A 'cold synthesis' of heroin and implications in heroin signature analysis utility of trifluoroacetic/acetic anhydride in the acetylation of morphine.
Treatment of morphine, at room temperature, with a mixture of trifluoroacetic anhydride (TFAA) and acetic acid (20-30min) affords good yields of heroin. GC-MS and HPLC examination shows that heroin produced by this route to be extremely clean, but the product contains slightly less heroin than observed via the more traditional acetic anhydride (AA) route (76.1% versus 83.55%); and greater quantities of 3-MAM and 6-MAM (6.9% versus 0.75% and 7.13% versus 0.63%). The concentration ratios of the major alkaloid impurities were found to be both production method (TFAA and AA) as well as morphine extraction methodology dependant. Data contained herein describe the impact of this new production method on current intelligence efforts, largely by-passing existing heroin signature programs and the UNDCP's efforts to restrict access to key synthetic precursors. Given the methodology dependency we find that examination of the major alkaloid ratios is unsuitable for the development of a new heroin signature program. Further examination of the TFAA methodology allowed the identification of TFAA specific marker compounds, namely bis-trifluoroacetylmorphine (30), 3-trifluoroacetyl-6-acetylmorphine (31), 3-acetyl-6-trifluoroacetylmorphine (32) and trifluoroacetylcodeine (33). However, the hydrolytic lability of trifluroacetyl esters requires careful treatment of suspect samples, thus we propose a modification to existing HSP's in instances were the 6-MAM/WM ratio falls within the average minimum and maximum values of 6.17 and 17.32.


[MicroRNA regulates animal adipocyte differentiation].
Adipose tissues play a critical role in the regulation of energy metabolism and homeostasis, and is also an important endocrine organ. Adipocyte differentiation is a complicated physiological process during which mesenchymal stem cells differentiate into adipocytes. This process is synergistically regulated by a large number of transcription factors, hormones and signaling pathway molecules. As a class of endogenous non-coding RNA (ncRNA), microRNAs (miRNAs) regulate gene expression mainly through post-transcriptional translational repression. In recent years, numerous studies have demonstrated that miRNA could have an impact on adipocyte differentiation and adipogenesis by modulating the expression levels of several adipogenic transcription factors and key signaling molecules. In this review, we summarize the mechanism of miRNA in regulating the differentiation of white/brown/beige adipocytes and the relevant signaling pathways and key factors, in the hope of providing theoretical guidance and new thoughts for treating obesity and other metabolic diseases.


Smartphone apps for cancer: A content analysis of the digital health marketplace.
The purpose of this study was to examine the state of smartphone applications for cancer intended for the general public with a focus on interactive features, content sources, and application developer affiliations. The level of health provider involvement in screening or appraising application content was also assessed. A total of 123 apps were identified for analysis from two major mobile application marketplaces (Apple iTunes = 40; Google Play = 83). Application characteristics were collected, analyzed, and reported. These included the mobile platform, cost, application developer affiliation, date of last update, purpose of application, content sources, and interactive features. In the study sample, 50% of the applications focused on general information for cancer (62/123). Next, this was followed by applications for breast cancer (15%, 19/123) and skin cancer (7%, 8/123). Only 10% of application descriptions (12/123) identified sources for application content. Interactive features included the ability to monitor symptoms, side effects, treatments, and chronic pain (20%, 25/123). Only 3% of the applications (4/123) stated content had been evaluated by health providers. This study contributes an updated analysis of applications for cancer available in the digital health marketplace. The findings have implications for information quality and supportive resources for cancer care. More transparent information about content sources, organizational affiliations, and level of health provider oversight in screening application content is warranted. Recommendations for improving the quality of cancer applications are also offered.


Associations between smokers' knowledge of causes of smoking harm and related beliefs and behaviors: Findings from the International Tobacco Control (ITC) Four Country Smoking and Vaping Survey.
Most smokers know that smoking is harmful to health, but less is known about their understanding of what causes the harms. The primary aim was to examine smokers' perceptions of the relative contributions to smoking-related morbidity from combustion products, nicotine, other substances present in unburned tobacco, and additives. A secondary aim was to evaluate the association of these perceptions with nicotine vaping product use intentions, and quitting motivation/intentions. Participants were current smokers and recent ex-smokers from Australia, Canada, England and the United States (N = 12,904, including 8511 daily smokers), surveyed in the 2018 International Tobacco Control Four Country Smoking and Vaping Survey. Respondents reported on how much they thought combustion products, nicotine, chemicals in the tobacco and additives in cigarettes contribute to smoking-related morbidity (none/very little; some but less than half; around half; more than half; all or nearly all of it; don't know). Overall, 4% of participants provided estimates for all four component causes that fell within the ranges classified correct, with younger respondents and those from England most likely to be correct. Respondents who rated combustion as clearly more important than nicotine in causing harm (25%) were the least likely to be smoking daily and more likely to have quit and/or to be vaping. Among daily smokers, all four cause estimates were independently related to overall health worry and extent of wanting to quit, but the relative rating of combustion compared to nicotine did not add to prediction. Those who answered 'don't know' to the sources of harm questions and those suggesting very little harm were consistently least interested in quitting. Most smokers' knowledge of specific causes of harm is currently inadequate and could impact their informed decision-making ability.


CheA Kinase of bacterial chemotaxis: chemical mapping of four essential docking sites.
The chemotaxis pathway of Escherichia coli and Salmonella typhimurium is the paradigm for the ubiquitous class of 2-component signaling pathways in prokaryotic organisms. Chemosensing begins with the binding of a chemical attractant to a transmembrane receptor on the cell surface. The resulting transmembrane signal regulates a cytoplasmic, multiprotein signaling complex that controls cellular swimming behavior by generating a diffusible phosphoprotein. The minimal functional unit of this signaling complex, termed the core complex, consists of the transmembrane receptor, the coupling protein CheW, and the histidine kinase CheA. Though the structures of individual components are largely known and the core complex can be functionally reconstituted, the architecture of the assembled core complex has remained elusive. To probe this architecture, the present study has utilized an enhanced version of the protein-interactions-by-cysteine-modification method (PICM-beta) to map out docking surfaces on CheA essential for kinase activity and for core complex assembly. The approach employed a library of 70 single, engineered cysteine residues, scattered uniformly over the surfaces of the five CheA domains in a cysteine-free CheA background. These surface Cys residues were further modified by the sulfhydryl-specific alkylating agent, 5-fluorescein-maleimide (5FM). The functional effects of individual Cys and 5FM-Cys surface modifications were measured by kinase assays of CheA activity in both the free and core complex-associated states, and by direct binding assays of CheA associations with CheW and the receptor. The results define (i) two mutual docking surfaces on the CheA substrate and catalytic domains essential for the association of these domains during autophosphorylation, (ii) a docking surface on the CheA regulatory domain essential for CheW binding, and (iii) a large docking surface encompassing regions of the CheA dimerization, catalytic, and regulatory domains proposed to bind the receptor. To test the generality of these findings, a CheA sequence alignment was analyzed, revealing that the newly identified docking surfaces are highly conserved among CheA homologues. These results strongly suggest that the same docking sites are widely utilized in prokaryotic sensory pathways. Finally, the results provide new structural constraints allowing the development of improved models for core complex architecture.


Chronic rhinosinusitis and nasal polyps: the role of generic and specific questionnaires on assessing its impact on patient's quality of life.
Chronic rhinosinusitis (CRS) including nasal polyps is a chronic inflammatory disease of the nasal and paranasal sinus mucosa that, despite differing hypotheses of its cause, remains poorly understood. Primary symptoms are nasal blockage, loss of smell, rhinorrhea, and facial pain or pressure. Chronic rhinosinusitis causes significant physical symptoms, has a negative impact on quality of life (QoL), and can substantially impair daily functioning. A global evaluation of patients must include, together with nasal symptoms, nasal endoscopy, and CT scan, the measurement of QoL. To assess QoL in CRS, specific and generic questionnaires may be used. Chronic rhinosinusitis has a considerable impact on a patient's QoL but comorbidities, such as asthma and atopy, have an accumulative negative effect. Both medical and surgical treatments lead to a similar improvement on the QoL of CRS and nasal polyp patients.


