superior to bupivacaine alone and may be better than bupivacaine with tramadol.


CTX-M-9 group ESBL-producing Raoultella planticola nosocomial infection: first report from sub-Saharan Africa.
Raoultella are Gram-negative rod-shaped aerobic bacteria which grow in water and soil. They mostly cause nosocomial infections associated with surgical procedures. This case study is the first report of a Raoultella infection in Africa. Case presentation We report a case of a surgical site infection (SSI) caused by Raoultella planticola which developed after caesarean section (CS) and surgery for secondary small bowel obstruction. The patient became febrile with neutrophilia (19,157/µL) 4 days after laparotomy and started to develop clinical signs of a SSI on the 8th day after laparotomy. The patient continued to be febrile and became critically ill despite empirical treatment with ceftriaxone and vancomycin. Raoultella species with extended antimicrobial resistance (AMR) carrying the CTX-M-9 β-lactamase was isolated from the wound discharge. Considering the antimicrobial susceptibility test, ceftriaxone was replaced by ceftazidime. The patient recovered and could be discharged on day 29 after CS. Raoultella planticola was isolated from an infected surgical site after repeated abdominal surgery. Due to the infection the patient's stay in the hospital was prolonged for a total of 4 weeks. It is noted that patients undergoing surgical and prolonged inpatient treatment are at risk for infections caused by Raoultella. The development of a SSI caused by Raoultella planticola with extended AMR has to be assumed to be a consequence of ineffective antibiotic utilization. The presented case advices that rare bacteria as Raoultella should be considered as potential cause of nosocomial SSI with challenging treatment due to high levels of AMR.


Recruiting young pre-symptomatic children for a clinical trial in type 1 diabetes: Insights from the Fr1da insulin intervention study.
Although detection of children at high risk of developing type 1 diabetes and diagnosis of early stages is possible, up to now there exists no approved therapy to delay or prevent type 1 diabetes. Thus it is vital to develop evidence-based interventions. For this a sufficient number of trial participants is crucial but difficult to obtain especially in asymptomatic children. Identifying family characteristics that lead to or impede trial participation and analyze reasons stated by families for non-participation. Participants for the Fr1da Insulin Intervention study are recruited from the Fr1da study, a population based screening for early stage type 1 diabetes in Bavaria. Families with eligible children were invited to enroll. We analyzed sex and age of the child, distance of the family to the study center in Munich and the existence of a first degree family member with type 1 as possible influential factors for study participation. We also analyzed reasons stated by families who declined study participation in a phone interview. Of 146 eligible children 77 (53%) were enrolled into the trial. None of the tested family characteristics differed significantly between the enrolling and the families not participating, but in general enrolling families lived closer to the study site than families not participating. This is also reflected in the reasons given by non-participating families. The most frequent reason stated were time restrictions. The second most frequent reason was the venous blood draw. The factors for non-participation identified in this project need be taken into account for the design of future trials in young children to ensure proper recruitment and thus to generate valid results for medical treatment of children. More research on the reason of participation and non-participation in clinical trials is needed.


The Intersection between Oral Microbiota, Host Gene Methylation and Patient Outcomes in Head and Neck Squamous Cell Carcinoma.
The role of oral microbiota in head and neck squamous cell carcinoma (HNSCC) is poorly understood. Here we sought to evaluate the association of the bacterial microbiome with host gene methylation and patient outcomes, and to explore its potential as a biomarker for early detection or intervention. Here we performed 16S rRNA gene amplicon sequencing in sixty-eight HNSCC patients across both tissue and oral rinse samples to identify oral bacteria with differential abundance between HNSCC and controls. A subset of thirty-one pairs of HNSCC tumor tissues and the adjacent normal tissues were characterized for host gene methylation profile using bisulfite capture sequencing. We observed significant enrichments of Fusobacterium and Peptostreptococcus in HNSCC tumor tissues when compared to the adjacent normal tissues, and in HNSCC oral rinses when compared to healthy subjects, while ten other bacterial genera were largely depleted. These HNSCC-related bacteria were discriminative for HNSCC and controls with area under the receiver operating curves (AUCs) of 0.84 and 0.86 in tissue and oral rinse samples, respectively. Moreover, Fusobacterium nucleatum abundance in HNSCC cases was strongly associated with non-smokers, lower tumor stage, lower rate of recurrence, and improved disease-specific survival. An integrative analysis identified that enrichment of F. nucleatum was associated with host gene promoter methylation, including hypermethylation of tumor suppressor genes LXN and SMARCA2, for which gene expressions were downregulated in the HNSCC cohort from The Cancer Genome Atlas. In conclusion, we identified a taxonomically defined microbial consortium associated with HNSCC that may have clinical potential regarding biomarkers for early detection or intervention. Host-microbe interactions between F. nucleatum enrichment and clinical outcomes or host gene methylation imply a potential role of F. nucleatum as a pro-inflammatory driver in initiating HNSCC without traditional risk factors, which warrants further investigation for the underlying mechanisms.


Determination of zearalenone and its metabolites in urine and tissue samples of cow and pig by LC-MS/MS.
For the sensitive and selective determination of zeranol, taleranol, α-zearalenol, β-zearalenol and zearalenone in animal urine and tissue a LC-MS/MS method has been developed. Sample preparation included extraction of meat samples and enzymatic digest of urine samples followed by solid-phase extraction with RP-18 columns for sample clean-up. Mass spectrometric determination was carried out with an atmospheric pressure chemical ionisation interface (APCI) in the multi-reaction monitoring mode (MRM). Using the negative ion mode detection limits between 0.1 and 0.5 ppb and determination limits between 0.5 and 1 ppb could be achieved. With zearalanone as internal standard, a linear range between 0.5 (1.0) and 100 ppb in urine samples (cow; pig) and between 1 and 100 ppb in meat samples (cow, calf, pig) could be established. Depending on the biological matrix and analyte standard deviations were below 8.2 %, with recovery rates between 86 and 102 % in spiked samples. The applicability of the method was demonstrated via several contaminated cow and pig urine samples.


Review: Precision Livestock Farming technologies in pasture-based livestock systems.
Precision Livestock Farming (PLF) encompasses the combined application of single technologies or multiple tools in integrated systems for real-time and individual monitoring of livestock. In grazing systems, some PLF applications could substantially improve farmers' control of livestock by overcoming issues related to pasture utilisation and management, and animal monitoring and control. A focused literature review was carried out to identify technologies already applied or at an advanced stage of development for livestock management in pastures, specifically cattle, sheep, goats, pigs, poultry. Applications of PLF in pasture-based systems were examined for cattle, sheep, goats, pigs, and poultry. The earliest technology applied to livestock was the radio frequency identification tag, allowing the identification of individuals, but also for retrieving important information such as maternal pedigree. Walk-over-weigh platforms were used to record individual and flock weights. Coupled with automatic drafting systems, they were tested to divide the animals according to their needs. Few studies have dealt with remote body temperature assessment, although the use of thermography is spreading to monitor both intensively reared and wild animals. Global positioning system and accelerometers are among the most applied technologies, with several solutions available on the market. These tools are used for several purposes, such as animal location, theft prevention, assessment of activity budget, behaviour, and feed intake of grazing animals, as well as for reproduction monitoring (i.e., oestrus, calving, or lambing). Remote sensing by satellite images or unmanned aerial vehicles (UAVs) seems promising for biomass assessment and herd management based on pasture availability, and some attempts to use UAVs to monitor, track, or even muster animals have been reported recently. Virtual fencing is among the upcoming technologies aimed at grazing management. This system allows the management of animals at pasture without physical fences but relies on associative learning between audio cues and an electric shock delivered if the animal does not change direction after the acoustic warning. Regardless of the different technologies applied, some common constraints have been reported on the application of PLF in grazing systems, especially when compared with indoor or confined livestock systems. Battery lifespan, transmission range, service coverage, storage capacity, and economic affordability were the main factors. However, even if the awareness of the existence and the potential of these upcoming tools are still limited, farmers' and researchers' demands are increasing, and positive outcomes in terms of rangeland conservation, animal welfare, and labour optimisation are expected from the spread of PLF in grazing systems.


Thiocyclam does not induce structural chromosome aberrations in human lymphocytes in vitro.
Thiocyclam (trade name Evisect) is a broad-spectrum nereistoxin analogue insecticide used widely for agricultural applications. The aim of this investigation was to determine its genotoxic effects in the chromosome aberration (CA) test and determining of mitotic index (MI), using lymphocytes from peripheral blood samples of healthy human donors. A negative and a positive control (MMC) were also included. Chromosomal analyses of the metaphase plates of the samples treated with 14 different concentrations (from 0.1 to 120 μg/ml) of thiocyclam, indicating the lack effect on chromosomes. Thus thiocyclam is not genotoxic but highly toxic on cell proliferation in human lymphocytes.


