Four-dimensional quantitative analysis of the gait of mutant mice using coarse-grained motion capture.
To analyze an abnormal gait pattern in mutant mice (Hugger), we conducted coarse-grained motion capture. Using a simple retroreflective marker-based approach, we could detect high-resolution mutant-specific gait patterns. The phenotypic gait patterns are caused by extreme vertical motion of limbs, revealing inefficient motor functions. To elucidate the inefficiency, we developed a musculoskeletal computer model of the mouse hindlimb based on X-ray CT data. By integrating motion data with the model, we determined mutant-specific musculotendon lengths, suggesting that three major muscles were involved in the abnormal gait. This approach worked well on laboratory mice, which were putatively too small to be motion capture subjects. Motion capture technology was originally developed for human study, and our approach may help fill neuroscience gaps between mouse and human behavioral phenotypes.


Experiences of family caregivers caring for critically ill children hospitalized in a pediatric intensive care unit: a qualitative systematic review protocol.
This review aims to synthesize the best available evidence on the experiences of family caregivers in caring for their critically ill children who have been hospitalized in a pediatric intensive care unit. The participation of family caregivers in providing health care for critically ill children is increasingly important. Family caregivers are defined as adult family members, including parents and siblings, and are often described as hidden patients, as their health can be neglected when caring for others. Understanding how family caregivers of critically ill children describe their experience will be beneficial in providing family-centered care to these children. This review will consider studies that include adult family caregivers caring for children hospitalized with critical illness in pediatric intensive care units. Any family with a child experiencing a life-threatening illness that may result in significant morbidity or mortality will be considered. Studies that disclose the physical, psychosocial, financial and spiritual experiences of family caregivers will be considered with no geographical limitation. Only English-language studies will be included, with no date limitation. MEDLINE, CINAHL, PsycINFO, Embase, ProQuest Dissertations and Theses, Scopus, ASSIA, SciELO, and Google Scholar will be searched for relevant papers following the completion of the three-step search process. Retrieval of full-text studies, assessment of methodological quality and data extraction will be performed independently by two reviewers. Meta-aggregation will be performed, and a ConQual presented.


Parallel Analysis of Pre- and Postoperative Circulating Tumor DNA and Matched Tumor Tissues in Resectable Pancreatic Ductal Adenocarcinoma: A Prospective Cohort Study.
Circulating tumor DNA (ctDNA) is a promising biomarker for early tumor detection and minimal residual disease (MRD) assessment in early-stage cancer, but quantifying minute amounts of ctDNA is challenging and well-designed studies on ctDNA in early-stage cancer are still lacking. Here, we adapted a sensitive next-generation sequencing (NGS) technology and performed parallel analysis of pre- and postoperative ctDNA and matched tumor tissues in a prospective cohort of patients with resectable pancreatic ductal adenocarcinoma (PDAC). In total, 70 consecutive patients undergoing curative resection for resectable PDAC were enrolled. We performed integrated digital error suppression-enhanced cancer personalized profiling by deep sequencing NGS of triple-matched samples (pre/postoperative plasma cell-free DNA [cfDNA], tumor tissue, and genomic DNA) targeting 77 genes. Preoperative ctDNA was detected in 37.7% of the evaluable patients, with a median variant allele frequency of 0.09%. Twelve additional oncogenic mutations were detected exclusively in preoperative ctDNA but not in tissue. When quantitative concentrations of ctDNA were estimated in haploid genome equivalents per milliliter (hGE/mL), the risk of early recurrence was high in patients with postoperative ctDNA >1 hGE/mL. cfDNA variants from 24.5% of patients had features compatible with clonal hematopoiesis. An optimized NGS approach might add value beyond tissue analysis through the highly sensitive detection of minute amounts of ctDNA in resectable PDAC. Postoperative ctDNA concentration could be a tool for MRD assessment. Moreover, parallel analyses of matched tissues and leukocytes might be required to accurately detect clinically relevant ctDNA.


Caffeic acid prevents acetaminophen-induced liver injury by activating the Keap1-Nrf2 antioxidative defense system.
Acute liver failure induced by acetaminophen (APAP) overdose is the main cause of drug-induced liver injury (DILI). Caffeic acid (CA) is a phenolic compound from many natural products. This study aims to investigate the protective mechanism of CA in APAP-induced liver injury. The results of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, liver glutathione (GSH) and reactive oxygen species (ROS) levels demonstrated the protection of CA against APAP-induced liver injury. Liver histological observation provided further evidences of CA-induced protection. CA was found to reverse the APAP-induced decreased cell viability in human normal liver L-02 cells and HepG2 cells. CA also reduced the increased cellular ROS level induced by APAP in hepatocytes. The results of luciferase assay and Western-blot analysis showed that CA increased the transcriptional activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in the presence of APAP. Nrf2 siRNA reduced the protection of CA against APAP-induced hepatotoxicity. CA also reversed the APAP-induced decreased mRNA and protein expression of heme oxygenase 1 (HO-1) and quinone oxidoreductase 1(NQO1). In addition, HO-1 inhibitor zinc protoporphyrin (ZnPP) and NQO1 inhibitor diminutol (Dim) reduced the protection of CA against APAP-induced hepatotoxicity. CA also decreased the expression of kelch-like ECH-associated protein-1(Keap1). Molecular docking indicated the potential interacting of CA with Nrf2 binding site in the Keap1 protein. CA had little effect on the enzymatic activity of cytochrome P450 (CYP) 3A4 and CYP2E1 in vitro. In conclusion, we demonstrated that CA prevented APAP-induced hepatotoxicity by decreasing Keap1 expression, inhibiting binding of Keap1 to Nrf2, and thus activating Nrf2 and leading to increased expression of antioxidative signals including HO-1 and NQO1.


Prevalence of Multiplicity and Appropriate Adjustments Among Cardiovascular Randomized Clinical Trials Published in Major Medical Journals.
Multiple analyses in a clinical trial can increase the probability of inaccurately concluding that there is a statistically significant treatment effect. However, to date, it is unknown how many randomized clinical trials (RCTs) perform adjustments for multiple comparisons, the lack of which could lead to erroneous findings. To assess the prevalence of multiplicity and whether appropriate multiplicity adjustments were performed among cardiovascular RCTs published in 6 medical journals with a high impact factor. In this cross-sectional study, cardiovascular RCTs were selected from all over the world, characterized as North America, Western Europe, multiregional, and rest of the world. Data were collected from past issues of 3 cardiovascular journals (Circulation, European Heart Journal, and Journal of the American College of Cardiology) and 3 general medicine journals (JAMA, The Lancet, and The New England Journal of Medicine) with high impact factors published between August 1, 2015, and July 31, 2018. Supplements and trial protocols of each of the included RCTs were also searched for multiplicity. Data were analyzed December 20 to 27, 2018. Data from the selected RCTs were extracted and verified independently by 2 researchers using a structured data instrument. In case of disagreement, a third reviewer helped to achieve consensus. An RCT was considered to have multiple treatment groups if it had more than 2 arms; multiple outcomes were defined as having more than 1 primary outcome, and multiple analyses were defined as analysis of the same outcome variable in multiple ways. Multiplicity was examined only for the analysis of the primary end point. Outcomes of interest were percentages of primary analyses that performed multiplicity adjustment of primary end points. Of 511 cardiovascular RCTs included in this analysis, 300 (58.7%) had some form of multiplicity; of these 300, only 85 (28.3%) adjusted for multiplicity. Intervention type and funding source had no statistically significant association with the reporting of multiplicity risk adjustment. Trials that assessed mortality vs nonmortality outcomes were more likely to contain a multiplicity risk in their primary analysis (66.3% [177 of 267] vs 50.4% [123 of 244]; P < .001), and larger trials vs smaller trials were less likely to make any adjustments for multiplicity (35.6% [52 of 146] vs 21.4% [33 of 154]; P = .001). Findings from this study suggest that cardiovascular RCTs published in medical journals with high impact factors demonstrate infrequent adjustments to correct for multiple comparisons in the primary end point. These parameters may be improved by more standardized reporting.


Qualitative data collection to identify truck drivers' attitudes toward a transition to platooning systems.
The platooning technology allows for two or more trucks running in convoy at a pre-defined distance between each other, being virtually connected using connectivity technology and automated driving support systems. It is recognized that truck platooning systems bring economical and environmental advantages. Thus, it is time for a transition from the existing truck freight activity towards truck platooning systems. This requires an important improvement in terms of in-vehicle technology, together with infrastructure improvement and truck drivers' acquisition of new technology-related skills. A holistic approach is previewed to identify both the requirements for the development of truck platooning services and the requests for their safe deployment in the real world. Then, qualitative data were collected from truck drivers working for two different Portuguese freight companies using Focus Groups (FG). Thus, three FG sessions were organized and carried out with a total of 22 truck drivers. Considering that age and experience on the job are important factors to take into consideration for technological changes on the job, their potential impact on truck drivers' activity was addressed on the focus group discussions. Anyway, the potential users' attitudes regarding any innovation on the job were addressed as a prevention of further negative attitudes or misuse. Having safety in mind as a permanent attitude toward on job innovation is actually the most important factor toward success.


Laparoscopic inguinal herniorrhaphy.
Between September 1991 and April 1992, 30 patients were admitted for repair of an inguinal hernia. Four elderly patients were excluded because of other medical conditions. Of the remaining 26 patients laparoscopic hernia repair was carried out successfully in 24; the procedure was abandoned in 2 because of dense adhesions in the pelvis from inflammatory disease. Nineteen of the 24 patients were discharged within 24 hours of operation; the other 5 were treated as outpatients. All patients returned to their normal employment within 7 days of operation. There were no wound infections and no evidence of recurrence at follow-up of up to 10 months. The authors believe that laparoscopic repair may usher in a new era of hernia management.