Ventricular asynchrony of time-to-peak systolic velocity in structurally normal heart by tissue Doppler imaging.
Echocardiographic measurements of time-to-peak systolic velocities (Ts) are helpful for assessing the degree of cardiac asynchrony. We assessed the degree of ventricular asynchrony in structurally normal heart according to Ts by tissue Doppler imaging. We performed conventional echocardiography and tissue velocity imaging for 65 healthy adult volunteers to measure the Ts of 12 left ventricular segments in the mid and basal levels delay of Ts and standard deviation (SD) of Ts in all and basal segments. Six frequently used markers of dyssynchrony were measured and were also compared between men and women. Data are presented as median (25th and 75th percentile). Septal-lateral and anteroseptal-posterior delays were 50 (20, 90) and 20 (0, 55) ms. The delay between the longest and the shortest Ts in basal and all segments were 100 (80, 120) and 110 (83, 128) ms, respectively. SD of Ts was 39 (24, 52) ms for basal and 41 (28, 51) ms for all segments. Overall, 76.9% of cases had at least one marker of dyssynchrony. Frequencies of dyssynchrony markers were almost significantly higher in women compared to men. The most frequently observed dyssynchrony marker was SD of Ts of all segments (70.8%) and the lowest was anteroseptal-posterior delay (21.5%). Normal population almost had dyssynchrony by previously described markers and many of these markers were more frequent in women. Conducting more studies on normal population by other tissue Doppler modalities may give better description of cardiac synchronicity.


Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer.
The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, plays an important role in the control of cell growth and differentiation. Disruption of its signaling leads to neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis.EGFR is overexpressed in a variety of solid tumors, including colorectal cancer (CRC), and its overexpression is associated with poorer prognosis. One class of agents that is currently used to target EGFR in the treatment of metastatic CRC (mCRC) is the monoclonal antibodies. While the monoclonal antibody EGFR inhibitors lack many of the severe side effects commonly observed with cytotoxic chemotherapy, they are associated with a set of unique dermatological toxicities. This paper reviews the safety profile of the anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of mCRC.


Sensing the deadliest toxin: technologies for botulinum neurotoxin detection.
Sensitive and rapid detection of botulinum neurotoxins (BoNTs), the most poisonous substances known to date, is essential for studies of medical applications of BoNTs and detection of poisoned food, as well as for response to potential bioterrorist threats. Currently, the most common method of BoNT detection is the mouse bioassay. While this assay is sensitive, it is slow, quite expensive, has limited throughput and requires sacrificing animals. Herein, we discuss and compare recently developed alternative in vitro detection methods and assess their ability to supplement or replace the mouse bioassay in the analysis of complex matrix samples.


Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation.
β-Sheet-rich α-synuclein (αS) aggregates characterize Parkinson's disease (PD). αS was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in α-helix-rich tetramers. Crosslinking traps principally tetrameric αS in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal human brain contains abundant αS tetramers. The PD-causing mutation A53T decreases tetramers in mouse brain. Neurons derived from an A53T patient have decreased tetramers. Neurons expressing E46K do also, and adding 1-2 E46K-like mutations into the canonical αS repeat motifs (KTKEGV) further reduces tetramers, decreases αS solubility and induces neurotoxicity and round inclusions. The other three fPD missense mutations likewise decrease tetramer:monomer ratios. The destabilization of physiological tetramers by PD-causing missense mutations and the neurotoxicity and inclusions induced by markedly decreasing tetramers suggest that decreased α-helical tetramers and increased unfolded monomers initiate pathogenesis. Tetramer-stabilizing compounds should prevent this.


Depth profile characterization of ultra shallow junction implants.
A need for analysis techniques, complementary to secondary ion mass spectrometry (SIMS), for depth profiling dopants in silicon for ultra shallow junction (USJ) applications in CMOS technologies has recently emerged following the difficulties SIMS is facing there. Grazing incidence X-ray fluorescence (GIXRF) analysis in the soft X-ray range is a high-potential tool for this purpose. It provides excellent conditions for the excitation of the B-K and the As-L(iii,ii) shells. The X-ray standing wave (XSW) field associated with GIXRF on flat samples is used here as a tunable sensor to obtain information about the implantation profile because the in-depth changes of the XSW intensity are dependent on the angle of incidence. This technique is very sensitive to near-surface layers and is therefore well suited for the analysis of USJ distributions. Si wafers implanted with either arsenic or boron at different fluences and implantation energies were used to compare SIMS with synchrotron radiation-induced GIXRF analysis. GIXRF measurements were carried out at the laboratory of the Physikalisch-Technische Bundesanstalt (PTB) at the electron storage ring BESSY II using monochromatized undulator radiation of well-known radiant power and spectral purity. The use of an absolutely calibrated energy-dispersive detector for the acquisition of the B-Kalpha and As-Lalpha fluorescence radiation enabled the absolute determination of the total retained dose. The concentration profile was obtained by ab initio calculation and comparison with the angular measurements of the X-ray fluorescence.


Cordycepin as a Promising Inhibitor of SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp).
SARS-CoV-2, which emerged in Wuhan, China, is a new global threat that has killed millions of people and continues to do so. This pandemic has not only threatened human life but has also triggered economic downturns across the world. Researchers have made significant strides in discovering molecular insights into SARSCoV- 2 pathogenesis and developing vaccines, but there is still no successful cure for SARS-CoV-2 infected patients. The present study has proposed a drug-repositioning pipeline for the design and discovery of an effective fungal-derived bioactive metabolite as a drug candidate against SARS-CoV-2. Fungal derivative "Cordycepin" was selected for this study to investigate the inhibitory properties against RNA-dependent RNA polymerase (RdRp) (PDB ID: 6M71) of SARS-CoV-2. The pharmacological profile, intermolecular interactions, binding energy, and stability of the compound were determined utilizing cheminformatic approaches. Subsequently, molecular dynamic simulation was performed to better understand the binding mechanism of cordycepin to RdRp. The pharmacological data and retrieved molecular dynamics simulations trajectories suggest excellent drug-likeliness and greater structural stability of cordycepin, while the catalytic residues (Asp760, Asp761), as well as other active site residues (Trp617, Asp618, Tyr619, Trp800, Glu811) of RdRp, showed better stability during the overall simulation span. Promising results of pharmacological investigation along with molecular simulations revealed that cordycepin exhibited strong inhibitory potential against SARSCoV- 2 polymerase enzyme (RdRp). Hence, cordycepin should be highly recommended to test in a laboratory to confirm its inhibitory potential against the SARS-CoV-2 polymerase enzyme (RdRp).


Molecular Chemistry of Atmospheric Brown Carbon Inferred from a Nationwide Biomass Burning Event.
Lag Ba'Omer, a nationwide bonfire festival in Israel, was chosen as a case study to investigate the influence of a major biomass burning event on the light absorption properties of atmospheric brown carbon (BrC). The chemical composition and optical properties of BrC chromophores were investigated using a high performance liquid chromatography (HPLC) platform coupled to photo diode array (PDA) and high resolution mass spectrometry (HRMS) detectors. Substantial increase of BrC light absorption coefficient was observed during the night-long biomass burning event. Most chromophores observed during the event were attributed to nitroaromatic compounds (NAC), comprising 28 elemental formulas of at least 63 structural isomers. The NAC, in combination, accounted for 50-80% of the total visible light absorption (>400 nm) by solvent extractable BrC. The results highlight that NAC, in particular nitrophenols, are important light absorption contributors of biomass burning organic aerosol (BBOA), suggesting that night time chemistry of •NO3 and N2O5 with particles may play a significant role in atmospheric transformations of BrC. Nitrophenols and related compounds were especially important chromophores of BBOA. The absorption spectra of the BrC chromophores are influenced by the extraction solvent and solution pH, implying that the aerosol acidity is an important factor controlling the light absorption properties of BrC.