Contrast-enhanced ultrasound for the preoperative assessment of laryngeal carcinoma: a preliminary study.
Contrast-enhanced ultrasound (CEUS) is considered an attractive imaging technique to evaluate tumor microcirculation. However, the validity of CEUS for assessing laryngeal carcinoma is unclear. To compare the performance of CEUS with conventional US and contrast-enhanced computed tomography (CECT) in the diagnosis and preoperative T-staging of laryngeal carcinoma. Forty-one consecutive patients with laryngeal carcinoma underwent conventional high-frequency US, CEUS, and CECT before surgery. The CEUS characteristics of laryngeal carcinoma were recorded. The imaging findings of CEUS and conventional US were compared with CECT findings and the postoperative pathological examination. CEUS showed hyperenhancement in 38 cases and isoenhancement in three cases. Homogeneous distribution of contrast agent was found in 20 cases and heterogeneous distribution in 21 cases, of which 16 cases showed local perfusion defects. In the enhanced phase, rapid entry was observed in 37 cases, synchronous entry was observed in two cases, and slow entry was observed in two cases. Rapid exit was observed in 25 cases and slow exit was observed in 16 cases. The pretherapeutic T-staging accuracy was not significantly different between conventional US, CEUS, and CECT (P ≥ 0.500). A high sensitivity and specificity were achieved by CEUS in the evaluation of involvement of thyroid cartilage. Compared with conventional US and CECT, CEUS has a reliable initial T-staging accuracy and diagnostic properties for detecting laryngeal cartilage invasion.


PIK3C2A is a gene-specific target of microRNA-518a-5p in imatinib mesylate-resistant gastrointestinal stromal tumor.
Imatinib mesylate resistance occurs in some patients with gastrointestinal stromal tumors (GISTs) during the course of treatment. In this study, we investigated the relationship between microRNAs (miRNAs) and imatinib-resistant GISTs, and the effect of miR-518a-5p on PIK3C2A in imatinib-resistant GISTs. A total of 20 matched-pair GIST samples from imatinib-resistant patients were included in the study. Each of the paired tumor specimens were from the same patient who had surgical removal of GISTs preimatinib and postimatinib treatment. Seven pairs of tissues were resected for microarray analysis, and the remaining 13 pairs were utilized for miRNAs analysis. Target genes were selected based on bioinformatics from multiple biological databases. Luciferase reporter assays were used to confirm the binding of miR-518a-5p to PIK3C2A 3'UTR. GIST882R-NC, 882R-miR-518a-5p-OE, and 882R-miR-518a-5p-KD cell lines were constructed using lentiviral vectors. miR-518a-5p and PIK3C2A expression in 882R-NC, 882R-OE, and 882R-KD cells was assessed by real-time PCR and western blotting. A cell counting kit was used to detect the influence of miR-518a-5p to cell proliferation. TUNEL staining was applied to detect the influence of miR-518a-5p to cell apoptosis. Microarray analysis showed that miR-518a-5p was downregulated in imatinib-resistant GISTs, and the expression of miR-518a-5p was confirmed with good concordance between real-time PCR and miRNA microarray results. Luciferase reporter assays indicated that miR-518a-5p bound to the PIK3C2A 3'UTR. Compared with 882R-OE, PIK3C2A expression was significantly increased in 882R-KD cells. MiR-518a-5p reduced 882R proliferation and promoted 882R apoptosis. In conclusion, PIK3C2A is a gene-specific target of miR-518a-5p in imatinib mesylate-resistant GISTs. Low expression of miR-518a-5p is likely to upregulate PIK3C2A and affect the cellular response to the drug, causing resistance to imatinib in GISTs.


Interaction between laminin-5γ2 and integrin β1 promotes the tumor budding of colorectal cancer via the activation of Yes-associated proteins.
Colorectal cancer (CRC) is a common cancer type and a threat to human health. Tumor budding (TB) is the presence of a single cancer cell or clusters of up to five cancer cells prior to the invasive front of an aggressive carcinoma and is an independent prognosis factor for CRC. The molecular mechanism of TB is still unclear, and drugs that inhibit this process are still in the blank stage. This study found that TBs exhibit characteristics of partial EMT with a decreased expression of E-cadherin and no substantial differences in the expression of N-cadherin and vimentin. We also observed the interaction of integrin with extracellular matrix components, laminin-5γ2 (LN-5γ2), play essential roles in the TB of CRC. We then verified that the interaction between LN-5γ2 and integrin β1 promotes the TB of CRC via the activation of FAK and Yes-associated proteins (YAP). A natural drug monomer, cucurbitacin B, was screened using virtual screening methods for the interaction interface of proteins. We found that this monomer could block the interaction interface between LN-5γ2 and integrin β1 and substantially inhibit the TB of CRC cells via inactivation of YAP. This study provides new insights into the mechanism of TB mechanism and the development of drugs targeting the TB of CRC.


Juvenile polyposis syndrome: An overview.
Juvenile polyposis syndrome (JPS) is a rare precancerous condition that confers an increased risk of developing gastrointestinal cancers. The inheritance pattern is autosomal dominant. JPS should be clinically suspected when the other hamartomatous polyposis syndromes are excluded (i.e., Peutz- Jeghers and Cowden), in presence of numerous juvenile polyps in the colorectum or in other GI locations. Among the syndromic features, JPS can present with concomitant extra-intestinal manifestations, above all cutaneous manifestations such as telangiectasia, pigmented nevi, and skeletal stigmata. Pathogenic germline variants of either BMPR1A or SMAD4 cause the syndrome. In JPS a cumulative risk of CRC of 39-68% has been estimated. The oncological risk justifies and imposes prevention strategies that aim at the cancer risk reduction through endoscopic screening, as recommended by international scientific societies. The aim of this review is to summarize clinical and genetic features of JPS and to elucidate the steps of the clinical management from diagnosis to surveillance.


Improving efficiency of clinical skills training: a randomized trial.
The rising number of medical students and the impact this has on students' learning of clinical skills is a matter of concern. Cooperative learning in pairs, called dyad training, might help address this situation. The aim of this study was to evaluate the effect of dyad training on students' patient encounter skills. Experimental, randomized, observer-blinded trial. Forty-nine pre-clerkship medical students without prior clinical experience. All students underwent a 4-h course on how to manage patient encounters. Subsequently, the students were randomized into a dyad practice group (n = 24) or a single practice group (n = 25). Both groups practiced for 4 h on four different case scenarios, using simulated patients. Students in the dyad group practiced together and took turns as the active participant, whereas students in the single group practiced alone. Performance tests of patient encounter skills were conducted 2 weeks after the training by two blinded raters. Students had no clinical training during those weeks. A questionnaire-based evaluation surveyed students' confidence in their patient management skills. The dyad group scored significantly higher on the performance test, mean 40.7 % (SD 6.6), than the single group, mean 36.9 % (SD 5.8), P = 0.04, effect size 0.61. Inter-rater reliability was 0.69. The dyad group expressed significantly higher confidence in managing future clinical patient encounters than the single group, mean 7.6 (SD 0.9) vs. mean 6.5 (SD 1.1), respectively, P < 0.001, effect size 1.16. Dyad training of pre-clerkship medical students' patient encounter skills is effective, efficient, and prompts higher confidence in managing future patient encounters compared to training alone. This training format may help maintain high-quality medical training in the face of an increasing number of students in medical schools.


The experience and understanding of pain management in recently discharged adult trauma patients: A qualitative study.
Pain following injury is often intense, prolonged and debilitating. If poorly managed, this acute pain has the potential to delay rehabilitation and lead to chronic pain. Recent quantitative Australian research recommends implementing further information and interventions to improve trauma patient outcomes, however, to ensure effectiveness, exploration of the patient perspective is imperative to ensure the success of future pain management strategies. This study aimed to gain understanding about the experience of pain management using prescribed analgesic regimens of recently discharged adult trauma patients. Semi-structured interviews were used to explore the experiences and understandings of trauma patients in managing pain using prescribed analgesic regimens during the initial post-hospital discharge period. Twelve participants were purposively selected over a 6-month period at a level one trauma outpatient clinic based on questionnaire responses indicating pain related concerns. Qualitative data were thematically analysed. The overarching finding was that injuries and inadequate pain management incapacitate the patient at home. Four main themes were developed: injury pain is unique and debilitating; patients are uninformed at hospital discharge; patients have low confidence with pain management at home; and patients make independent decisions about pain management. Patients felt they were not given adequate information at hospital discharge to support them to make effective decisions about their pain management practices at home. There is a need for more inclusive and improved hospital discharge processes that includes patient and family education around pain management following injury. To achieve this, clinician education, support and training is essential.