[What is mastopathy at risk? Epidemiologic and clinical basis].
One out of 11 women is destined to develop breast cancer. All women should be "under observation". Does a "normal" breast really exist? A discharge from a single orifice could suggest a papillomatosis, a real borderline lesion, the adenofibroma practically never degenerates, the essential problem is that of the fibrocystic disease, (or mastosis) which was the object of a recent detailed analysis (W. Dupont and D. Page), pre-menstrual mastodynia does not seem to be a risk factor. On the other hand, certain dystrophic lesions constitute a high risk, such as atypical epithelial hyperplasia, especially if it is associated with a direct family history of breast cancer. Recent studies on mammary cysts insist on their hormone and electrolyte content, the presence of EGF, as well as that of certain proteins (GCDFP 15). They also insist on the local tissue enzymatic activities, the importance of myoepithelial cells and of fibroblasts. On a practical level, the attention is drawn on: cysts whose diameter exceeds 5 mm, certain histological lesions found during the biopsies. The value of mammography and thermography in the assessment of the high risk is discussed. Finally, the present well-established notions are recalled: the family history, late pregnancies, the diet, the weight, certain pathological associations, the endogenous hormonal balance bearing on E2/P and the blood prolactin level, the exogenous hormone intake.


Soft-glass imaging microstructured optical fibers.
We demonstrate the fabrication of multi-core (imaging) microstructured optical fiber via soft-glass preform extrusion through a 3D printed titanium die. The combination of extrusion through 3D printed dies and structured element (capillary) stacking allows for unprecedented control of the optical fiber geometry. We have exploited this to demonstrate a 100 pixel rectangular array imaging microstructured fiber. Due to the high refractive index of the glass used (n = 1.62), such a fiber can theoretically have a pixel pitch as small as 1.8 µm. This opens opportunities for ultra-small, high-resolution imaging fibers fabricated from diverse glass types.


Targeted Dual-Modality Imaging in Renal Cell Carcinoma: An Ex Vivo Kidney Perfusion Study.
Antibodies labeled with both a near-infrared fluorescent dye and a radionuclide can be used for tumor-targeted intraoperative dual-modality imaging. Girentuximab is a chimeric monoclonal antibody against carbonic anhydrase IX (CAIX), an antigen expressed in 95% of clear cell renal cell carcinoma (ccRCC). This study aimed to assess the feasibility of targeted dual-modality imaging with (111)In-girentuximab-IRDye800CW using ex vivo perfusion of human tumorous kidneys. Seven radical nephrectomy specimens from patients with ccRCC were perfused during 11 to 15 hours with dual-labeled girentuximab and subsequently rinsed during 2.5 to 4 hours with Ringer's Lactate solution. Then, dual-modality imaging was performed on a 5- to 10-mm-thick lamella of the kidney. Fluorescence imaging was performed with a clinical fluorescence camera set-up as applied during image-guided surgery. The distribution of Indium-111 in the slice of tumor tissue was visualized by autoradiography. In two perfusions, an additional dual-labeled control antibody was added to demonstrate specific accumulation of dual-labeled girentuximab in CAIX-expressing tumor tissue. Both radionuclide and fluorescence imaging clearly visualized uptake in tumor tissue and tumor-to-normal tissue borders, as confirmed (immuno)histochemically and by gamma counting. Maximum uptake of girentuximab in tumor tissue was 0.33% of the injected dose per gram (mean, 0.12 %ID/g; range, 0.01-0.33 %ID/g), whereas maximum uptake in the normal kidney tissue was 0.04 %ID/g (mean, 0.02 %ID/g; range, 0.00-0.04 %ID/g). Dual-labeled girentuximab accumulated specifically in ccRCC tissue, indicating the feasibility of dual-modality imaging to detect ccRCC. A clinical study to evaluate intraoperative dual-modality imaging in patients with ccRCC has been initiated. Clin Cancer Res; 22(18); 4634-42. ©2016 AACR.


Temporal and spatial analysis of psittacosis in association with poultry farming in the Netherlands, 2000-2015.
Human psittacosis is a highly under diagnosed zoonotic disease, commonly linked to psittacine birds. Psittacosis in birds, also known as avian chlamydiosis, is endemic in poultry, but the risk for people living close to poultry farms is unknown. Therefore, our study aimed to explore the temporal and spatial patterns of human psittacosis infections and identify possible associations with poultry farming in the Netherlands. We analysed data on 700 human cases of psittacosis notified between 01-01-2000 and 01-09-2015. First, we studied the temporal behaviour of psittacosis notifications by applying wavelet analysis. Then, to identify possible spatial patterns, we applied spatial cluster analysis. Finally, we investigated the possible spatial association between psittacosis notifications and data on the Dutch poultry sector at municipality level using a multivariable model. We found a large spatial cluster that covered a highly poultry-dense area but additional clusters were found in areas that had a low poultry density. There were marked geographical differences in the awareness of psittacosis and the amount and the type of laboratory diagnostics used for psittacosis, making it difficult to draw conclusions about the correlation between the large cluster and poultry density. The multivariable model showed that the presence of chicken processing plants and slaughter duck farms in a municipality was associated with a higher rate of human psittacosis notifications. The significance of the associations was influenced by the inclusion or exclusion of farm density in the model. Our temporal and spatial analyses showed weak associations between poultry-related variables and psittacosis notifications. Because of the low number of psittacosis notifications available for analysis, the power of our analysis was relative low. Because of the exploratory nature of this research, the associations found cannot be interpreted as evidence for airborne transmission of psittacosis from poultry to the general population. Further research is needed to determine the prevalence of C. psittaci in Dutch poultry. Also, efforts to promote PCR-based testing for C. psittaci and genotyping for source tracing are important to reduce the diagnostic deficit, and to provide better estimates of the human psittacosis burden, and the possible role of poultry.


Non-technical Issues in Design and Development of Personal Portable Devices.
Mobile technologies are constantly evolving and with the development of Internet of Things we can expect continuous increase of various applications. Mobile technologies have undeniable opportunities to play an important role in health services. Concerning purely technical aspects, almost every problem can be solved. However, there are still many unsolved and unclear issues related with ethics and governance mechanisms for mobile phone applications. These issues are even more critical in medical and health care applications of mobile technologies. This paper tries to analyse ethical, and privacy-related challenges that may occur when introducing Personal Portable Devices (PPD) to collect and record personal health data in health care and welfare environment.


Influence of posture on routine hemostasis testing.
Biological variability is an important aspect for appropriate interpretation of hemostasis testing, but unreliable evidence has been provided to date regarding the effect of different postures on first-line clotting tests such as activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen. Variation of APTT, PT and fibrinogen was therefore investigated in 19 healthy volunteers after 25 min in supine position, 20 min in sitting position and 20 min stationary standing in upright position. The change from supine to sitting position caused a significant decrease of PT and a significant increase of fibrinogen. The variation of fibrinogen exceeded the quality specifications for bias. The change from supine to standing position caused a significant bias in all the parameters tested, with a decrease of PT and an increase of fibrinogen that exceeded the quality specifications for bias. The change from sitting to standing position also caused a significant bias in all the parameters tested, but none of these variations was greater than the quality specifications for bias. The results of this investigation show that patient posture may have a significant impact on results of routine hemostasis testing, especially when patient position is changed from supine to standing.


Changes in cognitive evoked potentials during non pharmacological treatment in children with attention deficit/hyperactivity disorder.
Attention deficit/hyperactivity disorder (ADHD) is one of the most widely spread condition of school aged children affecting 5% of children of this age. The unified consensus of the precise diagnosis of this condition is still absent. This fact encourages the researchers to seek the alternative neurometric tools which will help the clinicians in diagnosis making process of ADHD. The neurophysiologic approaches especially event-related potentials (ERPs) are mostly important from this point of view. The later response of ERPs (P3) reflects the most important parts of executive functioning frequently affected in ADHD children - the process of mental effortfullness to select the appropriate behavior and decision making. Besides the diagnosis the treatment of ADHD is also the point of concern of neurologists and neurophyschologists. In recent years EEG biofeedback ( Neurofeedback-NF) have become the alternative treatment as in some cases pharmacological drugs are non effective. The positive impact of NF was based on improvement detected by various questionnaires which are less valid but its effectiveness on ERPs parameters is still unknown. Thus we aimed to study the changes of ERPs after NF therapy. We have studied 93 children with ADHD of combined subtype (ADHDcom) without any kind of pharmacological treatment. Age range 9-12 years. The children were divided into two subgroups: The first ADHDcom-1 (48 children) were children where NF treatment was carried out and the second subgroup of ADHDcom-2 (45 children) were non treated children. We have observed statistically significant improvement of parameters of later response like P3 in ADHD-1 compared with ADHD-2 whereas NF was non effective for earlier component like N1. NF can positively affect on the P3 parameters which is very important in ADHD children as P3 reflects the speed of information processing as well as selection of appropriate action and decision making which are frequently affected in ADHD children.


Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial.
CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only. CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants. Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2-39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment. Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy. Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.


Converting to gamma-radiation sterilization: an overview for medical device manufacturers.
Gamma radiation is becoming increasingly popular as a method of sterilizing disposable medical devices. The conversion from ethylene oxide sterilization to gamma radiation may involve redesigning products and packaging, and establishing a new method of sterilization. However, the conversion process can be regarded as an opportunity to enhance product design, improve processes, and reduce costs. In this article, the authors explain how conversion can be manageably achieved by providing a step-by-step conversion programme.