Evaluation of two enzyme immunoassays for detection of immunoglobulin G antibodies to mumps virus.
To determine suitability for national serosurveys, we compared two commercial enzyme-linked immunosorbent assays (ELISAs) for mumps antibody, Enzygnost Anti-Parotitis-Virus/IgG (which uses a whole-virus antigen) and Microimmune Mumps IgG Screen ELISA (which uses a recombinant nucleoprotein antigen), by testing 1,915 opportunistically collected sera submitted to diagnostic laboratories across Australia in 1997 to 1998. The proportion of positive results increased with age in both ELISAs but was significantly higher with the Microimmune than with the Enzygnost ELISA overall (88% versus 63%; P < 0.01) and in all age groups. However, the proportion of equivocal results was significantly higher with the Enzygnost than with the Microimmune ELISA (9% versus 4%; P < 0.01). Of the 572 sera with discrepant or equivocal results, 508 had sufficient sample remaining to perform the neutralization test (NT). A proportion with concordant results in both ELISAs were also tested by the NT. For sera with discrepant results, there was significantly better agreement between the NT and Microimmune than between the NT and Enzygnost (310/444 [70%] versus 135/348 [39%]; P < 0.01). Of 64 sera with equivocal Microimmune results, 45 (70%) were positive in the NT compared with 140 of 160 (88%) equivocal Enzygnost results (P < 0.01). Compared with the NT, the Microimmune ELISA is more sensitive (96% versus 80%) but apparently less specific (36% versus 85%) than the Enzygnost ELISA. However, this is likely to be due to the generally lower sensitivity of the NT, since the Microimmune results reflect expected seroprevalence, based on vaccine uptake in the age groups studied. We conclude that the Microimmune ELISA is a more appropriate assay than the Enzygnost ELISA for estimation of mumps seroprevalence.


p-mTOR expression is associated with better prognosis in luminal breast carcinoma.
Despite considerable interest in the PI3K/AKT/mTOR pathway in breast carcinomas (BC), published data reports contradictory results regarding the association of phosphorylated mammalian target of Rapamycin (p-mTOR) expression with clinico-pathological features and prognosis in BC. Here, we evaluate the main clinico-pathological associations with p-mTOR expression in BC, with focus on the different molecular subtypes. In this retrospective study, 331 BC patients were included in final analysis. Outcome measures included disease-free survival (DFS) and overall survival (OS) times. Baseline data and outcome measures were compared between immunohistochemical p-mTOR expressing and non-expressing BCs. Subgroup analysis was performed to assess the effect of p-mTOR expression in the outcome for each BC molecular subtype. 43.8% of the tumours were positive for p-mTOR, with a significant correlation between p-mTOR expression with smaller (<2 cm) (p=0.021) and lower-grade tumours (p<0.001). Expression of p-mTOR was also associated with longer DFS (HR of 0.32, p<0.001) and OS (HR of 0.20, p<0.001). In a multivariable analysis, the HR remained significant with minimal change (HR=0.26, p=0.002 for OS; HR=0.40, p=0.002 for DFS). In subgroup analysis, luminal p-mTOR-expressing tumours demonstrated longer DFS and OS (HR 0.33, p=0.003; HR 0.20, p=0.003, respectively) independently of size, grade, lymph node status and Her-2 overexpression. p-mTOR expression is associated with smaller, lower-grade and with luminal BC. In multivariable analysis, p-mTOR expression was associated with longer DFS and OS, independently of the size, grade and lymph node status, especially in luminal BCs.


Maxine Deborrah Hyde: First Female Graduate of Case Western Reserve University's Neurological Surgery Residency Program and Second Black Female Neurosurgeon in the United States.
The historical diversity gap in the neurosurgical workforce persists to this day. Women, despite constituting over half of the yearly total of medical school graduates, comprise only 6% of certified practicing neurosurgeons in the United States. Furthermore, Black Americans make up under 4% of U.S. neurosurgeons, despite making up around 14% of the national population. The purpose of this account is to highlight the life and career of Dr. Maxine Deborrah Hyde and illustrate the importance and necessity of diversity and inclusivity in advancing the field of neurosurgery. Through this paper, we aspire to encourage the development of new diversity initiatives. Original scientific and bibliographic materials of Hyde were examined, and an extensive analysis of her life was compiled. Despite growing up during the era of Jim Crow, Dr. Hyde persevered and became the valedictorian of Oak Park High School. As a first-generation college student at Tougaloo College, she later earned her MS from Cleveland State University. Dr. Hyde graduated with honors from Case Western Reserve University School of Medicine in 1977. Thereafter, she became the first female and first Black graduate of Case Western's neurosurgery residency and the second Black woman to receive certification from the American Board of Neurological Surgery. Later in life, Dr. Hyde established the Beacon of Hope Scholarship Foundation to assist disadvantaged students in overcoming educational barriers. Dr. Hyde was a trailblazer who overcame systematic barriers and paved the way for future generations of aspiring neurosurgeons.


Efficacy and safety of intravenous secukinumab in noninfectious uveitis requiring steroid-sparing immunosuppressive therapy.
Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibited promising activity in a proof-of-concept study when administered in intravenous (IV) doses to patients with active, chronic, noninfectious uveitis. This study compared the efficacy and safety of different IV and subcutaneous (SC) doses of secukinumab in patients with noninfectious uveitis. Multicenter, randomized, double-masked, dose-ranging, phase 2 clinical trial. Thirty-seven patients with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis who required corticosteroid-sparing immunosuppressive therapy. Patients were randomized to secukinumab 300 mg SC every 2 weeks for 4 doses, secukinumab 10 mg/kg IV every 2 weeks for 4 doses, or secukinumab 30 mg/kg IV every 4 weeks for 2 doses. Intravenous or SC saline was administered to maintain masking. Efficacy was assessed on day 57 (2-4 weeks after last dose). Percentage of patients with treatment response, defined as (1) at least a 2-grade reduction in vitreous haze score or trace or absent vitreous haze in the study eye without an increase in corticosteroid dose and without uveitis worsening or (2) reduction in corticosteroid dosages to prespecified levels without uveitis worsening. Percentage of patients with remission, defined as anterior chamber cell and vitreous haze scores of 0 or 0.5+ in both eyes without corticosteroid therapy or uveitis worsening. Secukinumab 30 mg/kg IV and 10 mg/kg IV, compared with the 300 mg SC dose, produced higher responder rates (72.7% and 61.5% vs. 33.3%, respectively) and remission rates (27.3% and 38.5% vs. 16.7%, respectively). Statistical and clinical superiority for the 30 mg/kg IV dose compared with the 300 mg SC dose was established in a Bayesian probability model. Other measures, including time to response onset, change in visual acuity, and change in vitreous haze score, showed numeric trends favoring IV dosing. Secukinumab, administered in IV or SC formulations, appeared safe and was well tolerated. Intravenous secukinumab was effective and well tolerated in noninfectious uveitis requiring systemic corticosteroid-sparing immunosuppressive therapy. Greater activity with IV dosing suggests that patients may not receive sufficient drug with SC administration. High-dose IV secukinumab may be necessary to deliver secukinumab in therapeutic concentrations.


[Reproductive disorders and preservation of fertility in males with benign and malignant brain tumors].
Brain tumors rank third in the incidence rate among cancer nosologies. However, improvement of neurosurgical treatment methods and the use of modern regimens of chemotherapy and radiotherapy have increased survival of patients with benign and malignant brain tumors. A significant proportion of patients with brain tumors are young people in the reproductive age who are interested in maintaining their fertility. Surgical removal of tumors, mainly in the hypothalamo-pituitary area as well as the use of chemotherapy and radiotherapy for malignant brain tumors of any localization may be complicated by hypogonadism and infertility. At present, a simple and reliable method of preserving male fertility is sperm cryopreservation. Neurosurgeons as well as oncologists and radiologists should inform patients with brain tumors about a potential risk of hypogonadism and infertility after treatment and about opportunities of sperm cryopreservation, which increases the chances of having future genetic progeny.