Hepatocellular Carcinoma in The Gambia and the role of Hepatitis B and Hepatitis C.
Hepatocellular Carcinoma is the commonest form of cancer in The Gambia, and although Hepatitis B and Hepatitis C are known risk factors, accurate baseline data on Hepatitis B and Hepatitis C distribution in the region are limited. Similarly data including information on the involvement of the viruses in HCC remains unknown. The current study was undertaken to estimate the risk of HCC in relation to HCV and HBV in The Gambia. Thirteen patients with histological proven history of HCC and 39 healthy controls were enrolled in the study. Each subject blood was screened individually for anti-HCV using ORTHO HCV 3.0 ELISA test system (Ortho-Clinical Diagnostics, Inc, U.S.A) and for HBsAg using QUADRATECH CHECK 4-HBs one step generation hepatitis B surface antigen test kit (VEDALAB, France) following the manufacturers instructions. HBsAg and anti-HCV was detected in 38.5 % (5/13) and 7.7% (1/39) of the persons with a history of HCC respectively. HBsAg but not anti-HCV was detected in 12.8% (5/39 of the case control subjects. HBsAg and HCV rates among the HCC patients were higher in men than women. Rates were highest in patients 48 years and above (37.5%; 3/8). No patient was found with anti-HCV and anti-HBV. These results indicate that the involvement of HBV and HCV in HCC in the country is in a ratio of 5:1 and that these two viruses might be independently involved in the pathogenesis of the disease. The study revealed a statistically significant association (p = 0.04) between HBsAg and HCC patients. The results also indicate that up to 50% of HCC cases in the country may be due to non viral factors and calls for further studies in this regard. These findings call for provision of diagnostic facilities for these viruses in hospitals and for their routine screening in blood banks while intervention programmes should be put in place.


[Study on preparation of refined Xiong-gui sustained release pills].
To optimize the molding formula of refined Xiong-gui sustained release pills, types and assorted dosages of water-soluble and non water-soluble drug carrier were studied. An orthogonal design was performed to sift the pill formulation. The processing conditions were determining in terms of roundness, hardness, viscosity, fluidity, easily drop. According to the final optimal formula, the amount of drug release can be detected instantly, while remaining over 80% at 10 h.


Mutational biosynthesis of ansamitocin antibiotics: a diversity-oriented approach to exploit biosynthetic flexibility.
New ansamitocin derivatives were prepared by feeding aminobenzoic acid derivatives to cultures of Actinosynnema pretiosum HGF073, a mutant strain blocked in the biosynthesis of the required 3-amino-5-hydroxybenzoic acid (AHBA) starter unit. Use of several aminobenzoic acids as precursors led to a spectrum of products, reflecting the sequence of post-PKS tailoring steps involved in the generation of ansamitocins and adding novel aspects to the published suggestion model of post-PKS tailoring logic and flexibility. The studies provide insights into the substrate flexibility of the enzymes required for ansamitocin biosynthesis in A. pretiosum, whereas preliminary biological testing of the derivatives isolated and fully characterized by NMR spectroscopy allowed structure-activity relationship assignments to be made for a variety of intermediates occurring during the post-PKS tailoring sequence in ansamitocin biosynthesis.


Care of foot ulcers in the diabetic patient.
Practice profiles are reflective pieces written by nurses in practice, and based on continuing professional development articles. This week Sian Davies discusses diabetic foot ulcers.


Tailoring antibody testing and how to use it in the calculated panel reactive antibody era: the Northwestern University experience.
Patients with human leukocyte antigen antibodies constitute a significantly disadvantaged population among those awaiting renal transplantation. We speculated that more understanding of the patients' antibody makeup would allow a more "immunologic" evaluation of crossmatch data, facilitate the use of virtual crossmatch (XM), and lead to more transplantability of these patients. We retrospectively compared the transplantability and transplant outcome of two consecutive patient populations transplanted in our center. Group I (n=374) was evaluated using solid-phase base testing for determination of percentage panel reactive antibody ("PRA screen") with limited antibody identification testing. Group II (n=333) was tested in a more comprehensive manner with major emphasis on antibody identification, antibody strength assignment, and the use of pronase for crossmatch. Given this approach, 49% (166/333) of the transplanted patients in group II were sensitized compared with 40% (150/374) of the recipients in group I; P=0.012. Transplant outcome at 1-year posttransplant was similar in both groups. We conclude that comprehensive evaluation of human leukocyte antigen sensitization and application of immunologic in analyzing compatibility between donor and recipient can increase the transplantability of sensitized patients while maintaining similar outcome. Our approach is in line with United Network for Organ Sharing new guidelines for calculated panel reactive antibody and virtual XM analysis. We hope this report will prompt additional transplant programs to consider how they will use the new United Network for Organ Sharing algorithms.


Neurotensin and substance P immunoreactive nerve endings in the guinea pig carotid sinus and their ultrastructural counterparts.
The carotid sinus of the guinea pig was analysed immunohistochemically for the occurrence of neuropeptides. Immunoreactivity (IR) for neurotensin (NT) and substance P (SP) is distributed in two different populations of nerve endings and varicosities. NT-IR fibers penetrate deeply into the tunica media of the elastic segment of the carotid sinus and form the large, branched lanceolate nerve terminals. Electron-microscopic investigations have revealed that the NT-IR varicosities correspond to the large afferent baroreceptor endings containing abundant mitochondria. SP-IR fibers are located mainly at the media-adventitial border. They seem to be correlated to dense-core, vesicle-containing varicosities identified in the electron microscope. Therefore, these fibers may constitute afferent and efferent perivascular plexus regulating the vascular tone of the carotid sinus wall.


Sequencing of Renal Mass Biopsy and Ablation: Results from the National Cancer Database.
We assessed current utilization and sequencing of renal mass biopsy (RMB) and thermal ablation for renal cell carcinoma (RCC) patients in the United States. The 2004-2014 National Cancer Database was queried for adult patients with histopathologically diagnosed American Joint Committee on Cancer stage I RCC ≤5 cm undergoing RMB and thermal ablation. RMB sequencing was stratified into "staged RMB" (separate sessions for RMB/ablation) or "concomitant RMB" (same date RMB/ablation). Demographics, cancer variables and time trends were compared. Univariate and multivariable logistic regression identified predictors of concomitant RMB, and evaluated their impact on inpatient hospital stay and 30-day unplanned readmissions. A total of 6,323 patients were included, of whom 2,913 (46.1%) underwent staged RMB and 3,410 (53.9%) underwent concomitant RMB. Concomitant RMB was more frequently performed until 2012, and staged RMB thereafter (trend p <0.001). In multivariable logistic regression models, private insurance, clear cell RCC, right-sided disease and smaller tumor diameter demonstrated higher probability of concomitant RMB. Furthermore, geographical differences across the United States were evident (concomitant RMB West/South Central region 64.6% versus New England 29.3%, multivariable p <0.05). Concomitant RMB was associated with greater odds of inpatient hospital stay (multivariable OR=1.42, 95% CI=1. 27-1. 60; p <0.001) and 30-day unplanned hospital readmissions (OR=1.55, 95% CI=1.07-2.27; p=0.022). Staged RMB is more frequently performed in more recent years and is associated with lower odds of inpatient hospital stay and unplanned readmissions within 30 days. These potential benefits, combined with the potential to limit ablation of benign tumors, need to be weighed against additional health care costs and inconvenience associated with 2 interventions.


Successful treatment of large cutaneous facial Rosai-Dorfman disease using combination of subtotal resection and ALA-PDT: A case report.
Rosai-Dorfman disease (RDD), also called sinus histiocytosis with massive lymphadenopathy, is a rare, benign and self-limited histiocytosis. We present a case of cutaneous Rosai-Dorfman disease (CRDD) on the right cheek that responded well to combination of subtotal resection and ALA-PDT. We believe that the combination of subtotal resection and ALA-PDT treatment for large cutaneous facial Rosai-Dorfman disease patients is a more effective, highly satisfying, and quick therapy worth promoting.


Childhood conduct problems are associated with increased partnership and parenting difficulties in adulthood.
This paper uses data from a sample of 337 parents studied at age 30 to examine the linkages between childhood conduct problems assessed at ages 7-9 and later partnership and parenting outcomes. The key findings of this study were: 1) increasing levels of childhood conduct problems were associated with increased risk of partnership difficulties, including relationship ambiguity, inter-partner conflict/violence and lower levels of relationship satisfaction; 2) increasing levels of childhood conduct problems were associated with increased risk of parenting difficulties, including over-reactivity, lax and inconsistent discipline, child physical punishment and lower levels of parental warmth and sensitivity. These findings were consistent across both parent reports and interviewer ratings, and in nearly all cases remained after extensive adjustment for confounding and selection bias. Study findings add to the growing body of evidence documenting the adverse consequences of early conduct problems for later adult interpersonal relationships and parenting behaviors.