Genetic risk score is associated with T2DM and diabetes complications risks.
Type 2 diabetes mellitus (T2DM) is a prototypical complex disease with polygenic architecture playing an important role in determining susceptibility to develop the disease (and its complications) in subjects exposed to modifiable lifestyle factors. A current challenge is to quantify the degree of the individual's genetic risk using genetic risk scores (GRS) capturing the results of genome-wide association studies while incorporating possible ethnicity- or population-specific differences. This study included three groups of T2DM (T2DM-I, N = 1,032; T2DM-II, N = 353; and T2DM-III, N = 399) patients and 2,481 diabetes-free subjects. The status of the microvascular and macrovascular diabetes complications were known for the T2DM-I patients. Overall, 21 single nucleotide polymorphisms (SNPs) were analyzed, and selected subsets were used to determine the GRS (both weighted - wGRS and unweighted - uGRS) for T2DM risk predictions (6 SNPs) and for predicting the risks of complications (7 SNPs). The strongest T2DM markers (P < 0.0001) were within the genes for TCF7L2 (transcription factor 7-like 2), FTO (fat mass and obesity associated protein) and ARAP1 (ankyrin repeat and PH domain 1). The T2DM-I subjects with uGRS values greater (Odds Ratio, 95 % Confidence Interval) than six had at least twice (2.00, 1.72-2.32) the risk of T2DM development (P < 0.0001), and these results were confirmed in the independent groups (T2DM-II 1.82, 1.45-2.27; T2DM-III 2.63, 2.11-3.27). The wGRS (>0.6) further improved (P < 0.000001) the risk estimations for all three T2DM groups. The uGRS was also a significant predictor of neuropathy (P < 0.0001), nephropathy (P < 0.005) and leg ischemia (P < 0.0005). If carefully selected and specified, GRS, both weighted and unweighted, could be significant predictors of T2DM development, as well as the diabetes complications development.


Design and preparation of cyclopeptamine antifungal agents.
The lack of agents for infections caused by pathogenic fungi has demanded further investigation of a key lead structure which has shown promise, echinocandin B. In recent years, two analogs of this cyclic hexapeptide are proceeding through the clinic exhibiting proof of concept for the target of these drugs. This target, the ss-1,3-glucan synthesis complex, produces the majority of fungal cell wall glucan in many of the most pathogenic fungi such as Candida. A methodical structure-activity relationship review of several major fragments of these highly functionalized molecules is described. This information is useful for determination of the minimum functional/structural requirements for design of an optimal compound in this series. Analogs are presented with their accompanying whole cell antifungal activities.


Monte Carlo simulations shed light on Bathsheba's suspect breast.
In 1654, Rembrandt van Rijn painted his famous painting Bathsheba at her Bath. Over the years, the depiction of Bathsheba's left breast and especially the presence of local discoloration, has generated debate on whether Rembrandt's Bathsheba suffered from breast cancer. Historical, medical and artistic arguments appeared to be not sufficient to prove if Bathsheba's model truly suffered from breast cancer. However, the bluish discoloration of the breast is an intriguing aspect from a biomedical optics point of view that might help us ending the old debate. By using Monte Carlo simulations in combination with the retinex theory of color vision, we showed that is highly unlikely that breast cancer results in a local bluish discoloration of the skin as is present on Bathsheba's breast.


Associations among disease conditions, bone mineral density, and prevalent vertebral deformities in men and women 50 years of age and older: cross-sectional results from the Canadian Multicentre Osteoporosis Study.
This cross-sectional cohort study of 5566 women and 2187 men 50 years of age and older in the population-based Canadian Multicentre Osteoporosis Study was conducted to determine whether reported past diseases are associated with bone mineral density or prevalent vertebral deformities. We examined 12 self-reported disease conditions including diabetes mellitus (types 1 or 2), nephrolithiasis, hypertension, heart attack, rheumatoid arthritis, thyroid disease, breast cancer, inflammatory bowel disease, neuromuscular disease, Paget's disease, and chronic obstructive pulmonary disease. Multivariate linear and logistic regression analyses were performed to determine whether there were associations among these disease conditions and bone mineral density of the lumbar spine, femoral neck, and trochanter, as well as prevalent vertebral deformities. Bone mineral density measurements were higher in women and men with type 2 diabetes compared with those without after appropriate adjustments. The differences were most notable at the lumbar spine (+0.053 g/cm2), femoral neck (+0.028 g/cm2), and trochanter (+0.025 g/cm2) in women, and at the femoral neck (+0.025 g/cm2) in men. Hypertension was also associated with higher bone mineral density measurements for both women and men. The differences were most pronounced at the lumbar spine (+0.022 g/cm2) and femoral neck (+0.007 g/cm2) in women and at the lumbar spine (+0.028 g/cm2) in men. Although results were statistically inconclusive, men reporting versus not reporting past nephrolithiasis appeared to have clinically relevant lower bone mineral density values. Bone mineral density differences were -0.022, -0.015, and -0.016 g/cm2 at the lumbar spine, femoral neck, and trochanter, respectively. Disease conditions were not strongly associated with vertebral deformities. In summary, these cross-sectional population-based data show that type 2 diabetes and hypertension are associated with higher bone mineral density in women and men, and nephrolithiasis may be associated with lower bone mineral density in men. The importance of these associations for osteoporosis case finding and management require further and prospective studies.


Complaints, complainants, and rulings regarding drug promotion in the United Kingdom and Sweden 2004-2012: a quantitative and qualitative study of pharmaceutical industry self-regulation.
In many European countries, medicines promotion is governed by voluntary codes of practice administered by the pharmaceutical industry under its own system of self-regulation. Involvement of industry organizations in policing promotion has been proposed to deter illicit conduct, but few detailed studies on self-regulation have been carried out to date. The objective of this study was to examine the evidence for promotion and self-regulation in the UK and Sweden, two countries frequently cited as examples of effective self-regulation. We performed a qualitative content analysis of documents outlining the constitutions and procedures of these two systems. We also gathered data from self-regulatory bodies on complaints, complainants, and rulings for the period 2004-2012. The qualitative analysis revealed similarities and differences between the countries. For example, self-regulatory bodies in both countries are required to actively monitor promotional items and impose sanctions on violating companies, but the range of sanctions is greater in the UK where companies may, for instance, be audited or publicly reprimanded. In total, Swedish and UK bodies ruled that 536 and 597 cases, respectively, were in breach, equating to an average of more than one case/week for each country. In Sweden, 430 (47%) complaints resulted from active monitoring, compared with only two complaints (0.2%) in the UK. In both countries, a majority of violations concerned misleading promotion. Charges incurred on companies averaged €447,000 and €765,000 per year in Sweden and the UK, respectively, equivalent to about 0.014% and 0.0051% of annual sales revenues, respectively. One hundred cases in the UK (17% of total cases in breach) and 101 (19%) in Sweden were highlighted as particularly serious. A total of 46 companies were ruled in breach of code for a serious offence at least once in the two countries combined (n = 36 in the UK; n = 27 in Sweden); seven companies were in serious violation more than ten times each. A qualitative content analysis of serious violations pertaining to diabetes drugs (UK, n = 15; Sweden, n = 6; 10% of serious violations) and urologics (UK, n = 6; Sweden, n = 13; 9%) revealed various types of violations: misleading claims (n = 23; 58%); failure to comply with undertakings (n = 9; 23%); pre-licensing (n = 7; 18%) or off-label promotion (n = 2; 5%); and promotion of prescription drugs to the public (n = 6; 15%). Violations that go undetected or unpunished by self-regulatory bodies are the main limitation of this study, since they are likely to lead to an underestimate of industry misconduct. The prevalence and severity of breaches testifies to a discrepancy between the ethical standard codified in industry Codes of Conduct and the actual conduct of the industry. We discuss regulatory reforms that may improve the quality of medicines information, such as pre-vetting and intensified active monitoring of promotion, along with larger fines, and giving greater publicity to rulings. But despite the importance of improving regulatory arrangements in an attempt to ensure unbiased medicines information, such efforts alone are insufficient because simply improving oversight and increasing penalties fail to address additional layers of industry bias.


Towards a mechanistic understanding of variation in aquatic food chain length.
Ecologists have long sought to understand variation in food chain length (FCL) among natural ecosystems. Various drivers of FCL, including ecosystem size, resource productivity and disturbance, have been hypothesised. However, when results are aggregated across existing empirical studies from aquatic ecosystems, we observe mixed FCL responses to these drivers. To understand this variability, we develop a unified competition-colonisation framework for complex food webs incorporating all of these drivers. With competition-colonisation tradeoffs among basal species, our model predicts that increasing ecosystem size generally results in a monotonic increase in FCL, while FCL displays non-linear, oscillatory responses to resource productivity or disturbance in large ecosystems featuring little disturbance or high productivity. Interestingly, such complex responses mirror patterns in empirical data. Therefore, this study offers a novel mechanistic explanation for observed variations in aquatic FCL driven by multiple environmental factors.


Health promotion through self-care and community participation: elements of a proposed programme in the developing countries.
The concepts of health promotion, self-care and community participation emerged during 1970s, primarily out of concerns about the limitation of professional health system. Since then there have been rapid growth in these areas in the developed world, and there is evidence of effectiveness of such interventions. These areas are still in infancy in the developing countries. There is a window of opportunity for promoting self care and community participation for health promotion. A broad outline is proposed for designing a health promotion programme in developing countries, following key strategies of the Ottawa Charter for health promotion and principles of self care and community participation. Supportive policies may be framed. Self care clearinghouses may be set up at provincial level to co-ordinate the programme activities in consultation with district and national teams. Self care may be promoted in the schools and workplaces. For developing personal skills of individuals, self care information, generated through a participatory process, may be disseminated using a wide range of print and audio-visual tools and information technology based tools. One such potential tool may be a personally held self care manual and health record, to be designed jointly by the community and professionals. Its first part may contain basic self care information and the second part may contain outlines of different personally-held health records to be used to record important health and disease related events of an individual. Periodic monitoring and evaluation of the programme may be done. Studies from different parts of the world indicate the effectiveness and cost-effectiveness of self care interventions. The proposed outline has potential for health promotion and cost reduction of health services in the developing countries, and may be adapted in different situations. Self care, community participation and health promotion are emerging but dominant areas in the developed countries. Elements of a programme for health promotion in the developing countries following key principles of self care and community participation are proposed. Demonstration programmes may be initiated to assess the feasibility and effectiveness of this programme before large scale implementation.