Effect of vitamin D3 supplementation level on the postmortem tenderization of beef from steers.
The objective of this experiment was to determine the effect of different doses of vitamin D3 (VITD) on beef feedlot performance, plasma and muscle Ca2+, tissue residues, and improvement of Warner-Bratzler shear force (WBS) and panel tenderness. A total of 167 steers were fed one of six levels of VITD. The VITD treatments (28 steers/treatment) were 0, 0.5 x 10(6), 1 x 10(6), 2.5 x 10(6), 5 x 10(6), and 7.5 x 10(6) IU/steer daily of VITD fed nine consecutive days before slaughter. Feedlot performance and plasma Ca2+ were measured during the last 21 days on feed. Warner-Bratzler shear force was measured on strip loin and top round steaks at 7, 10, 14, and 21 d postmortem. The VITD treatments of 5 and 7.5 x 10(6) IU/steer daily decreased (P < 0.05) ADG, and VITD supplementation of 2.5, 5, and 7.5 x 10(6) IU/steer daily decreased average dry matter feed intake (P < 0.05) at the end of the feeding trial. Plasma Ca2+ increased linearly with VITD treatment (P < 0.01). Calpastatin and calpain activity were not influenced by treatment (P > 0.05), but muscle Ca2+ was increased (P < 0.05) by VITD treatments of 1, 2.5, 5, and 7.5 10(6) IU/steer daily. Feeding VITD did not influence (P > 0.05) carcass quality or yield traits. Supplementing VITD at levels of 1, 2.5, 5, and 7.5 10(6) IU/steer daily increased (P < 0.05) VITD concentrations in strip loin and liver samples. Cooking liver decreased VITD concentrations 10 to 28%. Vitamin D3 treatments of 0.5 and 7.5 x 10(6) IU/d reduced strip loin steak WBS at d 7 (P < 0.05), but VITD treatments did not decrease strip loin steak WBS at any other time postmortem. The VITD treatments of 0.5, 1, and 5 x 10(6) IU/steer daily decreased top round steak WBS at 7 d, and all VITD treatments decreased 10-d top round steak WBS (P < 0.05). Supplementing steers with 0.5 x 10(6) IU/steer daily of VITD also decreased (P < 0.05) top round steak WBS at 21 d postmortem compared with controls. Sensory tenderness at 7 d postmortem was increased (P < 0.05) by all VITD treatments in top round steaks, yet strip loin tenderness scores were not affected (P > 0.05) by VITD treatment. Treatment with VITD quadratically decreased (P < 0.05) round WBS. Thus, VITD treatment will effectively improve tenderness when cattle tend to be tough and have no impact on cattle that produce tender beef. Feeding steers 0.5 x 10(6) IU of VITD daily for 9 d improved tenderness in two muscles without negatively affecting feedlot performance or tissue residues.


The Impact of Hypomania on Aerobic Capacity and Cardiopulmonary Functioning-A Case Report.
Background: Hypomanic episodes are characterized by increased goal-directed behavior and psychomotor agitation. While the affective, cognitive, and behavioral manifestations of such episodes are well-documented, their physiological influence on aerobic capacity and cardiopulmonary functioning are unknown. Methods: We describe a case report of an individual with schizophrenia who experienced a hypomanic episode while serving as a control participant (wait list) in a single-blind, randomized clinical trial examining the impact of aerobic exercise (AE) on neurocognition in people schizophrenia. As part of the trial, participants completed two scheduled clinical assessments and cardiopulmonary exercise tests (VO2max) at baseline and 12 weeks later at end of study. All participants received standard psychiatric care during the trial. Following a baseline assessment in which he displayed no evidence of mood lability, the subject returned on Week-12 for his scheduled follow-up assessment displaying symptoms of hypomania. He was able to complete the follow-up assessment, as well as third assessment 2 weeks later (Week-14) when his hypomanic symptoms ebbed. Results: While not engaging in AE, the subject's aerobic capacity, as indexed by VO2max, increased by 33% from baseline to Week-12. In comparison, participants engaged in the aerobic exercise training increased their aerobic capacity on average by 18%. In contrast, participants in the control group displayed a small decline (-0.5%) in their VO2max scores. Moreover, the subject's aerobic capacity increased even further by Week-14 (49% increase from baseline), despite the ebbing of his hypomania symptoms at that time. These changes were accompanied by increases in markers of aerobic fitness including peak heart rate, respiratory exchange rate, peak minute ventilation, watts, and peak systolic blood pressure. Resting systolic and diastolic blood pressure, and peak diastolic blood pressure remained unchanged. Conclusions: Our findings suggest that hypomania produce substantial increase in aerobic capacity and that such elevations may remain sustained following the ebbing of hypomanic symptoms. Such elevations may be attributed to increased mobility and goal-directed behavior associated with hypomania, as individuals in hypomanic states may ambulate more frequently, for longer duration, and/or at higher intensity. Our results provide a first and unique view into the impact of hypomania on aerobic capacity and cardiopulmonary functioning.


Small Molecule Inhibitors Targeting the "Undruggable" Survivin: The Past, Present, and Future from a Medicinal Chemist's Perspective.
Survivin, a homodimeric protein and a member of the IAP family, plays a vital function in cell survival and cycle progression by interacting with various proteins and complexes. Its expression is upregulated in cancers but not detectable in normal tissues. Thus, it has been regarded and validated as an ideal cancer target. However, survivin is "undruggable" due to its lack of enzymatic activities or active sites for small molecules to bind/inhibit. Academic and industrial laboratories have explored different strategies to overcome this hurdle over the past two decades, with some compounds advanced into clinical testing. These strategies include inhibiting survivin expression, its interaction with binding partners and homodimerization. Here, we provide comprehensive analyses of these strategies and perspective on different small molecule survivin inhibitors to help drug discovery targeting "undruggable" proteins in general and survivin specifically with a true survivin inhibitor that will prevail in the foreseeable future.


A study to assess the methodological quality of in vivo animal experiments published in Indian journal of pharmacology: A retrospective, cross-sectional, observational study.
Good reporting of experimental research is a vital part of research process. Although the reporting guidelines such as Animal research: Reporting in vivo experiments (ARRIVE) require the authors to stick to a standard format, they do not guarantee study reports' validity. For assessing the study reports validity, critical appraisal tools are required. The evaluation of the methodological quality of in vivo animal studies of Indian Journal of Pharmacology (IJP) published between 2011 and 2017 through critical appraisal was the primary objective. The secondary objective was to evaluate the adherence of selected studies to the ARRIVE guidelines. All in vivo animal studies published as full-text articles in IJP from January 2011 to December 2017 and satisfying the inclusion norms were included. A checklist based on the underlying principles of ARRIVE statement was applied to in vivo animal research (AR) published in IJP. For critical appraisal of reports, risk-of-bias domains were also applied on studies from in vivo AR. One hundred and sixty-one studies satisfied the inclusion criteria. Seventy-three articles (45.34%, 95% confidence interval [CI]: 0.37-0.53) discussed about randomization procedure. Eighteen articles (11.18%, 95% CI: 0.07-0.16) gave details about blinding when assessing results. None of the studies provided details of sample size calculation. Eight articles (4.97%, 95% CI: 0.02-0.09) commented on the study limitations. It was found that adherence to only some criteria of ARRIVE guidelines was subpar. There is a need for optimal reporting of random distribution of animals to experimental groups, concealment of allocation, blinded outcome evaluation, computation of sample size, and attrition of animals for improving the validity of AR.


Obesity and changes of alkaline phosphatase activity in the small intestine of 40- and 80-day-old rats subjected to early postnatal overfeeding or monosodium glutamate.
To investigate the relationship between development of obesity and the small intestinal functions two experimental models of male Wistar rats were used in the present work: 1) early postnatally overfed rats, nursed from birth to weaning in small litters (SL, 4 pups/nest), and 2) neonatally monosodium glutamate treated rats (MSG 2 mg/g b.w. administered s.c. for 4 days after birth) submitted to the same early nutritional manipulation. After weaning, all animals had free access to a standard pellet diet and at 40 and 80 days of age their body weight, body fat content and food consumption as well as changes of the brush-border-bound duodenal and jejunal alkaline phosphatase (AP) activity were compared with parameters of the offsprings raised under normal feeding conditions (NL, 8 pups/nest). At 40 and 80 days of age the postnatally overfed pups from SL nests became heavier, displayed a significantly increased epididymal plus retroperitoneal fat pad weight (P<0.01) and significantly higher AP activity in both segments of the small intestine (P<0.01) in comparison with rats nursed in NL nests, although their mean daily food intake did not differ from that of non-obese rats during the postweaning periods examined. In contrast, the same treatment of MSG rats had only a small effect on late appearance of obesity, i.e. in early postnatally overfed and normally fed MSG rats a similar pattern of body weight, food intake, adiposity and AP activity was found after weaning. The effect of MSG-treatment was also accompanied by the appearance of normophagia, hypophagia and stunted growth on day 40 and day 80, respectively. Moreover, the size of fat depots and the increase of brush-border-bound AP activity in MSG rats belonging to the SL and NL groups was quantitatively similar to the values size of these parameters observed in SL obese rats subjected to early postnatal overnutrition. These results indicate that postnatal nutritional experience (overnutrition) may represent a predisposing factor in control rats from small litters for the development of obesity in later life. Permanently increased small intestinal AP activity observed after weaning in both models of obesity when hyperphagia is not present suggest that these functional changes and associated alterations in food digestion could be a component of regulatory mechanisms contributing to the maintenance of their elevated body fat weight.