Leptin levels and IgF-binding proteins in malnourished children: effect of weight gain.
Although it is well known that leptin reflects body fat content in adults, the regulation of leptin levels during childhood malnutrition is poorly understood. Insulin-like growth factor I (IGF-I) and the IGF-binding proteins (IGFBPs) may play important roles in the regulation of body composition. We investigated the relation between leptin, IGF-I, and IGFBPs in children with protein-energy malnutrition (PEM; before and after recovering 10% of their initial body weights) in comparison with well-nourished children. Fifteen PEM and 16 healthy children were studied on admission and after 10% weight gains in the malnourished group. Leptin was measured with radioimmunoassay, IGF-I and IGFBPs were measured with immunoradiometric assay. Patients with PEM had a significantly lower body mass index and percentage of body fat than did the control children. Before weight gain, leptin, IGF-I, and IGFBP-3 were significantly lower and IGFBP-1 was elevated in the malnourished group compared with the control group. Among PEM patients, after 10% weight gains, the levels of leptin, IGF-I, and IGFBP-3 were significantly higher and IGFBP-1 significantly lower compared with the control group. Leptin correlated significantly with IGF-I in the normal children (r(s) = 0.86, P < 0.005). On admission, no correlation was observed between leptin and IGF-I (r(s) = 0.08, P < 0.16) and between leptin and IGFBP-3 (r(s) = 0.02, P < 0.27) in the malnourished group, but those levels improved after 10% recovery of their body weights (r(s) = 0.47, P < 0.002 and r(s) = 0.42, P < 0.005, respectively). In the PEM group, IGF-I correlated significantly with IGFBP-3 when the children gained weight (before: r(s) = 0.006, P < 0.31; after: r(s) = 0.32, P < 0.01). Our study showed results similar to those of anorexia nervosa studies, but the normalization of study variables was obtained in considerable less time for the same weight gain. The main finding of this study was that, after refeeding with only a 10% weight gain, the PEM children normalized their leptin, IGF-I, and IGFBP-3 levels. These results provide evidence that leptin can function as link between this hormonal response and improved nutrition status.


Modeling relapse in animals.
Alcohol addiction is a chronically relapsing disorder characterized by compulsive alcohol seeking and use. Alcohol craving and long-lasting vulnerability to relapse present a great challenge for the successful treatment of alcohol addiction. Therefore, relapse prevention has emerged as a critically important area of research, with the need for effective and valid animal models of relapse. This chapter provides an overview of the repertoire of animal models of craving and relapse presently available and employed in alcoholism research. These models include conditioned reinstatement, stress-induced reinstatement, ethanol priming-induced reinstatement, conditioned place preference, Pavlovian spontaneous recovery, the alcohol deprivation effect, and seeking-taking chained schedules. Thus, a wide array of animal models is available that permit investigation of behaviors directed at obtaining access to alcohol, as well as neurobehavioral mechanisms and genetic factors that regulate these behaviors. These models also are instrumental for identifying pharmacological treatment targets and as tools for evaluating the efficacy of potential medications for the prevention of alcohol craving and relapse.


Perception and reality-a study of public and professional perceptions of plastic surgery.
A questionnaire survey of the perception of plastic surgery amongst 1567 members of the public, general practitioners and medical students is presented. Closed-ended format questions were designed to assess understanding of the range of conditions managed by plastic surgeons. Respondents were asked to match nine surgical specialists with 40 conditions or procedures. To investigate understanding of the multidisciplinary nature of some surgery, respondents were asked which type of surgeon might have a supplementary role. Completed questionnaires from 1004 members of the public, 335 general practitioners, and 228 medical students are presented (responses rate>65%). Significant differences were identified between public respondents and other groups. Plastic surgery was associated with reconstruction for trauma and cancer and procedures with a strong aesthetic element by all three groups. The public were poorly informed about some core plastic surgery including burns, melanoma and hand surgery. General practitioner and student respondents had a better understanding of the diversity of the specialty. However, both groups considered orthopaedic surgeons and not plastic surgeons to be hand surgeons. The strengths and weaknesses of this study are discussed together with potential areas for education and promotion.


The bipolar needle for vasectomy. I. Experience with the first 1000 cases.
A battery-powered, bipolar electrocoagulator has been specifically developed for sealing the cut ends of the divided vas at vasectomy. With a minimum of electric power, the electrocoagulator destroys only the mucosa and one or two muscle cell layers of the vas, which leads to optimal fibrosis of the cut ends. This instrument has been used in more than 1000 vasectomies without a known failure and with a minimum of complications. An analysis of these cases is reported with emphasis upon the method's success in sealing the vas.


Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis.
Trabectedin in combination with pegylated liposomal doxorubicin (PLD) improves progression-free survival (PFS) compared to PLD alone in recurrent ovarian cancer (J Clin Oncol 2010;28:3107-14). Women, stratified by performance status (0-1 versus 2) and platinum sensitivity (platinum-free interval [PFI]<6 versus ≥ 6 months), were randomly assigned to receive PLD 30 mg/m(2) IV followed by a 3-h infusion of trabectedin 1.1mg/m(2) every 3 weeks or PLD 50mg/m(2) every 4 weeks. The study was powered to show a 33% increase in overall survival (OS) after 520 deaths had occurred. After a median follow-up of 47.4 months, there were 522 deaths among 672 subjects. The median OS for trabectedin+PLD and PLD arms was 22.2 and 18.9 months, respectively (hazard ratio [HR]=0.86; 95% confidence interval [CI]: 0.72-1.02; p=0.0835). An unexpected but significant imbalance in the PFI favouring the PLD arm (mean PFI: PLD=13.3 months, trabectedin+PLD=10.6 months) was identified. On the basis of this finding, an unplanned hypothesis generating analysis adjusting for the PFI imbalance and other prognostic factors suggested an improvement in OS associated with the trabectedin+PLD arm (HR=0.82; 95%CI: 0.69-0.98; p=0.0285). In another unplanned exploratory analysis, the subset of patients with a PFI of 6-12 months had the largest difference in OS (HR=0.64; 95%CI: 0.47-0.86; p=0.0027). The final OS analysis did not meet the protocol-defined criterion for statistical significance. Despite stratification on platinum sensitivity, there was an imbalance in mean platinum free interval that had an effect on OS.


Human amniotic mesenchymal stem cells-derived IGFBP-3, DKK-3, and DKK-1 attenuate liver fibrosis through inhibiting hepatic stellate cell activation by blocking Wnt/β-catenin signaling pathway in mice.
Liver fibrosis is an outcome of restoring process in chronic liver injury. Human amniotic mesenchymal stem cells (hAMSCs) derived from amniotic membrane have multilineage differentiation, immunosuppressive, and anti-inflammatory potential which makes them suitable for treating liver fibrosis. This study aimed to explore the effect and mechanism of hAMSCs on liver fibrosis. hAMSCs were transplanted into carbon tetrachloride (CCl4)-induced liver fibrosis mice via tail vein, and the effects of hAMSCs on hepatic fibrosis were assessed. The effects of hAMSCs and hAMSCs conditional medium (CM) on the activation of hepatic stellate cells (HSCs) were investigated in vivo and in vitro. Antibody array assay was used to identify the cytokines secreted by hAMSCs that may inhibit the activation of HSCs. Finally, the underlying mechanisms were explored by assessing IGF-1R/PI3K/AKT and GSK3β/β-catenin signaling pathways in the activated HSCs (LX-2) with hAMSCs and hAMSCs transfected with corresponding siRNAs. Our results showed that hAMSCs possessed the characterizations of mesenchymal stem cells. hAMSCs significantly reduced liver fibrosis and improved liver function in mice by inhibiting HSCs activation in vivo. Both hAMSCs and hAMSC-CM remarkably inhibited the collagen deposition and activation of LX-2 cells in vitro. Antibody array assay showed that insulin-like growth factor binding protein-3 (IGFBP-3), Dickkopf-3 (DKK-3), and Dickkopf-1 (DKK-1) were highly expressed in the co-culture group and hAMSC-CM group compared with LX-2 group. Western blot assay demonstrated that IGFBP-3, DKK-3, and DKK-1 derived from hAMSCs inhibit LX-2 cell activation through blocking canonical Wnt signaling pathway. Our results demonstrated that IGFBP-3, Dkk3, and DKK-1 secreted by hAMSCs attenuated liver fibrosis in mice through inhibiting HSCs activation via depression of Wnt/β-catenin signaling pathway, suggesting that hAMSCs or hAMSC-CM provides an alternative therapeutic approach for the treatment of liver fibrosis.


The role of Rho GTPases and associated kinases in regulating neurite outgrowth.
Neurones are highly specialised cells that can extend over great distances, enabling the complex networking of the nervous system. We are beginning to understand in detail the molecular mechanisms that control the shape of neurones during development. One family of proteins that are clearly essential are the Rho GTPases which have a pivotal role in regulating the actin cytoskeleton in all cell types. The Rho GTPases are responsible for the activation and downregulation of many downstream kinases. This review discusses individual kinases that are regulated by three members of the Rho GTPases, Rac, Rho and Cdc42 and their function during neurite outgrowth and remodelling.