Rheumatologic conditions in children who may present to the orthopaedic surgeon.
Juvenile idiopathic arthritis, formerly known as juvenile rheumatoid arthritis, is a heterogeneous group of diseases characterized by onset of chronic arthritis in childhood. Diagnosis requires onset of disease by age 16 years, persistent arthritis in any joint for ≥ 6 weeks, and exclusion of other conditions that cause arthritis (eg, infection, malignancy, acute rheumatic fever, inflammatory bowel disease). Most patients with juvenile idiopathic arthritis present with subacute arthritis with minimal pain and few constitutional symptoms. Laboratory evaluation and imaging are useful to exclude other diagnoses and establish the presence of systemic inflammation. However, these modalities are of limited value in screening for rheumatic diseases, and they may be misleading because of the high rate of false-positive results. Most rheumatologic conditions are diagnosed based on pattern recognition, which is established with a thorough history and physical examination.


IGF-I is a mitogen involved in differentiation-related gene expression in fetal rat brown adipocytes.
Fetal rat brown adipocytes at time zero of culture constitute a population of cells of broad spectrum, as estimated by cell size, endogenous fluorescence and lipid content, and show an intrinsic mitogenic competence. They express constitutively early growth-related genes such as c-myc, c-fos, and beta-actin, tissue specific-genes such as the uncoupling protein (UCP) and the lipogenic marker malic enzyme (ME). Fetal brown adipocytes bear a high expression of insulin-like growth factor receptor (IGF-IR), and show a high affinity IGF-I specific-binding to its receptor, and a high number of binding sites per cell. After cell quiescence, insulin-like growth factor I (IGF-I) was as potent as 10% FCS in inducing DNA synthesis, cell number increase, and the entry of cells into the cell-cycle. In addition, IGF-I or 10% FCS for 48 h increased the percentage of [3H]thymidine-labeled nuclei as compared to quiescent cells. Single cell autoradiographic microphotographs show typical multilocular fat droplets brown adipocytes, resulting positive to [3H]thymidine-labeled nuclei in response to IGF-I. IGF-I increased mRNA expression of the early-response genes c-fos (30 min), c-myc (2 and 24 h), and H-ras (4 and 24 h). 10% FCS also increased c-fos and c-myc, but failed to increase H-ras as an early event. IGF-I or 10% FCS, however, similarly increased the mRNA late expression of c-myc, H-ras, c-raf, beta-actin, and glucose 6-phosphate dehydrogenase (G6PD) at 72 h, as compared to quiescent cells. IGF-I or FCS maintained at 24 h or increased at 48 and 72 h UCP mRNA expression. The results demonstrate that IGF-I is a mitogen for fetal rat brown adipocytes, capable of inducing the expression of early and late growth-regulated genes, and of increasing the lipogenic marker ME and the tissue-specific gene UCP, suggesting the involvement of IGF-I in the differentiation as well as in the proliferation processes.


Lipid oxidation in fillets of herring (Clupea harengus) during frozen storage. Influence of prefreezing storage.
Fillets of herring (Clupea harengus) were kept on ice for 0, 3, 6, and 9 days prior to storage at -18 degrees C for 0, 21, 42, 63, and 84 days. At each storage point, peroxide value (PV), absorbance at 268 nm (A(268)), fluorescent products (FP), alpha-tocopherol, glutathione peroxidase (GSH-px) activity, and ascorbic acid were measured. As shown by regression analyses, samples held for 6 days on ice formed oxidation products at the highest rate during frozen storage, followed by, for PV and FP, the 9-day samples. These data indicate that severe changes that negatively affect the oxidation process took place in the herring muscle between 3 and 6 days after catch. Both the initial antioxidant levels and the rate of antioxidant loss at -18 degrees C decreased with increased prefreezing holding time, the latter being most obvious for GSH-px activity and ascorbic acid. alpha-Tocopherol showed the largest losses and had disappeared entirely from the 6- and 9-day samples at the end of the frozen storage. Partial least-squares regression analysis of the data showed that ice storage had a greater effect than frozen storage on changes in PV, A(268), FP, alpha-tocopherol, and ascorbic acid. For GSH-px activity, frozen storage had the greatest effect.


Metabolites related to renal function, immune activation, and carbamylation are associated with muscle composition in older adults.
Reduced skeletal muscle density in older adults is associated with insulin resistance, decreased physical function, and an increased all-cause mortality risk. To elucidate mechanisms that may underlie the maintenance of skeletal muscle density, we conducted a secondary analysis of previously published muscle composition and serum metabolomic data in 73 older adults (average age, 78y). Multivariable-adjusted linear regression was used to examine associations between 321 metabolites with muscle composition, defined as the ratio between normal density (NDM) with low density (LDM) thigh muscle cross sectional area (NDM/LDM). Sixty metabolites were significantly (p≤0.05 and q<0.30) associated with NDM/LDM. Decreased renal function and the immune response have been previously linked with reduced muscle density, but the mechanisms underlying these connections are less clear. Metabolites that were significantly associated with muscle composition were then tested for their association with circulating markers of renal function (blood urea nitrogen, creatinine, uric acid), and with the immune response (neutrophils/lymphocytes) and activation (kynurenine/tryptophan). 43 significant NDM/LDM metabolites (including urea) were co-associated with at least 1 marker of renal function; 23 of these metabolites have been previously identified as uremic solutes. The neutrophil/lymphocyte ratio was significantly associated with NDM/LDM (β±SE: -0.3±0.1, p=0.01, q=0.04). 35 significant NDM/LDM metabolites were co-associated with immune activation. Carbamylation (defined as homocitrulline/lysine) was identified as a pathway that may link renal function and immune activation with muscle composition, as 29 significant NDM/LDM metabolites were co-associated with homocitrulline/lysine, with at least 2 markers of renal function, and with kynurenine/tryptophan. When considering that elevated urea and uremic metabolites have been linked with an increased systemic microbial burden, that antimicrobial defense can be reduced in the presence of carbamylation, and that adipocytes can promote host defense, we propose the novel hypothesis that the age-related increase in adipogenesis within muscle may be a compensatory antimicrobial response to protect against an elevated microbial burden.


From Classic Whipple to Pylorus Preserving Pancreaticoduodenectomy and Ultimately to Pylorus Resecting - Stomach Preserving Pancreaticoduodenectomy: A Review.
Pancreaticoduodenectomy is the procedure of choice for benign or malignant tumors of the periampullary region. The preservation of the pylorus has been established as the mostly utilized approach during pancreaticoduodenectomy among the majority of specialized, in the surgical treatment of pancreatic cancer, centers worldwide. The factors that influenced this predilection are the shorter operation times, the less intraoperative blood loss, the decreased technical difficulty, and the quite similar short- and long-term outcomes compared to the classic Whipple. However, there is a notable trend in the literature highlighting the increased incidence of delayed gastric emptying following pylorus preserving pancreaticoduodenectomy. Among other factors, pylorus dysfunction attributable to the surgical maneuvers has been implemented in the etiology of this complication. In an attempt to overcome this limitation of the pylorus preserving pancreaticoduodenectomy, pylorus resecting pancreaticoduodenectomy with the preservation of the stomach was proposed. In theory, pylorus resecting pancreaticoduodenectomy could maintain the advantages of organ sparing surgery, but at the same time guarantee a more seamless gastric emptying. Only three RCTs, to date, aimed to evaluate the approach with only one reporting results in favor of the pylorus resecting pancreaticoduodenectomy in regard to the incidence of delayed gastric emptying. Further well-designed prospective randomized studies are needed for an accurate assessment of the true role of each of these surgical alternatives on the treatment of pancreatic cancer.


The diagnostic and prognostic value of plasma microRNA-125b-5p in patients with multiple myeloma.
Aberrant expression of microRNAs (miRNAs) contributes to the progression and outcomes of several types of tumor, while circulating miRNAs have been reported to act as biomarkers for several types of cancer. To identify specific circulating miRNAs associated with multiple myeloma (MM), a miRNA microarray analysis was used, which identified 8 upregulated miRNAs and 4 downregulated miRNAs in the plasma of 6 patients with MM compared with 6 healthy individuals. Based on the microarray results, the 8 miRNAs (miR-125b-5p, miR-483-3p, miR-4326, miR-6894-3p, miR-4498, miR-490-3p, miR-7155-5p and miR-937-3p), which were notably upregulated in MM patients were chosen for a second clinical study in 20 healthy controls and 35 patients with MM using reverse transcription- quantitative polymerase chain reaction. Receiver operating characteristic analysis demonstrated that miR-125b-5p and miR-490-3p displayed considerable diagnostic accuracy for MM with areas under the curve of 0.954 (P<0.001) and 0.866 (P=0.028), respectively. In addition, the plasma level of miR-125b-5p was associated with the international staging system disease stage. Patients with higher levels of plasma miR-125b-5p had a significantly shorter event-free survival. However, miR-490-3p levels were not associated with event-free survival (P>0.05). In summary, miR-125b-5p may serve as a potential clinical biomarker for MM.