Family-centered child welfare services: new life for a historic idea.
The recent emphasis on permanency planning in child welfare has strengthened the resolve of policy makers and service providers to serve the families of dependent children better. Permanency planning asks child welfare services either to reunite children in care with their families of origin or to find permanent substitute families for children, but the goal of a permanent family for every child has been much easier to articulate than it has been to achieve.


Management of vesical calculi: comparison of lithotripsy devices.
Although endoscopic lithotripsy of bladder stones has been well described and is widely practiced, comparison of the main modalities of mechanical, electrohydraulic, and ultrasonic lithotripsy is lacking. The exact role of these and other modalities such as the Swiss Lithoclast and extracorporeal shockwave lithotripsy is not clearly defined. The safety and efficacy of the various lithotripsy modalities available to treat bladder calculi were reviewed retrospectively over an 18-year period. A total of 106 patients were treated with some form of intracorporeal lithotripsy. In general, all devices proved to be effective with a low rate of complications. The addition of transurethral resection of the prostate to bladder stone management under the same anesthetic was also found to be a safe procedure for moderate benign prostatic hyperplasia. In summary, transurethral endoscopic lithotripsy is a safe and effective method of bladder stone management both alone and in combination with transurethral prostatectomy. All modalities of intracorporeal lithotripsy are effective; however, devices such as ultrasound lithotripters or the Swiss Lithoclast that utilize larger, rigid probes may be more efficient for patients with large or particularly hard vesical calculi.


Electron contamination in clinical high energy photon beams.
The electron contamination in photon beams has been investigated by means of contaminating lepton depth doses and dose profiles in different geometries with two 20 MV beams. Different components of this contamination have been investigated separately by systematically adding contamination to a "clean" reference field. At 20 MV, the air generated electrons were found to be almost negligible compared to the electrons originating from the accelerator head when measurements were performed in standard fields at SSDs between 80 and 120 cm. The total electron part of the depth dose curve was then almost the same, i.e., independent of SSD, when the collimator opening was held fixed. However, when different accessories such as a shaping block and different attenuating plates were located in the beam path below the collimators, a large SSD dependence of the electron contamination was noticed. A comparison was also made between two machines, one equipped with a multileaf collimator, with similar beam qualities at 20 MV. These measurements indicate that the interior view of the treatment head seen by the detector (mainly the flattening filter, monitor chamber, or other electron generating material) influences the magnitude of the electron contamination. When the collimator opening is decreased the electron contamination will also decrease as parts of the electron source will be shielded by the collimator blocks.


An evolutionarily conserved tripartite tryptophan motif stabilizes the prodomains of cathepsin L-like cysteine proteases.
Cathepsin L-like cysteine proteinases contain an evolutionarily highly conserved alpha-helical motif in the proregion. This is called the ER(F/W)N(I/V)N motif according to the conserved amino acids along one side of the helix. We studied the function of this motif using site-directed mutagenesis experiments of human procathepsin S. We replaced each of these amino acids with alanine and constructed deletion mutants lacking parts of the helix. All mutants were expressed in HEK 293 cells, but only one, W52A, was not processed to mature cathepsin S, nor was it phosphorylated or secreted into the culture medium. W52 is part of the hydrophobic core in the propeptide region of cathepsin S comprising two additional tryptophan residues, W28 and W31, also conserved among cathepsin L-like cysteine peptidases. Replacement of the latter with alanine led to consequences similar to those with the W52A mutation. Recombinant propeptides containing mutations of one of the three tryptophan residues were three orders of magnitude less effective as inhibitors of mature cathepsin S than the wild-type propeptide. The results point to a dominant role of the respective hydrophobic stack in the proper folding, transport and maturation of procathepsin S and related cathepsin L-like cysteine proteinases.


Multi-Segment Leads To Reduce RF Heating in MRI: A Computational Evaluation at 1.5T and 3T.
Implanted neurostimulators are currently in widespread use and allow patients to receive therapeutic nerve stimulation for a variety of conditions. Such devices often make use of long leads extending from the device to the relevant nerve to deliver their stimulation. These leads carry a significant radiofrequency (RF) safety concern for patients who also receive magnetic resonance imaging (MRI) scans. The incident RF energy from the MRI body coil can couple with the lead and produce dangerous levels of heating at the tip of the lead during a scan. Recent studies have shown one useful approach to mitigate this heating is to vary the conductivity of the wire along its length to decrease the coupling of the incoming RF energy from the MRI coil with the long lead. In this study, we adopt a similar approach and extend it by segmenting a long cylindrical lead model into two sections of differing conductivities and assessing the maximum 1g specific absorption rate (SAR) at the lead tip at both 64 MHz and 127 MHz. We also evaluated the effect of insulation thickness as well as conductivity of the phantom on the maximum 1g SAR. An 11-fold reduction in the SAR was achieved when using high conductivity ratios between the two wire segments for the 127 MHz coil and a 2-fold reduction was seen for the 64 MHz coil.Clinical relevance- Design of an implantable segmented lead has potential to mitigate RF heating concerns and open a wider patient population to both 1.5T and 3T MRI scans.


The selective effect of lockdown experience on citizens' perspectives: A multilevel, multiple informant approach to personal and community resilience during COVID-19 pandemic.
In the face of the first wave of COVID-19 contagion, citizens all over the world experienced concerns for their safety and health, as well as prolonged lockdowns - which brought about limitations but also unforeseen opportunities for personal growth. Broad variability in these psychological responses to such unprecedented experiences emerged. This study addresses this variability by investigating the role of personal and community resilience. Personal resilience, collective resilience, community disaster management ability, provided information by local authorities, and citizens' focus on COVID-19-related personal concerns and lockdown-related opportunities for personal growth were detected through an online questionnaire. Multilevel modelling was run with data from 3,745 Italian citizens. The potential of personal resilience as a driver for individuals to overcome adverse situations with positive outcomes was confirmed. Differently, the components of community resilience showed more complex paths, highlighting the need to pay more attention to its role in the face of far-reaching adverse events which hardly test individuals' as well as communities' adaptability and agency skills. The complexities linked to the multi-component and system-specific nature of resilience, as well as potential paths towards making the most out of citizens' and communities' ones, emerge. The theoretical and practical implications are discussed.


Growth hormone therapy in children with chronic renal failure.
Growth is impaired in a chronic renal failure. Anemia, acidosis, reduced intake of calories and protein, decreased synthesis of vitamin D and increased parathyroid hormone levels, hyperphosphatemia, renal osteodystrophy and changes in growth hormone-insulin-like growth factor and the gonadotropin-gonadal axis are implicated in this study. Growth is adversely affected by immunosuppressives and corticosteroids after kidney transplantation. Treating metabolic disorders using the recombinant human growth hormone is an effective option for patients with inadequate growth rates.