[Prediction of spinal cord ischemia with a retrievable stent graft on endovascular treatment for a case of thoracic aortic aneurysm].
Multiple aortic aneurysms in Behçet's disease were repaired with transluminaly placed endovascular stent grafts. Before deploying the stent graft device for permanent implantation for the saccular aneurysm located in the descending thoracic aorta, from which feeding arteries for the spinal cord possibly branched, a retrievable stent graft was inserted and evoked spinal cord potential (ESP) were monitored in order to predict spinal cord ischemia. The original retrievable stent graft, constructed of a self-expandable Z-shaped stainless steel stent covered with e-PTFE, can be easily withdrawn into a 18 Fr. sheath after deployment. Blood flow into intercostal arteries branching from that part of the descending aorta where the permanent stent graft is planned to be implanted, is intercepted by the retrievable stent graft. A change of ESP during the temporary implantation of the device indicates that spinal cord ischemia would be caused by permanent implantation of the stent graft. In this case, no change of ESP was observed and the patient showed no postoperative paraplegia. The retrievable stent graft was useful for prediction of spinal cord ischemia before endoluminal stent graft repair of the descending aortic aneurysm. However, the device is not flexible enough to fit a severely tortuous aorta, therefore we are obliged to select patients to some extent. Further improvement of the device is required to make prediction of spinal cord ischemia with the retrievable stent graft possible in all cases.


Case management interviews and the return to work of disabled employees.
This study measures the effect of case management interview (CMI) on 1,000 long-term sick-listed employees' probability of returning to work. In contrast to previous studies, we use instrumental variables to correct for selection effects in CMI. Using a competing hazard rate model, we find that CMI increases the probability of returning to work for the pre-sick leave employer, but has no effect on the probability of resuming work for a new employer. We argue that CMI either motivates the sick-listed employees to resume work or adjusts for asymmetric information between the employee and the pre-sick leave employer.


True aneurysm of the radial artery: report of a case with long-term follow-up.
Reports on aneurysm of the arteries of the wrist and hand are relatively rare. Presented here is a case of true aneurysm of the radial artery in a 41-year-old-man. The patient had an enlarging painful swelling on the volar aspect of the left wrist, of six months' duration. Under local anesthesia, a transverse incision over the wrist crease revealed an arterial aneurysm. The aneurysm was excised, followed by end-to-end anastomosis. The patient recovered uneventfully and was discharged nine days after the operation. A follow-up arteriogram, five days later, showed a patent radial artery with good blood flow. This is an excellent example of a successful reconstructive surgical procedure involving a small artery.


Discoidin domain receptor 1 mediates collagen-induced inflammatory activation of microglia in culture.
Discoidin domain receptor 1 (DDR1) is a nonintegrin collagen receptor tyrosine kinase with an extracellular domain homologous to discoidin 1 of a soil-living amoeba Dictyostelium discoideum. We have previously demonstrated that DDR1 mediates collagen-induced nitric oxide production in J774A.1 murine macrophages. Because collagen is one of the main components of extracellular matrix in the central nervous system, we hypothesized that collagen also induces inflammatory activation of brain microglia, and DDR1 may mediate collagen-induced microglial activation. Using BV-2 mouse microglial cells and mouse primary microglial cultures, we have demonstrated that (1) collagen induces inflammatory activation of microglia as evidenced by production of nitric oxide, expression of inducible nitric oxide synthase, COX-2, CD40, and matrix metalloproteinase-9; (2) DDR1 is expressed in microglia and is phosphorylated by collagen treatment; and (3) collagen-induced microglial activation is abrogated by DDR1 blockade but not by integrin neutralization. We have further shown that p38 MAPK, c-Jun N-terminal kinase, and nuclear factor-kappa B are involved in the collagen-DDR1-induced microglial activation. Our results suggest that collagen can induce inflammatory activation of brain microglia and that DDR1 mediates this effect of collagen in an integrin-independent manner.


Reduction of nitroheterocyclic compounds by mammalian tissues in vivo.
To determine whether nitro group reduction occurs in mammalian tissues, metronidazole (0.021, 0.064 and 10 mg/kg), misonidazole (0.015 mg/kg) and nitrofurazone (0.13 mg/kg), respectively, were administered to germfree rats. A reduced metabolite [1-(2-aminoimidazol-1-yl)-3-methoxypropan-2-ol] and two of its hydrolysis products, urea and (2-hydroxy-3-methoxypropyl)-guanidine, were found in the urines of germfree rats that received misonidazole. When nitrofurazone was administered, a reduced metabolite, 4-cyano-2-oxobutyraldehyde semicarbazone, was detected in the urines. However, acetamide and N-(2-hydroxyethyl)oxamic acid, fragmentation products from the reduction of metronidazole, were not found in significant concentrations in the urine when germfree rats received metronidazole. Apparently metronidazole is reduced so much more slowly than misonidazole and nitrofurazone in the tissues of germfree rats that its reductive metabolites are not detectable. This observation may be explained by the one-electron reduction potentials (E1 7) of these drugs, that of metronidazole (E1 7 = -486 mV) being lower than those of either misonidazole (E1 7 = -389 mV) or nitrofurazone (E1 7 = -257 mV). Under these circumstances, metronidazole reduction is not detected, either because its radical anion forms more slowly than that of the other nitroheterocyclic compounds or because its radical anion interacts more rapidly with oxygen to restore the parent compound.


Synthesis, RL and OSL characterization of thulium doped NaMgF3 neighborite.
The aim of this work is to study the dosimetric properties of tissue-equivalent thulium doped NaMgF3 neighborites and to determine their possible application as dosimeters in personal dosimetry. In this aspect, radioluminescence (RL) and optically stimulated luminescence (OSL) dosimetric properties of undoped and Tm3+ -doped NaMgF3 have been investigated for the first time. Samples were synthesized by solid state reaction and by considering a stoichiometric mixture of pure NaF and MgF2 reagents. Two emission peaks centered at 460 and 360 nm have been found in the RL emission spectrum of the doped samples, which can be ascribed to the 1D2 - 3F4 and 1D2 - 3H6 transitions of Tm3+ cations, respectively. Maximum OSL emission under blue light stimulation has been found for samples doped with 0.2 mol % of thulium. Furthermore, the OSL signal of this compound depends linearly on dose within the range 0.05-100 Gy. Besides, its OSL signal features satisfactory repeatability and a minimum detectable dose of 0.04 Gy. Finally, it has been found a low fading of the OSL signal of approximately 13% after the first 60 h, after which the OSL response remains constant. The obtained results suggest the feasibility of using this compound as an OSL detector in personal dosimetry.


Coproporphyrin-I: A Fluorescent, Endogenous Optimal Probe Substrate for ABCC2 (MRP2) Suitable for Vesicle-Based MRP2 Inhibition Assay.
Inside-out-oriented membrane vesicles are useful tools to investigate whether a compound can be an inhibitor of efflux transporters such as multidrug resistance-associated protein 2 (MRP2). However, because of technical limitations of substrate diffusion and low dynamic uptake windows for interacting drugs used in the clinic, estradiol-17β-glucuronide (E17βG) remains the probe substrate that is frequently used in MRP2 inhibition assays. Here we recapitulated the sigmoidal kinetics of MRP2-mediated transport of E17βG, with apparent Michaelis-Menten constant (Km) and Vmax values of 170 ±17 µM and 1447 ± 137 pmol/mg protein/min, respectively. The Hill coefficient (2.05 ± 0.1) suggests multiple substrate binding sites for E17βG transport with cooperative interactions. Using E17βG as a probe substrate, 51 of 97 compounds tested (53%) showed up to 6-fold stimulatory effects. Here, we demonstrate for the first time that coproporphyrin-I (CP-I) is a MRP2 substrate in membrane vesicles. The uptake of CP-I followed a hyperbolic relationship, adequately described by the standard Michaelis-Menten equation (apparent Km and Vmax values were 7.7 ± 0.7 µM and 48 ± 11 pmol/mg protein/min, respectively), suggesting the involvement of a single binding site. Of the 47 compounds tested, 30 compounds were inhibitors of human MRP2 and 8 compounds (17%) stimulated MRP2-mediated CP-I transport. The stimulators were found to share the basic backbone structure of the physiologic steroids, which suggests a potential in vivo relevance of in vitro stimulation of MRP2 transport. We concluded that CP-I could be an alternative in vitro probe substrate replacing E17βG for appreciating MRP2 interactions while minimizing potential false-negative results for MRP2 inhibition due to stimulatory effects.


Newer anticonvulsant medications in pediatric neurology.
Antiepileptic drugs (AEDs) are the mainstay of treatment for recurrent seizures. Uncontrolled seizures may cause medical, developmental, and psychological disturbances. The medical practitioner should thus strive to eliminate or minimize seizures. Treatment advances in epilepsy include 1) identification of the basic mechanisms of epilepsy and action of AEDs, 2) the introduction of new AEDs, and 3) the use of neurostimulation, including vagus nerve stimulation. Treatment with AEDs involves balancing each AED's efficacy against its side effects. In some patients, effective AEDs must be discontinued because of intolerable side effects. Although all AEDs have a proven efficacy, the choice of AEDs should be based on better efficacy for individual seizure types or epilepsy syndromes. Side effects also differ from drug to drug and must be taken into account. This article focuses on studies and expert opinion consensus to guide the choice of AEDs.