An efficient grid layout algorithm for biological networks utilizing various biological attributes.
Clearly visualized biopathways provide a great help in understanding biological systems. However, manual drawing of large-scale biopathways is time consuming. We proposed a grid layout algorithm that can handle gene-regulatory networks and signal transduction pathways by considering edge-edge crossing, node-edge crossing, distance measure between nodes, and subcellular localization information from Gene Ontology. Consequently, the layout algorithm succeeded in drastically reducing these crossings in the apoptosis model. However, for larger-scale networks, we encountered three problems: (i) the initial layout is often very far from any local optimum because nodes are initially placed at random, (ii) from a biological viewpoint, human layouts still exceed automatic layouts in understanding because except subcellular localization, it does not fully utilize biological information of pathways, and (iii) it employs a local search strategy in which the neighborhood is obtained by moving one node at each step, and automatic layouts suggest that simultaneous movements of multiple nodes are necessary for better layouts, while such extension may face worsening the time complexity. We propose a new grid layout algorithm. To address problem (i), we devised a new force-directed algorithm whose output is suitable as the initial layout. For (ii), we considered that an appropriate alignment of nodes having the same biological attribute is one of the most important factors of the comprehension, and we defined a new score function that gives an advantage to such configurations. For solving problem (iii), we developed a search strategy that considers swapping nodes as well as moving a node, while keeping the order of the time complexity. Though a naïve implementation increases by one order, the time complexity, we solved this difficulty by devising a method that caches differences between scores of a layout and its possible updates. Layouts of the new grid layout algorithm are compared with that of the previous algorithm and human layout in an endothelial cell model, three times as large as the apoptosis model. The total cost of the result from the new grid layout algorithm is similar to that of the human layout. In addition, its convergence time is drastically reduced (40% reduction).


An aspergilloma in an echinococcal cyst cavity.
Aspergilloma is a saprophytic infection which can colonize preexisting lung cavities. The most common underlying diseases are tuberculosis, sarcoidosis, cavitary lung cancer, etc. Although aspergilloma can also occur in operated hydatid cyst cavities, only a few cases have been reported in literature. A 32-year-old female patient underwent cystectomy for the diagnosis of perforated intraparenchymal giant hydatid cyst located in the right upper lobe, reaching down to the hilum. Capitonnage was not performed and it was observed that a residual cavity remained in the cystectomy area. The patient was discharged; however, during clinical and radiological follow-ups, it was found that the residual cyst cavity had expanded. As it was thought that one of the drainage bronchi in the cyst cavity could have opened, the patient was reoperated. During the operation, it was noted that purulent fluid and necrotic tissues were present in the cystic cavity. It was seen that the posterior upper lobe segment was consolidated and not ventilated. Contents of the cavity were removed and the posterior upper lobe segment was resected. Histopathological examination revealed that the tissue in the cavity was that of an aspergilloma, and that chronic organized pneumonia and diffuse interstitial fibrosis were present in the resected segment. Refraining from surgical obliteration (capitonnage) of cyst cavities in cases of giant hydatid cysts extending to the hilum can lead to opportunistic infections such as aspergilloma.


Experimental studies on genetically determined predisposition to catatonia in rats as a model of schizophrenia.
To check experimentally the hypothesis of schizophrenia being a manifestation of extremely low threshold of hypnotic (catatonic) type of reaction, changes of some neurophysiologic and neurochemical systems in rats with a genetic predisposition to catalepsy were compared to analogous changes found so far in schizophrenia or chronic amphetamine intoxication considered nowadays as the most adequate pharmacological model of schizophrenia. It is found that in rats predisposed to catalepsy the threshold of audiogenic seizures is elevated; the activity of tryptophan hydroxylase in striatum is higher in rats predisposed to catalepsy genetically and due to a chronic methylphenidate intoxication as compared to control animals; noradrenaline content and noradrenaline/dopamine ratio is lower in the diencephalon of rats predisposed to catalepsy than in controls; cataleptic rats have a higher content of homovanillic acid in N.accumbens , and a higher frequency of inversion of hemispheric asymmetry as estimated by levels of dopamine and dioxyphenylacetic acid in N.accumbens and caudate nucleus, than normal rats; MAO-B/MAO-A ratio is higher in the brain stem of cataleptic than normal rats. The effects of haloperidol and apomorphine on motor activity of cataleptic and normal animals point to a higher sensitivity of postsynaptic dopamine receptors in the former. Conditioned avoidance reaction is formed slower, but preserved longer in rats predisposed to catalepsy. Blood serum of wild rats predisposed to akinetic catatonic reactions, unlike the serum of normal wild rats, inhibits the electric activity of snail neurons. The above indicated changes are analogous to those known to be present in schizophrenia and/or chronic intoxication with amphetamine or its pharmacological analogues, which witnesses in favour of the proposed hypothesis.


Does free-market capitalism drive unequal access to health? An empirical analysis, 1970-2015.
Many scholars, particularly in public health, argue that neoliberal capitalist economic forces adversely affect communities by increasing inequalities, ultimately affecting health. Apparently, corporate capitalism affects health and communitarian concerns because governments place corporate profits over the publićs interests. Using unique data collected by the Varieties of Democracy (VDEM) project that capture the degree of access of the poorest segments of society to health services comparable with those available to the richest segments, this study finds that an index of economic freedom robustly reduces inequality of access to health. We argue that these results obtain because greater exposure to global markets increases the premium on the productivity of labour, increasing incentives for political elites to invest in productivity-enhancing public goods. Our results are robust to a number of alternative models and data, and robust to instrumental variables analyses addressing potential endogeneity. Rather than free-market capitalism increasing health-related neglect of society, our data suggest that free-market capitalist conditions promote equitable access to health. This is good news for governments wishing to grow their economies, reform broken health systems for gaining advantages in a competitive global economy, and serve communitarian interests, such as shared good health.


Clonal relationship among Vibrio parahaemolyticus isolated from Mediterranean mussels (Mytilus galloprovincialis) and grooved carpet shells (Ruditapes decussatus) harvested in Sardinia (Italy).
The aim of the present study was to investigate the genetic variability of Vibrio parahaemolyticus strains isolated from naturally contaminated Mediterranean mussels (Mytilus galloprovincialis) and Grooved carpet shells (Ruditapes decussatus) from three harvesting areas of Sardinia (Italy) using a combination of different typing methods: traditional phenotypic systems and molecular techniques. Ninety-nine putative V. parahaemolyticus strains isolated from shellfish collected before and after purification were included in the study. Seventy-two isolates were confirmed as V. parahaemolyticus and were submitted to REP, ERIC and BOX PCRs. The combined dendrogram showed the similarity of the data set of the three typing methods and demonstrates how the different techniques grouped the strains in two clusters in accordance with each singular dendrogram. Several strains rendered a unique pattern regardless of the typing method, which indicates the high discriminatory power of the methods. Moreover, the use of multiple typing methods allowed a more accurate characterization of the genetic profiles of isolates and the identification of clones hardly revealed through the common techniques. The intraspecific typing of environmental V. parahaemolyticus can be of great interest in order to recognize clonal relationships between environmental contamination, foodborne disease, and geographical/temporal distribution of this pathogen. The comparative analysis focusing on the obtained genetic profiles supports the possibility for typing methods to discriminate strains with similar phenotypic profile, identifying the level of genetic correlation among the strains and the presence of genetic clones.


Toxicity and efficacy of combined radioimmunotherapy and bevacizumab in a mouse model of medullary thyroid carcinoma.
Significant antitumor effects were previously observed with radioimmunotherapy (RIT) using an anti-carcinoembryonic antigen (CEA) monoclonal antibody (F6) labeled with iodine-131 in medullary thyroid cancer (MTC)-bearing nude mice. Nevertheless, no complete response was achieved. Because angiogenesis is critical for tumor growth, bevacizumab is used to treat solid tumor in clinical practice. The present pilot study evaluated toxicity and efficacy of RIT combined with bevacizumab in mice subcutaneously grafted with TT MTC cells. Groups of 4-6 nude mice were treated with 5 microg/g bevacizumab twice weekly during 4 weeks and/or 100 MBq of (131)I-F6. For combined therapy, bevacizumab was given at Day 0 followed by (131)I-F6 at Day 30. The control group received no treatment. Animal weight, hematological toxicity, tumor volume, and serum calcitonin were monitored for 2 or 4 months. Bevacizumab alone induced no cytopenia and no significant weight loss. A weight loss of 12 +/- 1% and 15 +/- 2% was observed in mice treated by RIT alone or bevacizumab + RIT, respectively. RIT alone and combined treatment induced leukopenia and anemia. RIT alone and RIT plus bevacizumab induced tumor responses with minimum relative tumor volume of 0.38 +/- 0.24 and 0.15 +/- 0.07%, respectively, and time to progression of 35 +/- 5 and 56 +/- 11 days, respectively. Pretreatment with bevacizumab improved RIT efficacy, with similar toxicity as compared as RIT alone.


Pharmacological investigation of the bioluminescence signaling pathway of the dinoflagellate Lingulodinium polyedrum: evidence for the role of stretch-activated ion channels.
Dinoflagellate bioluminescence serves as a whole-cell reporter of mechanical stress, which activates a signaling pathway that appears to involve the opening of voltage-sensitive ion channels and release of calcium from intracellular stores. However, little else is known about the initial signaling events that facilitate the transduction of mechanical stimuli. In the present study using the red tide dinoflagellate Lingulodinium polyedrum (Stein) Dodge, two forms of dinoflagellate bioluminescence, mechanically stimulated and spontaneous flashes, were used as reporter systems to pharmacological treatments that targeted various predicted signaling events at the plasma membrane level of the signaling pathway. Pretreatment with 200 μM Gadolinium III (Gd(3+) ), a nonspecific blocker of stretch-activated and some voltage-gated ion channels, resulted in strong inhibition of both forms of bioluminescence. Pretreatment with 50 μM nifedipine, an inhibitor of L-type voltage-gated Ca(2+) channels that inhibits mechanically stimulated bioluminescence, did not inhibit spontaneous bioluminescence. Treatment with 1 mM benzyl alcohol, a membrane fluidizer, was very effective in stimulating bioluminescence. Benzyl alcohol-stimulated bioluminescence was inhibited by Gd(3+) but not by nifedipine, suggesting that its role is through stretch activation via a change in plasma membrane fluidity. These results are consistent with the presence of stretch-activated and voltage-gated ion channels in the bioluminescence mechanotransduction signaling pathway, with spontaneous flashing associated with a stretch-activated component at the plasma membrane.