The steroid receptor coactivator, GRIP-1, is necessary for MEF-2C-dependent gene expression and skeletal muscle differentiation.
Nuclear receptor-mediated activation of transcription involves coactivation by cofactors collectively denoted the steroid receptor coactivators (SRCs). The process also involves the subsequent recruitment of p300/CBP and PCAF to a complex that synergistically regulates transcription and remodels the chromatin. PCAF and p300 have also been demonstrated to function as critical coactivators for the muscle-specific basic helix-loop-helix (bHLH) protein MyoD during myogenic commitment. Skeletal muscle differentiation and the activation of muscle-specific gene expression is dependent on the concerted action of another bHLH factor, myogenin, and the MADS protein, MEF-2, which function in a cooperative manner. We examined the functional role of one SRC, GRIP-1, in muscle differentiation, an ideal paradigm for the analysis of the determinative events that govern the cell's decision to divide or differentiate. We observed that the mRNA encoding GRIP-1 is expressed in proliferating myoblasts and post-mitotic differentiated myotubes, and that protein levels increase during differentiation. Exogenous/ectopic expression studies with GRIP-1 sense and antisense vectors in myogenic C2C12 cells demonstrated that this SRC is necessary for (1) induction/activation of myogenin, MEF-2, and the crucial cell cycle regulator, p21, and (2) contractile protein expression and myotube formation. Furthermore, we demonstrate that the SRC GRIP-1 coactivates MEF-2C-mediated transcription. GRIP-1 also coactivates the synergistic transactivation of E box-dependent transcription by myogenin and MEF-2C. GST-pulldowns, mammalian two-hybrid analysis, and immunoprecipitation demonstrate that the mechanism involves direct interactions between MEF-2C and GRIP-1 and is associated with the ability of the SRC to interact with the MADS domain of MEF-2C. The HLH region of myogenin mediates the direct interaction of myogenin and GRIP-1. Interestingly, interaction with myogenic factors is mediated by two regions of GRIP-1, an amino-terminal bHLH-PAS region and the carboxy-terminal region between amino acids 1158 and 1423 (which encodes an activation domain, has HAT activity, and interacts with the coactivator-associated arginine methyltransferase). This work demonstrates that GRIP-1 potentiates skeletal muscle differentiation by acting as a critical coactivator for MEF-2C-mediated transactivation and is the first study to ascribe a function to the amino-terminal bHLH-PAS region of SRCs.


Beyond a warming fingerprint: individualistic biogeographic responses to heterogeneous climate change in California.
Understanding recent biogeographic responses to climate change is fundamental for improving our predictions of likely future responses and guiding conservation planning at both local and global scales. Studies of observed biogeographic responses to 20th century climate change have principally examined effects related to ubiquitous increases in temperature - collectively termed a warming fingerprint. Although the importance of changes in other aspects of climate - particularly precipitation and water availability - is widely acknowledged from a theoretical standpoint and supported by paleontological evidence, we lack a practical understanding of how these changes interact with temperature to drive biogeographic responses. Further complicating matters, differences in life history and ecological attributes may lead species to respond differently to the same changes in climate. Here, we examine whether recent biogeographic patterns across California are consistent with a warming fingerprint. We describe how various components of climate have changed regionally in California during the 20th century and review empirical evidence of biogeographic responses to these changes, particularly elevational range shifts. Many responses to climate change do not appear to be consistent with a warming fingerprint, with downslope shifts in elevation being as common as upslope shifts across a number of taxa and many demographic and community responses being inconsistent with upslope shifts. We identify a number of potential direct and indirect mechanisms for these responses, including the influence of aspects of climate change other than temperature (e.g., the shifting seasonal balance of energy and water availability), differences in each taxon's sensitivity to climate change, trophic interactions, and land-use change. Finally, we highlight the need to move beyond a warming fingerprint in studies of biogeographic responses by considering a more multifaceted view of climate, emphasizing local-scale effects, and including a priori knowledge of relevant natural history for the taxa and regions under study.


Life-history correlates of evolution under high and low adult mortality.
Life-history theory predicts evolutionary changes in reproductive traits and intrinsic mortality rates in response to differences in extrinsic mortality rates. Trade-offs between life- history traits play a pivotal role in these predictions, and such trade-offs are mediated, at least in part, by physiological allocations. To gain insight into these trade-offs, we have been performing a long-term experiment in which we allow fruitflies, Drosophila melanogaster, to evolve in response to high (HAM) and low (LAM) adult mortality rates. Here we analyze the physiological correlates of the life-history trade-offs. In addition to changing development time and early fecundity in the direction predicted, high adult mortality affected three traits expressed early in life-body size, growth rate, and ovariole number-but had little or no effect on body composition (relative fat content), viability, metabolic rate, activity, starvation resistance, or desiccation resistance. Correlations among lines revealed trade-offs between early fecundity, late fecundity, and starvation resistance, which appear to be mediated by differential allocation of lipids.


Total synthesis of (-)-7-epicylindrospermopsin, a toxic metabolite of the freshwater cyanobacterium aphanizomenonovalisporum, and assignment of its absolute configuration.
[reaction: see text] The Z and E nitrones 38 and 39 from condensation of aldehyde 20 with hydroxylamine 36 underwent intramolecular dipolar cycloaddition to give the substituted 1-aza-7-oxobicyclo[2.2.1] heptanes 40 and 41 in a ratio of 2:1, respectively. Reductive N-O bond cleavage of 40 followed by carbonylation gave cyclic urea 47 in which inversion of the secondary alcohol was effected via an oxidation-reduction sequence. After conversion of the p-bromobenzyl ether 50 to azide 54, activation of the cyclic urea as its O-methylisourea and reduction of the azide led to spontaneous cyclization to afford the tricyclic nucleus 59 of cylindrospermopsin. Global deprotection, including hydrolysis of the 2,4-dimethyoxypyrimidine appendage to a uracil, and then monosulfation of the resultant diol 60 afforded a substance identical with natural (-)-7-epicylindrospermopsin (1). The asymmetric synthesis of (-)-7-epicylindrospermopsin defines its absolute configuration as 7S,8R,10S,12S,13R,14S.


Accuracy of RTVue optical coherence tomography, Pentacam, and ultrasonic pachymetry for the measurement of central corneal thickness.
To compare the reliability and the agreement in measuring central corneal thickness (CCT) using the following technologies: RTVue Fourier-domain optical coherence tomography (Optovue, Inc., Fremont, CA), Pentacam (Oculus, Inc., Wetzlar, Germany), and ultrasonic pachymetry (USP; Pocket-II; Quantel Medical, Inc., Bozeman, MT). Evaluation of diagnostic test. One hundred four eyes of 52 healthy subjects (mean age ± standard deviation, 28.6 ± 4.8 years). One eye from each subject was assigned randomly for a repeatability test in which a single operator performed 3 successive measurements. The other eye underwent an interoperator reproducibility test by 3 operators. Two centering methods of RTVue and 3 types of CCT from Pentacam were investigated. For USP, 1 drop of topical anesthetic was administered, and measurement was initiated 90 seconds later. Agreement among the instruments was evaluated using Bland-Altman plots. Various types of CCT were compared: central zone average and minimum thickness of RTVue centering on the vertex and the pupil; corneal thickness at the pupil center, apex, and thinnest location from Pentacam; and mean CCT of 5 repeated measurements of USP. The reliability of measurement was assessed using the repeatability or reproducibility coefficient (Rco), the coefficient of variation, and the intraclass correlation coefficient. The limit of agreement was used to analyze concordance. The Rco of RTVue was 4 to 5 μm, which was comparable with that of USP and better than that of Pentacam (10-11 μm). The Rco was not dependent on centering methods (RTVue) or types of CCT (Pentacam). The location of minimum thickness found by RTVue was less reliable than that of the Pentacam. The central zone average of RTVue was approximately 7 μm larger than the pupil center or apex thickness of Pentacam and approximately 13 μm larger than the CCT measurement of USP. Those discrepancies could be as high as 20 and 23 μm, respectively. The minimum thickness measured by the RTVue was similar to that of Pentacam. The RTVue is a rapid and reliable noncontact means of measuring CCT; however, the characteristics of CCT measured by RTVue must be understood when comparing the CCT obtained by the Pentacam or USP. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Rehabilitation interventions for cancer survivors: The influence of context.
Today more and more people survive cancer. Cancer survivors need help to recover both from the cancer and the treatment. Rehabilitative interventions have been set up to meet their needs. However, there are studies that report no major effects following careful, targeted intervention. Furthermore, it seems difficult to define whether an effect is caused by the intervention or whether it is due to contextual parameters such as human interactions, the organisation, the staff, the physical surroundings or the general atmosphere. The present study examines the influence of three contextual parameters in rehabilitation courses for cancer survivors in Denmark. The study was based on an ethnographic fieldwork with participant observation at nine week-long courses, on in-depth interviews and on written sources. Fieldwork is well-suited for studying interventions in context, such as social interactions between people and their physical, material and institutional surroundings. The analysis is based on Duranti's and Goodwin's theoretical approach to context. The findings are categorised into three contextual parameters. The setting, including its aesthetic value, its physical surroundings and the scheduling of the courses. The behavioural environment, which comprised work commitment and the care provided by the staff. The language environment insofar as it facilitated a sense of community. The results demonstrate the influence of contextual parameters not formalised in the intervention programme. Contexts affect the outcome of an intervention because they frame and inform the teaching, communication and various forms of social gathering. The study suggests that the effects of the intervention as measured by quantitative studies cannot be properly interpreted without taking into account the context within which the intervention is embedded.