Kurloff cell ultrastructure after combined formaldehyde-cetylpyridinium chloride fixation and high-iron diamine staining.
This study deals with the ultrastructure of the chondroitin sulphate proteoglycans of the Kurloff body, a large lysosomal organelle that stains metachromatically with Toluidine Blue and which is present in Kurloff cells (a blood cell unique to the guinea pig). Splenic tissues were fixed with 1% cetylpyridinium chloride (CPC) added to 4% paraformaldehyde and examined either after Spicer's high-iron diamine staining for sulphated anionic sites followed by post-fixation with ferrocyanide-osmium tetroxide or after a simple post-fixation with ferrocyanide-osmium tetroxide. CPC-precipitated sulphated sites were preferentially located at the periphery of the Kurloff body but, unexpectedly, were absent in the central matrix. Although their electron opacity was lower, these anionic sites were readily observable in the absence of HID-staining after sole post-fixation by ferrocyanide-reduced osmium. CPC-precipitated sulphated anionic sites were either associated with the myelin figures or constituted unexpected structures. They contained (i) tightly-stacked lamellae, with a very regular 4 nm periodicity, and (ii) groups of 2, 3, 4 short dense lines with a 3-5 nm periodicity. By taking into account the susceptibility of these HID-reactive structures towards chondroitinase ABC, these different sulphated components were assumed to be related to the proteochondroitin-4-sulphate previously characterized as the only major sulphated glycoconjugate of the Kurloff cell. Their colocalization with phospholipidic structures was suggested following observation of sections treated by a chloroform-methanol mixture.


[Evaluation of efficacy and safety of bevacizumab combined with chemotherapy for Chinese patients with advanced non-small cell lung cancer].
The current study reported the result of bevacizumab treatment administered to 25 Chinese patients with advanced non-small cell lung cancer (NSCLC) who were treated at the Peking Union Medical College Hospital as a part of the SAiL (MO19390) trial. This trial is an open, international multicenter, single-arm clinical study that assesses the safety and efficacy of first-line bevacizumab-based therapy in advanced NSCLC. Twenty-five Chinese patients with advanced non-squamous NSCLC received bevacizumab (15 mg/kg) combined with chemotherapy (carboplatin plus paclitaxel) treatment from August 2007 to February 2008. Adverse effects (AEs), objective response rate (ORR), median time to progression (TTP), and overall survival (OS) were measured. AEs were generally mild and reversible. The most frequent AEs were alopecia, peripheral neuropathy, rash, proteinuria, nausea/vomitting, fatigue, myalgia, bleeding, and hypertension. The partial remission and stable disease rates were 68% and 28%, respectively. The median TTP and OS of all patients were 11.2 and 19.3 months, respectively. Bevacizumab combined with carboplatin-based chemotherapy may be well tolerated and beneficial for Chinese patients with non-squamous NSCLC.


Modulation of hypothalamic neuronal activity through a novel G-protein-coupled estrogen membrane receptor.
Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation and motivated behaviors. The actions of 17beta-estradiol (E(2)) in the brain have been attributed to the activation of estrogen receptors alpha and beta, as well as G-protein-coupled or other membrane-associated estrogen receptors. Recently, we have identified a putative membrane-associated estrogen receptor that is coupled to desensitization of GABA(B) receptors in guinea pig and mouse hypothalamic neurons including proopiomelanocortin (POMC) neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the Galphaq-coupled phospholipase C-protein kinase C-protein kinase A pathway, and have established that STX is more potent than E(2) in mediating this desensitization in an ICI 182,780-sensitive manner in both guinea pig and mouse neurons. Both E(2) and STX are fully efficacious in estrogen receptor alpha, beta knock-out mice. Finally, we observed that the putative membrane-associated estrogen receptor is different from GPR30 in arcuate neurons using whole-cell patch recording in hypothalamic slices from GPR30 knock-out mice. Collectively, these findings suggest that the mER is distinct from ERalpha, ERbeta or GPR30.


Intensive care admissions among ovarian cancer patients treated with primary debulking surgery and neoadjuvant chemotherapy-interval debulking surgery.
Admissions to intensive care units (ICU) are costly, but are necessary for some patients undergoing radical cancer surgery. When compared to primary debulking surgery (PDS), neoadjuvant chemotherapy (NACT) with interval debulking surgery, is associated with less peri-operative morbidity. In this study, we compare rates, indications and lengths of ICU stays among ovarian cancer patients admitted to the ICU within 30days of cytoreduction, either primary or interval. A retrospective chart review was performed of patients with stage III-IV ovarian cancer who underwent surgical cytoreduction at two large academic medical centers between 2010 and 2014. Chi square tests, Student t-tests, and Mann-U Whitney tests were used. A total of 635 patients were included in the study. There were 43 ICU admissions, 7% of patients. Compared to NACT, a higher percentage of PDS patients required ICU admission, 9.4% vs 3.9% of patients (P=0.004). ICU admission indications did not vary between PDS and NACT patients. NACT patients admitted to the ICU had comparable mean surgical complexity scores to those PDS patients admitted to the ICU, 6.2 (95%CI 5.3-7.1) vs 4.5 (95%CI 3.1-6.0) (P=0.006). Length of ICU admission did not vary between groups, PDS 2.7days (95%CI 2.3-3.2) vs 3.5days (95%CI 1.5-5.6) for NACT (P=0.936). The rate of ICU admissions among patients undergoing PDS is higher than for NACT. Among patients admitted to the ICU, indications for admission, length of stay and surgical complexity were similar between patients treated with NACT and PDS.


Evidence for nonlikage of genes for HLA and hereditary angioedema.
Since the genes for several disorders of the complement system have been found to be linked to the HLA loci on chromosome 6, studies of the inhibitor of the activated first component of complement (Cl INH) and HLA in two families with hereditary angioedema (HAE) were undertaken. A total of 17 individuals were found to be affected in these three-generation families. Evidence was provided against close linkage of the genes for HLA and HAE. Other genetic markers studied were generally noninformative, although evidence was obtained against close linkage of the loci for HAE and ABO and HAE and transferrins. The reliable identification of individuals affected with HAE by Cl INH assay provides potential for establishing linkage relationships in the various phenotypes of this dominantly inherited condition.


The role of leukotrienes in asthma.
Leukotrienes (LT), both the cysteinyl LTs, LTC(4), LTD(4) and LTE(4), as well as LTB(4) have been implicated in the clinical course, physiologic changes, and pathogenesis of asthma. The cysteinyl LTs are potent bronchoconstrictors, which have additional effects on blood vessels, mucociliary clearance and eosinophilic inflammation. In addition, the cysteinyl LTs are formed from cells commonly associated with asthma, including eosinophils and mast cells. LTB(4), whose role is less well defined in asthma, is a potent chemoattractant (and cell activator) for both neutrophils and eosinophils. In the last 5 years, drugs have been developed which block the actions or formation of these mediators. Clinical and physiologic studies have demonstrated that they are modest short-acting bronchodilators, with sustained improvement in FEV(1) occurring in double-blind, placebo-controlled clinical trials for up to 6 months. These drugs have demonstrated efficacy in preventing bronchoconstriction caused by LTs, allergen, exercise and other agents. Additionally, there are multiple published studies which have demonstrated improvement in asthma symptoms, beta agonist use and, importantly, exacerbations of asthma in both adults and children. Comparison studies with inhaled corticosteroids (ICS) suggest that ICS are superior to leukotriene modifying drugs in moderate persistent asthma. However, several published studies now suggest that leukotriene modifying drugs are effective when added to ongoing therapy with ICS, either to improve current symptoms or to decrease the dose of ICS required to maintain control. While an anti-inflammatory effect is suggested, longer-term, earlier intervention, studies are needed to determine whether these compounds will have any effect on the natural history of the disease.


New antifungal tetrahydrofuran derivatives from a marine sponge-associated fungus Aspergillus sp. LS78.
Two new tetrahydrofuran derivatives named aspericacids A and B (1 and 2) were isolated from the metabolites produced by the sponge-associated Aspergillus sp. LS78. They represented an unusual type of tetrahydrofuran derivatives, possessing 2,5-disubstituted tetrahydrofuran ring coupled with a chain unsaturated fatty acid. The planar structures of 1 and 2 were determined by HRESIMS, 1D and 2D NMR spectroscopy. The absolute configuration of 1 was assigned using both experimental and computational electronic circular dichroism (ECD). In addition, aspericacid A (1) exhibited in vitro antifungal activity (MIC = 50 μg/mL), but 2 showed not significantly activity against any of the tested strains with the MIC values of 128 μg/mL.


Phenanthroline-carbolong interface suppress chemical interactions with active layer enabling long-time stable organic solar cells.
To restrain the chemical reaction at cathode interface of organic solar cells, two cathode interfacial materials are synthesized by connecting phenanthroline with carbolong unit. Consequently, the D18:L8-BO based organic solar cell with double-phenanthroline-carbolong achieve the highest efficiency of 18.2%. Double-phenanthroline-carbolong with larger steric hindrance and stronger electron-withdrawing property confirms to suppress the interfacial reaction with norfullerene acceptor, resulting the most stable device. Double-phenanthroline-carbolong based device can sustain 80% of its initial efficiency for 2170 h in dark N2 atmosphere, 96 h under 85 oC and keep 68% initial efficiency after been illuminated for 2200 h, which are significantly better than bathocuproin based devices. Moreover, superb interfacial stability of double-phenanthroline-carbolong cathode interface enables thermal posttreatment of organic sub-cell in perovskite/organic tandem solar cells and obtained a remarkable efficiency of 21.7% with excellent thermal stability, which indicates the potentially wide application of phenanthroline-carbolong materials for stable and efficient solar device fabrications.