An osteoporosis clinical pathway for the medical management of patients with low-trauma fracture.
Patients with an osteoporotic fracture have at least a 2-fold risk for additional fracture and should benefit from targeted diagnostic and treatment procedures for osteoporosis. To address this issue, we set up an osteoporosis clinical pathway (OCP) for the medical management of patients with low-trauma fracture. Following acute management of the fracture by the orthopedic team, patients are enrolled in the pathway, which is based on an interaction between the OCP multidisciplinary team, orthopedic surgeons and/or primary care physicians. After collection of patient data, suggestions for additional diagnostic examinations with their interpretation, and treatment proposals are made. Patients and their families are also invited to attend a multidisciplinary interactive educational program on physical therapy, lifestyle habits and nutrition. During a 36-month period, 385 patients (311 women, 74 men; mean age +/- SD: 73.0 +/- 13.5 years; hip fracture 45%, ankle/tibia 24%, proximal humerus 8.6%, spine 5.5%, pelvis 3.9%, distal forearm 3.6%, other sites 17.4%) were enrolled in the OCP. An osteoporosis awareness questionnaire administered within 10 days of fracture showed that 73% of patients believed that their fracture was not related to the disease. Dual-energy X-ray absorptiometry, performed in 63% of patients, showed that 86% had low bone mass or osteoporosis. Specific antiosteoporotic therapy was proposed for 33% of patients in addition to calcium and vitamin D supplements, the latter suggested for 93%. A survey performed in 216 patients 6 months later, indicated that 63% of the suggested treatments had been prescribed and that 67% of this group were continuing treatment. Such a clinical pathway for the medical management of low-trauma fracture can help to identify patients with osteoporosis in a high-risk population, provide support to the orthopedic surgeon and/or the primary care physician for diagnostic and treatment procedures, and should significantly contribute to increase awareness of the disease in patients and their families.


Size tunable fluorescent nano-graphite oxides: preparation and cell imaging applications.
Fluorescent nano-graphite oxides (NGO) with different size distribution were prepared via a one-pot hydrothermal route using ultrasmall graphite powder as starting material and subsequently separated using dialysis tubes with different molecular weight cutoff. The biomedical applications of these NGO for cell imaging were further investigated. Fourier transform infrared spectra demonstrated that many functional groups including the hydroxyl group, carboxyl group and epoxy group were present on NGO, which endowed them with good water solubility. These NGO showed size-dependent photoluminescence and excellent biocompatibility with A549 cells. As evidenced by laser scanning confocal microscopy images, NGO could be internalized by A549 cells and located in the cytoplasm. Given their good water solubility, size tunable photoluminescence and excellent biocompatibility, these NGO should be promising for bioimaging and various biomedical applications.


[Rate of spontaneous abortion in relation to the time of fetal viability assessment].
For the first time, the rate of spontaneous abortion is reported in a multicenter study of three different gynecological centers. In 1987 und 1988, the average spontaneous abortion rate in 315 pregnancies was 3.3%, after foetal heart actions had been verified by ultrasonic examination between the 7th and 12th week of gestation. A statistical significance has been calculated between the spontaneous abortion rate of 6.3%, if foetal heart beats were seen between the 7th and 9th week, and the spontaneous abortion rate of 1.0% with an evidence of foetal life (p less than 0.01) between the 10th to 12th week of gestation. The rate of spontaneous abortion of women above 34 years of age (8.9%) is statistically different (p less than 0.01) to that of women under 35 (1.9%). In women older than 34, the spontaneous abortion rate before the 10th week of gestation is 22.2% in contrast to 3.2% of women younger than 35 (p less than 0.01). Considering the evidence of foetal heart actions between the 10th and 12th week, the spontaneous abortion rate of women above the age of 34 is 1.9%, compared to 0.8% of women younger than 35. The statistical higher spontaneous abortion rate of women above the age of 34 before the 10th week of gestation and the lack of statistical difference of the abortion rate in this defined age group for foetal life to be proven from the 10th week on, should be an argument in favour of the 10th week of gestation as the earliest date of prenatal diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)


Brain activation of lower extremity movement in chronically impaired stroke survivors.
Lower extremity paresis poses significant disability to chronic stroke survivors. Unlike for the upper extremity, cortical adaptations in networks controlling the paretic leg have not been characterized after stroke. Here, the hypotheses are that brain activation associated with unilateral knee movement in chronic stroke survivors is abnormal, depends on lesion location, and is related to walking ability. Functional magnetic resonance imaging of unilateral knee movement was obtained in 31 patients 26.9 months (mean, IQ range: 11.3-68.1) after stroke and in 10 age-matched healthy controls. Strokes were stratified according to lesion location. Locomotor disability (30 ft walking speed) did not differ between patient groups (9 cortical, 12 subcortical, 10 brainstem lesions). Significant differences in brain activation as measured by voxel counts in 10 regions of interest were found between controls and patients with brainstem (P = 0.006) and cortical strokes (P = 0.002), and between subcortical and cortical patients (P = 0.026). Statistical parametric mapping of data per group revealed similar activation patterns in subcortical patients and controls with recruitment of contralateral primary motor cortex (M1), supplementary motor area (SMA), and bilateral somatosensory area 2 (S2). Cortical recruitment was reduced in brainstem and cortical stroke. Better walking was associated with lesser contralateral sensorimotor cortex activation in brainstem, but stronger recruitment of ipsilateral sensorimotor and bilateral somatosensory cortices in subcortical and cortical patients, respectively. A post hoc comparison of brainstem patients with and without mirror movements (50%) revealed lesser recruitment of ipsilateral cerebellum in the latter. Subcortical patients with mirror movements (58%) showed lesser bilateral sensorimotor cortex activation. No cortical patient had mirror movements. The data reveal adaptations in networks controlling unilateral paretic knee movement in chronic stroke survivors. These adaptations depend on lesion location and seem to have functional relevance for locomotion.


The role of ferroptosis in melanoma.
Melanoma is the deadliest form of skin cancer. Although treatment with targeted therapies and immune checkpoint inhibitors has dramatically improved survival in advanced melanoma, many patients do not benefit from these therapies or relapse after an initial period of response. Thus, future outcomes in these categories of melanoma patients will depend on the identification of novel therapeutic targets and methods to enhance existing targeted therapy and immunotherapy regimens. Ferroptosis is a newly identified form of iron-dependent regulated cell death that is morphologically, biochemically, and genetically distinct from apoptosis, autophagy, pyroptosis, and necroptosis. Dysregulation of ferroptosis has been linked to the development of several forms of cancer. This review examines ferroptosis in the context of melanoma. It presents an overview of ferroptosis biology, summarizes and interprets the current literature, and poses several outstanding questions and areas of future direction.


Characterisation of the Convective Hot-Air Drying and Vacuum Microwave Drying of Cassia alata: Antioxidant Activity, Essential Oil Volatile Composition and Quality Studies.
The preservation of active constituents in Cassia alata through the removal of moisture is crucial in producing a final product with high antioxidant activity. This study aims to determine the influences of various drying methods and drying conditions on the antioxidant activity, volatiles and phytosterols content of C. alata. The drying methods used were convective drying (CD) at 40 °C, 50 °C and 60 °C; freeze drying; vacuum microwave drying (VMD) at 6, 9 and 12 W/g; and two-stage convective pre-drying followed by vacuum microwave finish drying (CPD-VMFD) at 50 °C and 9 W/g. The drying kinetics of C. alata are best described by the thin-layer model (modified Page model). The highest antioxidant activity, TPC and volatile concentration were achieved with CD at 40 °C. GC-MS analysis identified the presence of 51 volatiles, which were mostly present in all samples but with quantitative variation. The dominant volatiles in fresh C. alata are 2-hexenal (60.28 mg 100 g-1 db), 1-hexanol (18.70 mg 100 g-1 db) and salicylic acid (15.05 mg 100 g-1 db). The concentration of phytosterols in fresh sample was 3647.48 mg 100 g-1 db, and the major phytosterols present in fresh and dried samples were β-sitosterol (1162.24 mg 100 g-1 db). CPD-VMFD was effective in ensuring the preservation of higher phytosterol content in comparison with CD at 50 °C. The final recommendation of a suitable drying method to dehydrate C. alata leaves is CD at 40 °C.


Recurrent intestinal haemorrhages caused by a lipoma in the ileocaecal valve in a patient with Von Willebrand's disease.
Lipomas of the digestive tract are rare and may give rise to obstruction, intussusception or haemorrhage. In a 74-year old woman with Von Willebrand's disease, a lipoma in the ileocaecal valve caused frequent intestinal haemorrhages and chronic anaemia over a period of more than 15 years. Diagnosis and therapy are discussed on the basis of the case history.


A new set of primers for COI amplification from freshwater microcrustaceans.
Despite the contribution of DNA barcoding towards understanding the biodiversity and distribution of species, the success of COI amplification has been quite variable when it comes to freshwater zooplankton (Elías-Gutiérrez & Valdez-Moreno 2008; Jeffery et al. 2011). Some genera of microcrustaceans seem to be more difficult to amplify than others. For example, Macrothrix, Scapholeberis, Diaphanosoma and cyclopoids have yielded limited results. Among several possible reasons for the inability to barcode freshwater microcrustaceans is that there does not exist a specific set of primers for COI amplification. To this end, we developed a zooplankton - specific set of primers, which significantly increased average amplification success (20% increase). With these primers, we observed an overall success of over 70% for Sididae and Chydoridae, and more than 80% for Daphniidae, Moinidae, Bosminidae, Macrothricidae, Ilyocryptidae and Diaptomidae. We also demonstrate a simple alteration to a common specimen fixation method that increases the overall recovery of barcodes from freshwater zooplankton. Collectively, we believe our results will greatly aid the recovery of barcodes from these difficult groups.