Diabetes is a risk factor for knee osteoarthritis progression.
Recent studies have suggested that metabolic factors (obesity, diabetes, hypertension and dyslipidemia) and their clustering in metabolic syndrome (MetS) might be involved in the pathophysiology of knee osteoarthritis (OA). We investigated their impact on radiographic progression by an annualised measure of the joint space narrowing (JSN) of the medial tibiofemoral compartment. 559 patients older than 50 years with symptomatic knee OA were recruited for the placebo arm of the SEKOIA trial. The presence of diabetes, hypertension and dyslipidemia was determined at baseline interview. Body mass index (BMI) was calculated, obesity was considered >30 kg/m(2). MetS was defined by the sum of metabolic factors ≥ 3. Minimal medial tibiofemoral joint space on plain radiographs was measured by an automated method at baseline and then annually for up to 3 years. The mean age of patients was 62.8 [62.2-63.4] years; 392 were women. A total of 43.8% was obese, 6.6% had type 2 diabetes, 45.1% hypertension, 27.6% dyslipidemia and 13.6% MetS. Mean annualised JSN was greater for patients with type 2 diabetes than without diabetes (0.26 [-0.35 to -0.17] vs 0.14 [-0.16 to -0.12] mm; P = 0.001). This association remained significant after adjustment for sex, age, BMI, hypertension and dyslipidemia (P = 0.018). In subgroup analysis, type 2 diabetes was a significant predictor of JSN in males but not females. The other metabolic factors and MetS were not associated with annualised JSN. Type 2 diabetes was a predictor of joint space reduction in men with established knee OA. No relationships were found between MetS or other metabolic factors and radiographic progression.


Autosomal recessive Charcot-Marie-Tooth disease: from genes to phenotypes.
The prevalence of Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR-CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3 years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino-varus, claw-like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR-CMT.


Prediction of emergency department patient disposition decision for proactive resource allocation for admission.
We investigate the capability of information from electronic health records of an emergency department (ED) to predict patient disposition decisions for reducing "boarding" delays through the proactive initiation of admission processes (e.g., inpatient bed requests, transport, etc.). We model the process of ED disposition decision prediction as a hierarchical multiclass classification while dealing with the progressive accrual of clinical information throughout the ED caregiving process. Multinomial logistic regression as well as machine learning models are built for carrying out the predictions. Utilizing results from just the first set of ED laboratory tests along with other prior information gathered for each patient (2.5 h ahead of the actual disposition decision on average), our model predicts disposition decisions with positive predictive values of 55.4%, 45.1%, 56.9%, and 47.5%, while controlling false positive rates (1.4%, 1.0%, 4.3%, and 1.4%), with AUC values of 0.97, 0.95, 0.89, and 0.84 for the four admission (minor) classes, i.e., intensive care unit (3.6% of the testing samples), telemetry unit (2.2%), general practice unit (11.9%), and observation unit (6.6%) classes, respectively. Moreover, patients destined to intensive care unit present a more drastic increment in prediction quality at triage than others. Disposition decision classification models can provide more actionable information than a binary admission vs. discharge prediction model for the proactive initiation of admission processes for ED patients. Observing the distinct trajectories of information accrual and prediction quality evolvement for ED patients destined to different types of units, proactive coordination strategies should be tailored accordingly for each destination unit.


The Overtreatment and Cost Effectiveness of Primary versus Secondary Maintenance Therapy with Poly-Adenosine Ribose Phosphate Inhibitors (PARPi) for Epithelial Ovarian Cancer (EOC).
No data exist to suggest PARP inhibitor (PARPi) therapy as first-line maintenance is superior to PARPi therapy as second-line maintenance. To determine the efficacy and cost of primary versus secondary olaparib or niraparib maintenance in Epithelial Ovarian Cancer (EOC). A retrospective cohort study was performed in women with EOC to determine the survival following primary or secondary PARPi maintenance. We modeled the costs of olaparib and niraparib based on previously published costs and duration of therapy based on the Solo 1/Solo 2 and Prima and Nova trials, respectively. Among 40 patients treated with PARPi as primary or secondary maintenance there was no difference in overall survival (p=0.97). Among 166 women with stage III/IV germ-line BRCA mutated EOC, 28.8% were disease free for >3 years (18.6% never recurred and 10.2% recurred >3 years after chemotherapy). Since 29% of the BRCA mutated patients did not recur within 3 years, primary olaparib maintenance therapy was significantly more expensive than secondary olaparib maintenance therapy by 260%. Primary niraparib maintenance therapy was slightly more expensive than secondary niraparib maintenance therapy by 4%, 51%, and 15% for BRCA mutated, HR deficient, and HR proficient patients, respectively. By eliminating the overtreatment of patients with primary PARPi therapy, the cost savings for 100 women with EOC with BRCA mutations would be $37,335,360 for olaparib and $8,197,592 for niraparib. Up to 29% of BRCA mutated patients may be overtreated with primary PARPi maintenance with significantly increased treatment costs.


[Enteric microbiocenosis in the population of an industrial city].
According to the state of atmosphere, Irkutsk has been among 45 cities and towns of Russia with high levels of air pollution for tens of years. The body's normal microflora is directly related to environmental factors. The degree of a risk for dysbiotic disorders in intestinal microbiocenosis was estimated in the persons living in the industrial city's areas with different levels of ambient air pollution. A total of 400 apparently healthy individuals aged 1-14 and 15 years or older who lived in different areas of the city. Within one industrial city, the persons living in the "dirtiest" areas showed negative trends associated with bifidobacterium and lactobacillus deficiency and the widespread of Staphylococcus aureus and Candida albicans.


Walmsley's Web watch.
The ADEE site serves as a portal to other educational sites around the world. The address can be book-marked and used as a focus to explore and use the Web in a constructive way without becoming overwhelmed with the large amount of information that is present. There are, of course, many other sites that act as a resource and contain links to other web pages. This site is simple to use, contains links to web pages that are of high quality and will prove useful to people wishing to update their current knowledge.


Modelling ammonium-oxidizing population shifts in a biofilm reactor.
The dynamic reactor behaviour of a nitrifying inverse turbulent bed reactor, operated at varying loading rate, was described with a one-dimensional two-step nitrification biofilm model. In contrast with conventional biofilm models, this model includes the competition between two genetically different populations of ammonia-oxidizing bacteria (AOB), besides nitrite-oxidizing bacteria (NOB). Previously gathered experimental evidence showed that different loading rates in the reactor resulted in a change in the composition of the AOB community, besides a different nitrifying performance. The dissolved oxygen concentration in the bulk liquid was put forward as the key variable governing the experimentally observed shift from Nitrosomonas europaea (AOB1) to Nitrosomonas sp. (AOB2), which was confirmed by the developed one-dimensional biofilm model. Both steady state and dynamic analysis showed that the influence of microbial growth and endogenous respiration parameters as well as external mass transfer limitation have a clear effect on the competition dynamics. Overall, it was shown that the biomass distribution profiles of the coexisting AOB reflected the ecological niches created by substrate gradients.


Phosphorylated neuronal nitric oxide synthase in neuropathic pain in rats.
Neuropathic pain caused by nervous system damage or system dysfunction. The pathogenesis and the mechanism underlying neuropathic pain remains unclear. The only known neurobiological component involved in the neuropathic pain is nitric oxide (NO). NO is synthesized by nitric oxide synthase (nNOS) from L-arginine and oxygen. nNOS is involved in the inflammatory pain and neuropathic pain. In this study, we aimed to identify whether KN93 reduced the pain in the rats. Sixty adult male SD rat were randomly divided into 4 groups. Sham group and model group were not received treatment. Experimental group received intrathecal injection of KN93, and negative control group received DMSO injection 30 min before pain test. After last test of pain threshold, the rats were sacrificed and lumbar spinal tissues were sampled for analysis of the expression of pnNOS and pCaMK II by quantitative PCR and Western blotting. Pain threshold was increased in the rats received KN93 treatment (P<0.01), and the expression levels of pnNOS was increased (P<0.05) in experimental group and accompanied with decrease of CaMK II expression (P<0.05). By administration of KN93, the interaction of nNOS and the adaptor protein CAPON was reduced through inhibition of CaMK II by KN93. In conclusion, this study reveals that KN93 can reduce neuropathic pain via inhibiting the activity of CaMK II, and then increase the level of phosphorylated nNOS, to reduce the interaction with CAPON.