Evaluation of the German WPA "program against stigma and discrimination because of schizophrenia--Open the Doors": results from representative telephone surveys before and after three years of antistigma interventions.
In 2001, the World Psychiatric Association's global antistigma-program "Fighting stigma and discrimination because of schizophrenia--Open the Doors" was initiated in Germany. Several measures to tackle the stigma in certain target populations have been proven successful, but the effectiveness of the program on the general population level has not yet been examined. Before the start of a number of antistigma interventions in 2001, a professional survey institute was commissioned to conduct a representative telephone survey in 6 German cities (N=7225). The cities were chosen with respect to the implementation of antistigma programs (Düsseldorf, Munich), awareness programs (Bonn, Cologne; with the aim to enhance early recognition of schizophrenia), and none of the programs (Berlin, Essen). A panel design follow-up survey (N=4622) was conducted in 2004. Stereotypes, beliefs and attitudes about schizophrenia and social distance--i.e. the distance between different groups of society--towards people with schizophrenia, and the knowledge of antistigma projects were assessed. Overall, social distance decreased significantly between 2001 and 2004 (p=0.001). At the city level, this effect was only significant in those cities where antistigma projects were implemented (p<0.001), although the observed attitude changes were small. In cities with antistigma projects, social distance primarily decreased in the social distance subscale "transient social relations" (p<0.001), but not in the subscale "closer social relations". Both subcales did not change significantly in cities without antistigma projects. The present study provides limited evidence for the efficacy of antistigma interventions on the population level in Germany. Further research is needed to separate direct effects of antistigma interventions from more general, indirect influences on social distance.


Larrey hernia complicated with colonic obstruction in a 77-year-old woman: a case report.
Congenital Larrey hernia has a rare incidence and is frequently diagnosed in the later decades of life. This case study presents a 77-year-old woman with Larrey hernia and an intestinal obstruction complication, treated with laparatomic surgery.


Identification of a novel leptin receptor (LEPR) variant and proof of functional relevance directing treatment decisions in patients with morbid obesity.
Deficiency in the leptin-leptin receptor (LEPR) axis leads to severe, and potentially treatable, obesity in humans. To guide clinical decision-making, the functional relevance of variants in the LEPR gene needs to be carefully investigated. We characterized the functional impact of LEPR variants identified in two patients with severe early-onset obesity (1: compound heterozygous for the novel variant p.Tyr411del and p.Trp664Arg; 2: heterozygous for p.Arg612His) by investigating leptin-mediated signaling, leptin binding, receptor expression on cell surfaces, and receptor dimerization and activation for either wild-type and/or mutant LEPR. Leptin-induced STAT3-phosphorylation was blunted the novel p.Tyr411del or the p.Trp664Arg variant and mildly reduced with the p.Arg612His variant. Computational structure prediction suggested impaired leptin binding for all three LEPR variants. Experimentally, reduced leptin binding of all mutant proteins was due to diminished LEPR expression on the cell surface, with the p.Trp664Arg mutations being the most affected. Considering the heterozygosity in our patients, we assessed the heterodimerization capacity with the wild-type LEPR, which was retained for the p.Tyr411del and p.Arg612His variants. Finally, mimicking (compound) heterozygosity, we confirmed abolished STAT3-phosphorylation for the variant combination [p.Tyr411del + p.Trp664Arg] as found in patient 1, whereas it was retained for [p.Arg612His + wilde type] as found in patient 2. The novel p.Tyr411del mutation causes complete loss of function alone (and combined with p.Trp664Arg) and is likely the cause for the early onset obesity, qualifying the patient for pharmacologic treatment. Heterozygosity for the p.Arg612His variant, however, appears unlikely to be solely responsible for the phenotype.


A formulation of the lifetime distribution and the existence of its moments.
The lifetime distribution is formulated in terms of g(t), defined as the ratio of the hazard function to the tail probability function, to study the properties of the lifetime distribution. A criterion is provided for the asymptotic behaviour of g(t) and the hazard function. Criteria for the existence and non-existence of the moments of any probability distribution of a non-negative random variable are obtained in terms of the derivatives of g(t). Examples are given to illustrate the use of the criteria and applications made to stochastic models of population growth as well as other lifetime distributions.


Synthesis, antimicrobial and antiviral testing of some new 1-adamantyl analogues.
A new series of 1-adamantyl derivatives was designed, synthesized and evaluated for their antimicrobial and antiviral activities. Representative derivatives of the newly synthesized compounds were tested. Ampicillin, clotimazole and the antiviral antibiotic aphidicolin were used as positive controls. Compound 18 proved to be the most active member of this series as antimicrobial against Staphylococcus aureus and Candida albicans and as antiviral with IC50 value of 0.21 mg/ml and CD50 value of 0.02 mg/ml while compound 19 proved to be the most active member of this series as antiviral with IC50 value of 0.21 mg/ml and CD50 value of 0.01 mg/ml.


Study of the immunopotentiator effects of dialyzable leukocyte extracts obtained out of leukocytes previously used for interferon production.
The existence of immunopotentiator factors able to induce blastogenesis, chemotaxis and able of inhibiting migration of leukocytes was investigated in alcohol precipitates of different batches of dialyzed leukocyte extracts (DLE). These were prepared either out of fresh leukocytes from a large pool of buffy coats obtained from all blood collected from healthy donors with irrelevant antigen sensitiveness (DLE-NS) or from similar leukocytes which were incubated during 19 h for interferon production (DLE-NS-I). Alternatively, the same factors were investigated on a batch of DLE obtained from a donor exquisitely sensitive to Candida antigen (C-DLE-CS). It was observed that all the three batches contained equal amounts of either specific or nonspecific immunological enhancing factors. The similarity of the intensity of specific factors between the so-called nonspecific batches (DLE-NS and DLE-NS-I) and the specific batch (C-DLE-CS) was interpreted to be the result of the random selection of the donors for the preparation of the nonspecific batches, which consequently contain randomized relevant specificities. It is postulated, therefore, that batches of DLE which represent a large waste of leukocytes used for interferon production can be a useful tool for double-blind DLE therapy purposes.


The association of internal mammary and medial supraclavicular lymph node radiation technique with clinical outcomes: Results from the EORTC 22922/10925 randomised trial.
The multicentre EORTC 22922/10925 trial (ClinicalTrials.gov, NCT00002851) was conducted between 1996 and 2004. The trial evaluated the effect of irradiation of the internal mammary and medial supraclavicular lymph node chains (IM-MS) vs no further radiation therapy (RT) on survival and cause of death in breast cancer stage I-III patients. At 15.7 years of median follow-up, a significant reduction of breast cancer specific mortality (BCSM) and any recurrence, not translating in improved overall survival (OS), and low absolute rates of side effects were found. The aim of the current analysis was to evaluate the association of RT techniques of IM-MS lymph node irradiation with long-term outcomes. Three RT techniques were used for IM-MS: a standard technique using a fixed set-up combining photon/electron beams to the IM and tangential fields to the breast or chest wall vs a standard-modified technique with minor adaptation for beam settings vs a more individualised technique based on individual localisation of the IM. Techniques used were fixed per institution over the duration of the trial. We performed an exploratory and descriptive analysis of the outcomes after 15 years follow-up for the three RT techniques. Between July 1996 and January 2004, 46 radiation oncology departments from 13 countries accrued 4004 patients. Median follow-up was 15.7 years. The number of patients treated by each technique was 2440 (61%) by standard vs 635 (16%) by standard-modified vs 929 (23%) patients by individualised technique. The absolute improvements of oncological outcomes in terms of disease-free survival (DFS), OS and BCSM with IM-MS RT compared to no IM-MS RT were 6.8%, 4.9% and -5.8% for the individualised technique, vs 1.6%, 2.9% and -4.3% for modified standard and -1.4%, 1.1% and -3% for standard technique, respectively. The increase in 15-year rates of side effects due to IM-MS RT, both scored longitudinally and cross-sectionally, were similar among the techniques. Even though a straightforward comparison by technique is not possible because of variations in baseline characteristics between institutions, our findings suggest that the use of more individualised RT techniques is associated with higher rates of oncological improvements without increased risks for late side effects.