Schizencephaly-diagnostics and clinical dilemmas.
Schizencephaly is an uncommon congenital disorder of cerebral cortical development. The defect is characterized by the presence of a cleft in the brain extending from the surface of the pia mater to the cerebral ventricles. The margins of the cleft are lined with heterotropic, dysplastic gray matter. The causes of schizencephaly are heterogeneous and can include teratogens, prenatal infection, maternal trauma, or EMX2 mutations. In the present paper, the authors described difficulties in employing diagnostic imaging in differentiating between type II (open-lip) schizencephaly and much more common intracranial fluid spaces of a different origin (arachnoid cysts and hydrocephalus). In all the three cases, the treatment consisted in implantation of a shunt system; nevertheless, it should be emphasized that a surgical intervention in the third presented case (type II schizencephaly) aimed at relieving the symptoms of intracranial hypertension-a directly life-threatening condition-since shunting is not a method of treating schizencephaly itself. Although proper interpretation of the character of intracranial fluid spaces is of significance for further therapeutic management, yet, the key decision as to the surgical intervention is made based on clinical presentation, predominantly on symptoms of intracranial hypertension.


Calcium wave propagation in chains of endothelial cells with nonlinear reaction dynamics: Green's function approach.
We present a Green's function-based perturbative approach to solving nonlinear reaction-diffusion problems in networks of endothelial cells. We focus on a single component (Ca2+), piecewise nonlinear model of endoplasmic calcium dynamics and trans-membrane diffusion. The decoupling between nonlinear reaction dynamics and the linear diffusion enables the calculation of the diffusion part of the Green's function for network of cells with nontrivial topologies. We verify analytically and then numerically that our approach leads to the known transition from propagation of calcium front to failure of propagation when the diffusion rate is varied relative to the reaction rates. We then derive the Green's function for a semi-infinite chain of cells with various boundary conditions. We show that the calcium dynamics of cells in the vicinity of the end of the semi-infinite chain is strongly dependent on the boundary conditions. The behavior of the semi-infinite chain with absorbing boundary conditions, a simple model of a multicellular structure with an end in contact with the extracellular matrix, suggests behavioral differentiation between cells at the end and cells embedded within the chain.


AIDS-related opportunistic mycoses seen in a tertiary care hospital in North India.
Sixty symptomatic confirmed human immunodeficiency virus (HIV)-positive adult patients, of both sexes, suspected of having a fungal infection were taken as a study population, and the clinicomycological profile was correlated with the immunological status of the patients with particular reference to CD4 counts. Relevant samples were collected and subjected to direct microscopy, fungal culture and serology. CD4 counts were determined by flow cytometry. Patients belonged to the age group of 17-65 years, with a male : female ratio of 4.8 : 1. Heterosexuality was the commonest mode of transmission. Candidiasis was the most common diagnosis (41.7 %), followed by cryptococcosis (10.0 %), and pneumocystinosis and aspergillosis (8.3 % each). Two cases of histoplasmosis were also diagnosed. A low mean CD4 count of <200 cells microl(-1) was seen with most fungal infections. A total of 73 % of patients belonged to World Health Organization (WHO) stage 4, while 23.33 % belonged to stage 3. Thirty one patients (51.67 %) belonged to Centers for Disease Control and Prevention (CDC) stage C3. Various fungal infections correlated well with the mean CD4 counts. It was difficult to correlate statistically WHO and CDC staging because of the small sample size. However, it was possible to assess to a limited extent the possibility of using clinical diagnosis to predict the status of progression of HIV infection in a resource-poor outpatient setting.


Incremental inputs improve the automated detection of implant loosening using machine-learning algorithms.
The aim of this study was to evaluate the ability of a machine-learning algorithm to diagnose prosthetic loosening from preoperative radiographs and to investigate the inputs that might improve its performance. A group of 697 patients underwent a first-time revision of a total hip (THA) or total knee arthroplasty (TKA) at our institution between 2012 and 2018. Preoperative anteroposterior (AP) and lateral radiographs, and historical and comorbidity information were collected from their electronic records. Each patient was defined as having loose or fixed components based on the operation notes. We trained a series of convolutional neural network (CNN) models to predict a diagnosis of loosening at the time of surgery from the preoperative radiographs. We then added historical data about the patients to the best performing model to create a final model and tested it on an independent dataset. The convolutional neural network we built performed well when detecting loosening from radiographs alone. The first model built de novo with only the radiological image as input had an accuracy of 70%. The final model, which was built by fine-tuning a publicly available model named DenseNet, combining the AP and lateral radiographs, and incorporating information from the patient's history, had an accuracy, sensitivity, and specificity of 88.3%, 70.2%, and 95.6% on the independent test dataset. It performed better for cases of revision THA with an accuracy of 90.1%, than for cases of revision TKA with an accuracy of 85.8%. This study showed that machine learning can detect prosthetic loosening from radiographs. Its accuracy is enhanced when using highly trained public algorithms, and when adding clinical data to the algorithm. While this algorithm may not be sufficient in its present state of development as a standalone metric of loosening, it is currently a useful augment for clinical decision making. Cite this article: Bone Joint J 2020;102-B(6 Supple A):101-106.


Replacement of obstructed right ventricular-pulmonary arterial valved conduits with nonvalved conduits in children.
Six to thirty percent of right ventricular-to-pulmonary arterial (RV-PA) valved conduits in children fail within 5 years. Experience with correction of tetralogy of Fallot has shown that a competent pulmonary valve is not essential for excellent late results in most patients. Between March 1980 and November 1984, 26 patients who were 12.5 +/- 3.3 years old underwent conduit replacement 6.7 +/- 2.4 years after definitive repair of congenital heart defects in which a xenograft RV-PA valved conduit had been used. A new Dacron tube graft (n = 15) or pericardial (n = 8), dura mater (n = 2), or Dacron patch (n = 1) over the previous conduit bed was used as replacement. Preoperative mean right ventricular systolic pressure was 90.5 +/- 20 mm Hg and mean gradient across the conduit was 67.9 +/- 24.5 mm Hg. After replacement with a nonvalved conduit, right ventricular systolic pressure was reduced to 45.2 +/- 10.8 mm Hg (p less than .001), with a gradient of 8.9 +/- 7.6 mm Hg (p less than .001). There were no operative deaths. Follow-up at 19.5 +/- 14.9 months (range = 0 to 53) showed that all patients were in New York Heart Association class I (n = 21) or class II (n = 5). In the absence of pulmonary hypertension, hypoplastic pulmonary arteries, significant right ventricular dysfunction, or unrepaired tricuspid regurgitation, replacement of an obstructed conduit with a nonvalved conduit gives excellent early results and may diminish the need for late reoperation.


Espin cytoskeletal proteins in the sensory cells of rodent taste buds.
Espins are multifunctional actin-bundling proteins that are highly enriched in the microvilli of certain chemosensory and mechanosensory cells, where they are believed to regulate the integrity and/or dimensions of the parallel-actin-bundle cytoskeletal scaffold. We have determined that, in rats and mice, affinity purified espin antibody intensely labels the lingual and palatal taste buds of the oral cavity and taste buds in the pharyngo-laryngeal region. Intense immunolabeling was observed in the apical, microvillar region of taste buds, while the level of cytoplasmic labeling in taste bud cells was considerably lower. Taste buds contain tightly packed collections of sensory cells (light, or type II plus type III) and supporting cells (dark, or type I), which can be distinguished by microscopic features and cell type-specific markers. On the basis of results obtained using an antigen-retrieval method in conjunction with double immunofluorescence for espin and sensory taste cell-specific markers, we propose that espins are expressed predominantly in the sensory cells of taste buds. In confocal images of rat circumvallate taste buds, we counted 21.5 +/- 0.3 espin-positive cells/taste bud, in agreement with a previous report showing 20.7 +/- 1.3 light cells/taste bud when counted at the ultrastructural level. The espin antibody labeled spindle-shaped cells with round nuclei and showed 100% colocalization with cell-specific markers recognizing all type II [inositol 1,4,5-trisphosphate receptor type III (IP(3)R(3))(,) alpha-gustducin, protein-specific gene product 9.5 (PGP9.5)] and a subpopulation of type III (IP(3)R(3), PGP9.5) taste cells. On average, 72%, 50%, and 32% of the espin-positive taste cells were labeled with antibodies to IP(3)R(3), alpha-gustducin, and PGP9.5, respectively. Upon sectional analysis, the taste buds of rat circumvallate papillae commonly revealed a multi-tiered, espin-positive apical cytoskeletal apparatus. One espin-positive zone, a collection of approximately 3 mum-long microvilli occupying the taste pore, was separated by an espin-depleted zone from a second espin-positive zone situated lower within the taste pit. This latter zone included espin-positive rod-like structures that occasionally extended basally to a depth of 10-12 mum into the cytoplasm of taste cells. We propose that the espin-positive zone in the taste pit coincides with actin bundles in association with the microvilli of type II taste cells, whereas the espin-positive microvilli in the taste pore are the single microvilli of type III taste cells.


Type 1 diabetes: what is the role of autoimmunity in β cell death?
The current dogma of type 1 diabetes pathogenesis asserts that an autoimmune attack leads to the destruction of pancreatic β cells, with subsequent hyperglycemia. This dogma is based on islet autoantibodies emerging prior to the onset of type 1 diabetes. In this issue of the JCI, Warncke et al. report on their investigation of the development of hyperglycemia below the diabetes threshold as an early proxy of β cell demise. Surprisingly, they found that an elevation in blood glucose preceded the appearance of autoimmunity. This observation calls into question the importance of autoimmunity as the primary cause of β cell destruction and has implications for prevention and treatment in diabetes.


Three domains of competency in global health education: recommendations for all medical students.
In the setting of world population growth and migration, global health issues have an increasing impact on domestic conditions and our medical practitioners. The authors ask: What exactly constitutes global health, and how much do U.S. and Canadian medical students or practitioners need to know about it? To address this topic, the authors convened an American Society for Tropical Medicine and Hygiene Committee on Medical Education, sought input from the Global Health Education Consortium, and surveyed members of the American Committee on Clinical Tropical Medicine and Travelers' Health for educational priorities within the tropical medicine field. The information gained from these sources has been distilled into three domains of global health competency that the authors propose each medical school curriculum should try to achieve for all students: global burden of disease, traveler's medicine, and immigrant health. The authors present here the rationale for altering curricula to include these three topics as a starting point for discussion among medical educators.