A case study in resort climatology of Phoenix, Arizona, USA.
Tourists often use weather data as a factor for determining vacation timing and location. Accuracy and perceptions of weather information may impact these decisions. This study: (a) examines air temperature and dew points from seven exclusive resorts in the Phoenix metropolitan area and compares them with official National Weather Service data for the same period, and (b) utilizes a comfort model called OUTCOMES-OUTdoor COMfort Expert System-in a seasonal appraisal of two resorts, one mesic and one xeric, compared with the urban Sky Harbor International Airport first-order weather station site in the central urban area of Phoenix, Arizona, USA (lat. 33.43 degrees N; long. 112.02 degrees W; elevation at 335 m). Temperature and humidity recording devices were placed within or immediately adjacent to common-use areas of the resorts, the prime recreational sites used by guests on most resort properties. Recorded data were compared with that of the official weather information from the airport station, a station most accessible to potential tourists through media and Web sites, to assess predicted weather for vacation planning. For the most part, Sky Harbor's recorded air temperatures and often dew points were higher than those recorded at the resorts. We extrapolate our findings to a year-round estimate of human outdoor comfort for weather-station sites typical of resort landscapes and the Sky Harbor location using the OUTCOMES model to refine ideas on timing of comfortable conditions at resorts on a diurnal and seasonal basis.


Built-in Electric Field in Quasi-2D CsPbI3 Perovskites Using High-Polarized Zwitterionic Spacer for Enhanced Charge Separation/Transport.
Two-dimensional (2D) halide perovskites are promising candidates for the fabrication of stable and high-efficiency solar cells. However, the low power conversion efficiency (PCE) of cell devices using 2D perovskites is attributed to reduced charge transport caused by poor organic barrier conductivity. In this study, we propose the use of a high-polarized organic zwitterionic spacer, p-aminobenzoic acid (PABA), to construct novel quasi-2D perovskite structures with enhanced self-driven charge separation and transfer. The NH3+ and COO- groups in PABA generate an aligned electric field, promoting carrier separation and aggregation on the opposite edges of the inorganic layer. This enables efficient in-plane transportation along the inorganic layer. Additionally, PABA intercalated quasi-2D perovskite exhibits improved stability compared with counterparts with diamine cation spacers due to the strong interaction between -COO- and inorganic layers. Our findings suggest that high-polarized organic zwitterionic spacers, with NH3+ and COO- functionality, hold promise for stable and efficient quasi-2D perovskite solar cells.


The Efficacy and Safety of Adjuvant Lomustine to Chemotherapy for Recurrent Glioblastoma: A Meta-analysis of Randomized Controlled Studies.
Lomustine is regarded as 1 common anti-vascular endothelial growth factor agent. The efficacy of adjuvant lomustine to chemotherapy remains controversial for recurrent glioblastoma. We conduct this meta-analysis to explore the influence of adjuvant lomustine on treatment efficacy of recurrent glioblastoma. We have searched PubMed, EMBASE, Web of Science, EBSCO, and Cochrane library databases through August 2019 and included randomized controlled trials assessing the efficacy and safety of adjuvant lomustine for recurrent glioblastoma. Four randomized controlled trials are included in the meta-analysis. Overall, compared with the control group for recurrent glioblastoma, adjuvant lomustine has no substantial effect on objective response (risk ratio [RR], 1.32; 95% confidence interval [CI], 0.91 to 1.93; P = 0.15), complete response (RR, 1.76; 95% CI, 0.26-11.90; P = 0.56), progressive response (RR, 1.32; 95% CI, 0.88-1.99; P = 0.18), median progression-free survival (standard mean difference [SMD], 0.73; 95% CI, -0.65 to 2.11; P = 0.30), or median overall survival (SMD, 0.26; 95% CI, -0.30-0.83; P = 0.36), but results in the increase in 6-month progression-free survival (SMD, 1.71; 95% CI, 0.38-3.04; P = 0.01). There is no increase in grade ≥3 adverse events after adjuvant lomustine treatment (RR, 1.55; 95% CI, 0.84-2.89; P = 0.16) compared with control intervention. Adjuvant lomustine to other chemotherapy may provide no obvious benefits for the treatment of recurrent glioblastoma.


Crystallographic structure of a complex between trypsin and a nonapeptide derived from a Bowman-Birk inhibitor found in Vigna unguiculata seeds.
Natural inhibitors of proteases have been classified into different families, among them is the Bowman-Birk Inhibitor (BBI) family. Members of BBI have two structurally reactive loops that simultaneously inhibit trypsin and chymotrypsin. Here, we have investigated the binding of bovine trypsin by a cyclic nonapeptide, named PTRY9 (CTKSIPPQC), derived of the black-eyed pea trypsin/chymotrypsin inhibitor (BTCI) from Vigna unguiculata seeds. This peptide was synthetically produced with the disulfide bond restraining its conformation to mimic the reactive loop that inhibits trypsin. PTRY9 complexed to pancreatic bovine trypsin was crystallized in orthorhombic and trigonal space groups, P212121 and P3221, with maximum resolutions of 1.15 and 1.61 Å, respectively. The structures presented refinement parameters of Rwork = 14.52 % and Rfree = 15.59 %; Rwork = 15.60 % and Rfree = 18.78 %, and different surface area between the peptide and the enzyme of 1024 Å2 and 1070 Å2, respectively. The binding site of the PTRY9 is similar to that found for BTCI as shown by a r.m.s.d. of 0.358 Å between the superimposed structures and the electrostatic complementary pattern at the enzyme-peptide interface. Additionally, enzyme inhibition assays show that the affinity of trypsin for PTRY9 is smaller than that for BTCI. In vitro assays revealed that, like BTCI, this synthetic peptide is not cytotoxic for normal mammary epithelial MCF-10A cells, but exerts cytotoxic effects on MDA.MB.231 invasive human breast cancer cells.


Operative versus conservative treatment of acute Achilles tendon ruptures: preliminary results of clinical outcome, kinematic MRI and contrast-enhanced ultrasound.
There is no uniform consensus on the gold standard therapy for acute Achilles tendon rupture. The aim of this pilot study was to compare operative and conservative treatment regarding imaging findings and clinical outcome. Surgically or conservatively treated patients with acute Achilles tendon rupture were retrospectively evaluated. Differences in tendon length and diameter with and without load were analysed using kinematic MRI, tendon perfusion, structural alterations, movement and scar tissue by means of grey-scale and contrast-enhanced ultrasound (CEUS). Intra- and interobserver agreement were recorded. No significant difference was detected regarding clinical outcome, B mode ultrasonography, contrast-enhanced sonography or MRI findings, although alterations in MRI-based measurements of tendon elasticity were found for both groups. Considerable elongation and thickening of the injured tendon were detected in both groups. Both, conservative and surgical treatment showed comparable outcomes in our preliminary results and may suggest non-inferiority of a conservative approach.


A Computable Phenotype Model for Classification of Men Who Have Sex With Men Within a Large Linked Database of Laboratory, Surveillance, and Administrative Healthcare Records.
Background: Most public health datasets do not include sexual orientation measures, thereby limiting the availability of data to monitor health disparities, and evaluate tailored interventions. We therefore developed, validated, and applied a novel computable phenotype model to classify men who have sex with men (MSM) using multiple health datasets from British Columbia, Canada, 1990-2015. Methods: Three case surveillance databases, a public health laboratory database, and five administrative health databases were linked and deidentified (BC Hepatitis Testers Cohort), resulting in a retrospective cohort of 727,091 adult men. Known MSM status from the three disease case surveillance databases was used to develop a multivariable model for classifying MSM in the full cohort. Models were selected using "elastic-net" (GLMNet package) in R, and a final model optimized area under the receiver operating characteristics curve. We compared characteristics of known MSM, classified MSM, and classified heterosexual men. Findings: History of gonorrhea and syphilis diagnoses, HIV tests in the past year, history of visit to an identified gay and bisexual men's clinic, and residence in MSM-dense neighborhoods were all positively associated with being MSM. The selected model had sensitivity of 72%, specificity of 94%. Excluding those with known MSM status, a total of 85,521 men (12% of cohort) were classified as MSM. Interpretation: Computable phenotyping is a promising approach for classification of sexual minorities and investigation of health outcomes in the absence of routinely available self-report data.


Retigabine promotes ketamine's antidepressant effect in the forced swim test in male and female C57BL/6J mice.
Ketamine has been increasingly used as a rapid-onset antidepressant in specific clinical settings. However, as a psychedelic reagent, the potential of physical and psychological dependence limits its clinical use. Here, we added retigabine, a KCNQ channel opener, as an adjunctive treatment to observe its effect on ketamine's antidepressant property in a forced swim test in both male and female C57BL/6 J mice. Behavioral data demonstrated that intraperitoneal injection of ketamine exhibited a dose-dependent effect on animals' immobility performance in the forced swim test. Adding retigabine was sufficient to induce a remarkable antidepressant effect in mice treated with a relatively lower dose of ketamine which failed to be antidepressant when administrated separately. When simultaneously gave retigabine, ketamine's antidepressant effect in the forced swim test was significantly enhanced with a prolonged effective duration. Together, these results from both male and female mice indicated that adjunctive treatment with retigabine was an alternative to promote the antidepressant effect of ketamine, thus holding the possibility of encountering its possible physical and psychological dependence.