Detection of Tritrichomonas foetus by polymerase chain reaction in cultured isolates, cervicovaginal mucus, and formalin-fixed tissues from infected heifers and fetuses.
A rapid, reliable polymerase chain reaction (PCR) assay, originally developed for definitive laboratory identification of the bovine venereal pathogen Tritrichomonas foetus from cultures of male reproductive tract fluids, was used for testing the following: 1) cultured, geographically disparate trichomonad isolates, 2) formalin-fixed tissues from infected heifers and naturally infected fetuses, and 3) cervicovaginal mucus (CVM) from experimentally infected females. In 12 of 12 Western Hemisphere isolates of pathogenic T. foetus (isolated from outbreaks of clinical trichomoniasis or from screening surveys) and in 1 of 1 American Type Culture Collection strain of Tritrichomonas suis, PCR yielded a positive result, i.e., a 347-base pair amplicon in the 5.8S ribosomal RNA and internal transcribed spacer (5.8S-ITS) region of the genome, whereas cultures of Trichomonas vaginalis and Trichomonas gallinae did not produce a PCR product. The PCR assay was also positive in formalin-fixed, paraffin-embedded endometrial samples from 4 of 4 experimentally infected heifers, as well as in archived tissues from 2 of 2 T. foetus-infected aborted bovine fetuses that were submitted to the diagnostic laboratory from a natural outbreak. It was negative in fixed, embedded uterine tissues of 2 of 2 uninfected virgin heifers used as negative controls and in archived fixed gut tissue of a T. gallinae-infected pigeon. In another experiment, CVM aspirated from 4 of 4 experimentally infected heifers in the fifth or sixth postinfection week yielded a positive PCR product of the expected size, whereas CVM from 2 of 2 controls were PCR negative. Pending validation in larger clinical studies, the PCR assay for the 5.8S-ITS coding region of the T. foetus genome offers the prospect of definitive identification of this agent directly from CVM or from formalin-fixed tissues or when false-positive culture results are suspected.


The association of concurrent vitamin D and sex hormone deficiency with bone loss and fracture risk in older men: the osteoporotic fractures in men (MrOS) study.
Low 25-hydroxyvitamin D (VitD), low sex hormones (SH), and high sex hormone binding globulin (SHBG) levels are common in older men. We tested the hypothesis that combinations of low VitD, low SH, and high SHBG would have a synergistic effect on bone mineral density (BMD), bone loss, and fracture risk in older men. Participants were a random subsample of 1468 men (mean age 74 years) from the Osteoporotic Fractures in Men Study (MrOS) plus 278 MrOS men with incident nonspine fractures studied in a case-cohort design. "Abnormal" was defined as lowest quartile for VitD (<20 ng/mL), bioavailable testosterone (BioT, <163 ng/dL), and bioavailable estradiol (BioE, <11 pg/mL); and highest quartile for SHBG (>59 nM). Overall, 10% had isolated VitD deficiency; 40% had only low SH or high SHBG; 15% had both SH/SHBG and VitD abnormality; and 35% had no abnormality. Compared to men with all normal levels, those with both SH/SHBG and VitD abnormality tended to be older, more obese, and to report less physical activity. Isolated VitD deficiency, and low BioT with or without low VitD, was not significantly related to skeletal measures. The combination of VitD deficiency with low BioE and/or high SHBG was associated with significantly lower baseline BMD and higher annualized rates of hip bone loss than SH abnormalities alone or no abnormality. Compared to men with all normal levels, the multivariate-adjusted hazard ratio (95% confidence interval [CI]) for incident nonspine fracture during 4.6-year median follow-up was 1.2 (0.8-1.8) for low VitD alone; 1.3 (0.9-1.9) for low BioE and/or high SHBG alone; and 1.6 (1.1-2.5) for low BioE/high SHBG plus low VitD. In summary, adverse skeletal effects of low sex steroid levels were more pronounced in older men with low VitD levels. The presence of low VitD in the presence of low BioE/high SHBG may contribute substantially to poor skeletal health.


Use of a titanium papillary insert for the construction of interimplant papillae.
Constructing the interimplant papilla is important to achieve an optimally esthetic implant-supported restoration. To obtain support for the soft tissue between two implants so as to result in the desired interdental papilla-like shape, a papillary titanium insert was fabricated. It eliminates the need for any bone grafting procedures with less armamentarium and a reduction of the number of surgical entries. This article describes the papillary titanium insert and focuses on its advantages, manipulations, and handling.


Evidence from RCTs on optimal acupuncture treatment for knee osteoarthritis--an exploratory review.
There are many differing opinions on what constitutes an optimal acupuncture dose for treating any particular patient with any particular condition, and only direct comparisons of different methods in a clinical trial will provide information on which reliable decisions can be made. This article reviews the recent research into acupuncture treatment for osteoarthritis of the knee, to explore whether any aspects of treatment seem more likely to be associated with good outcome of treatment. Among four recent, high quality RCTs, one showed a much greater treatment response than the other three, and the possible factors are discussed. A recent systematic review included 13 RCTs, and this article discusses the possible explanations for differences in their outcomes. It is speculated that optimal results from acupuncture treatment for osteoarthritis of the knee may involve: climatic factors, particularly high temperature; high expectations of patients; minimum of four needles; electroacupuncture rather than manual acupuncture, and particularly, strong electrical stimulation to needles placed in muscle; and a course of at least 10 treatments. These factors offer some support to criteria for adequate acupuncture used in the recent review. In addition, ethnic and cultural factors may influence patients' reporting of their symptoms, and different versions of an outcome measure are likely to differ in their sensitivity - both factors which may lead to apparent rather than real differences between studies. The many variables in a study are likely to be more tightly controlled in a single centre study than in multicentre studies.


Industrious peasants in east and west: markets, technology, and family structure in Japanese and Western European agriculture.
Jan de Vries engages with Osamu Saito's discussion of Tokugawa Japan, in particular, his exploration of de Vries's concept of an industrious revolution for East Asia, which was published in this journal in 2010. The discussion bears on the ongoing debate over the timing and character of the Great Divergence, when advanced parts of Europe pulled ahead of Asia. de Vries argues that the constraint on the Japanese rural household to acquire and shed labour delayed the shift from supply-side industriousness to demand-motivated industriousness, which in turn meant that the Great Divergence was already in place before 1800.


Outcome Measures After ACL Injury in Pediatric Patients: A Scoping Review.
The incidence of anterior cruciate ligament (ACL) injuries in children is increasing. However, no standardized core set of outcome measures exists for evaluating pediatric ACL injuries. To perform a scoping review of the literature to identify patient-reported outcome measures (PROMs) and objective outcome measures used to evaluate pediatric patients after ACL injury and to classify these in accordance with the International Classification of Functioning, Disability, and Health (ICF) domains. Systematic review; Level of evidence, 4. The literature was systematically searched with the PubMed, EMBASE, CINAHL, and PEDro databases. The inclusion criteria were Danish, Norwegian, Swedish, German, or English language; publication between 2010 and 2018; pediatric ACL injury (patients ≤15 years old); and outcome measures. The selected papers were screened for title, abstract, and full text in accordance with predefined inclusion and exclusion criteria. A total of 68 papers (4286 patients; mean ± SD age, 12.2 ± 2.3 years) were included. Nineteen PROMs and 11 objective outcome measures were identified. The most frequently reported PROMs were the International Knee Documentation Committee (IKDC) Subjective Knee Form (51% of studies), Lysholm scoring scale (46% of studies) and Tegner activity rating scale (37% of studies). Additionally, return to sport was reported in 41% of studies. The most frequent objective measures were knee laxity (76% of studies), growth disturbances (69% of studies), range of motion (41% of studies), and muscle strength (21% of studies). With respect to the ICF domains, the IKDC covered all 3 ICF health domains, the Lysholm score covered the Body Structure and Function and the Activity Limitation domains, while the Tegner score covered the Participation Restriction domain. Objectively measured knee joint laxity, range of motion, and muscle strength covered 1 domain (Body Structure and Function). Pediatric patients with ACL injury were mainly evaluated subjectively with the IKDC and objectively by knee joint laxity. No consensus exists in the evaluation of children after ACL injury. The majority of applied outcome measures are developed for adults. To cover the ICF health domains, future research needs to consider reliable and valid outcome measures relevant for pediatric patients with ACL injury.


Influence of the coincubation of post-thawed bull semen with elevated β-hydroxybutyrate concentrations on sperm characteristics.
In this study, the relationships between post-thaw bull sperm characteristics and hyperketonemic conditions after coincubation with cow plasma or media were determined to investigate if such a condition could affect bull sperm characteristics. Two experiments were conducted. In experiment 1, blood samples were collected from 31 cows to prepare plasma. Cows were independently categorized into two groups according to plasma β-hydroxybutyrate (BHB) concentrations (above or below 1.2 mM). Thawed bull semen was diluted and incubated with diluted plasma; motility parameters were evaluated using Computer Assisted Semen Analysis (CASA). In experiment 2, a pooled sample of thawed semen was diluted and divided into three aliquots: without BHB (control) and treated with either 1.2 mM (1.2) or 3 mM (3) BHB. In addition to motility, flow cytometric analyses were carried out. In experiment 1, the overall motility decreased significantly in plasma containing high (≥1.2 mM) BHB compared to plasma containing low (<1.2 mM) BHB. In experiment 2, the overall motility tended to be lower in BHB (3 mM)-supplemented samples. The supplementation of 3 mM BHB increased the proportion of live superoxide-positive sperm and sperm with high mitochondrial potential, while the DNA fragmentation index decreased.