Immunohistochemical expression of matrix metalloproteinase-9 and inhibitor of matrix metalloproteinase-1 in prostate adenocarcinoma.
An immunohistochemical study on the cells proliferative activity by Ki-67 protein and localization of the matrix metalloproteinase-9 and the inhibitor of matrix metalloproteinase-1 was carried out at the benign prostatic hyperplasia (BPH) and the adenocarcinoma (AC) of different Gleason's grades. A significant decrease of the MMP-9 and TIMP-1 level in the AC of different gradations was observed. A moderate positive correlation between the Gleason score and cell proliferation Ki-67 index (rs = 0.674) and a moderate negative correlation with the level of such a score and expression of MMP-9 (rs = -0.660) was detected. A weak negative correlation exists also between the level of proliferative activity of secretory cells and the expression of MMP-9 by tumor cells (rs = -0.369). The invasive properties of AC cells that promote a degradation of the basal membrane and connective tissue in prostate may be explained by the imbalance between the MMP-9 and TIMP-1, which expression is significantly reduced in AC, in comparison with BPH.


Mediastinal germ cell tumors and histiocytosis.
Two cases of mediastinal germ cell tumors associated with primary hemoproliferative disorders are reported. The first case was a 23-year-old man who presented simultaneously with a mediastinal immature teratoma with focal yolk sac differentiation and a cytologically benign histiocytic proliferation associated with refractory thrombocytopenia. In the second case, an unsuspected mediastinal immature teratoma with focal yolk sac and hepatic differentiation was found postmortem in a 33-year-old man who had died of fulminant malignant histiocytosis. Although the histiocytosis in the former case failed to fulfill all the usual diagnostic criteria of malignant histiocytosis, both cases probably represent different manifestations of the same pathologic process. Review of the 19 published cases of hematologic malignancies associated with mediastinal germ cell tumors and of related experimental studies suggests a role for yolk sac differentiation in the pathogenesis of this syndrome.


Sinus involvement in inflammatory orbital pseudotumor.
Orbital pseudotumor is a difficult diagnosis to establish preoperatively. The relationship between sinus disease and orbital pseudotumor is controversial. We describe two patients with unilateral proptosis, diplopia, palpable orbital masses, ocular discomfort, and sinus problems of short duration. Echographically, both had low reflective masses in the orbit and the adjacent sinuses. Roentgenograms and echograms were interpreted as showing erosion of the bony orbital wall. A presumptive diagnosis of sinus malignant neoplasm with orbital extension was made. Sinus histopathologic examination in one case and nasal histopathologic examination in the other showed chronic inflammatory changes compatible with the diagnosis of pseudotumor. At orbitotomy, one patient had vessels communicating between the orbital and sinus lesions, and both patients had irregular pitting of the bone next to the histologically proved orbital pseudotumors. The lytic erosive changes predicted preoperatively were not present. Simultaneous orbital and sinus pseudotumors seem to be a distinct clinicopathologic entity. Those concerned with the diagnosis and management of orbital disease should be aware of this entity.


Loading dynamics of a sliding DNA clamp.
Sliding DNA clamps are loaded at a ss/dsDNA junction by a clamp loader that depends on ATP binding for clamp opening. Sequential ATP hydrolysis results in closure of the clamp so that it completely encircles and diffuses on dsDNA. We followed events during loading of an E. coli β clamp in real time by using single-molecule FRET (smFRET). Three successive FRET states were retained for 0.3 s, 0.7 s, and 9 min: Hydrolysis of the first ATP molecule by the γ clamp loader resulted in closure of the clamp in 0.3 s, and after 0.7 s in the closed conformation, the clamp was released to diffuse on the dsDNA for at least 9 min. An additional single-molecule polarization study revealed that the interfacial domain of the clamp rotated in plane by approximately 8° during clamp closure. The single-molecule polarization and FRET studies thus revealed the real-time dynamics of the ATP-hydrolysis-dependent 3D conformational change of the β clamp during loading at a ss/dsDNA junction.


Time-Course Progression of Whole Transcriptome Expression Changes of Trigeminal Ganglia Compared to Dorsal Root Ganglia in Rats Exposed to Nerve Injury.
Mechanisms underlying neuropathic pain (NP) are complex with multiple genes, their interactions, environmental and epigenetic factors being implicated. Transcriptional changes in the trigeminal (TG) and dorsal root (DRG) ganglia have been implicated in the development and maintenance of NP. Despite efforts to unravel molecular mechanisms of NP, many remain unknown. Also, most of the studies focused on the spinal system. Although the spinal and trigeminal systems share some of the molecular mechanisms, differences exist. We used RNA-sequencing technology to identify differentially expressed genes (DEGs) in the TG and DRG at baseline and 3 time points following the infraorbital or sciatic nerve injuries, respectively. Pathway analysis and comparison analysis were performed to identify differentially expressed pathways. Additionally, upstream regulator effects were investigated in the two systems. DEG (differentially expressed genes) analyses identified 3,225 genes to be differentially expressed between TG and DRG in naïve animals, 1,828 genes 4 days post injury, 5,644 at day 8 and 9,777 DEGs at 21 days postinjury. A comparison of top enriched canonical pathways revealed that a number of signaling pathway was significantly inhibited in the TG and activated in the DRG at 21 days postinjury. Finally, CORT upstream regulator was predicted to be inhibited in the TG while expression levels of the CSF1 upstream regulator were significantly elevated in the DRG at 21 days postinjury. This study provides a basis for further in-depth studies investigating transcriptional changes, pathways, and upstream regulation in TG and DRG in rats exposed to peripheral nerve injuries. PERSPECTIVE: Although trigeminal and dorsal root ganglia are homologs of each other, they respond differently to nerve injury and therefore treatment. Activation/inhibition of number of biological pathways appear to be ganglion/system specific suggesting that different approaches might be required to successfully treat neuropathies induced by injuries in spinal and trigeminal systems.


Intraocular relapse of childhood acute lymphoblastic leukaemia.
Relapse of childhood acute lymphoblastic leukaemia (ALL) involving the eye is a rare but challenging problem. Twenty cases occurred in patients treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia XI and ALL97 trials between 1991 and 2001, representing 2.2% of ALL relapses. Seventeen occurred as a first relapse, either in isolation or combined with relapse at another site, and three occurred as a second relapse. All patients with intraocular disease at first relapse were treated with both chemotherapy and radiotherapy, but the doses and protocols used varied. Eleven of these 17 patients are alive and in complete remission with a median follow up of 4 years 2 months from relapse. All 11 children that were treated with a full chemotherapy relapse protocol, together with local radiotherapy have survived. Patients treated with chemotherapy of shorter duration and intensity, despite radiotherapy and/or bone marrow transplantation, did poorly with only one survivor, currently in chronic relapse. Consequently, we suggest that children with eye relapse of ALL be treated with an intensive relapse chemotherapy protocol with local ocular radiotherapy, whether the relapse occurs in isolation or in combination with relapse at another site.


Hypnotizability and outcome in brief psychotherapy.
The relationship between hypnotizability and clinical improvement following brief psychotherapy was investigated. Prior to treatment 32 patients were assessed for hypnotizability utilizing an objective standardized measure of hypnotizability. Measures of psychopathology were obtained at the conclusion of ten sessions and six months post-treatment. A positive relationship was found between outcome and hypnotizability. This was most pronounced at the conclusion of ten sessions. Use of hypnotic techniques as a therapeutic adjunct did not necessarily lead to greater therapeutic effects. Different approaches in using hypnotherapy are indicated depending on the hypnotizability of the patient.


N-acetylcysteine prevents bladder tissue fibrosis in a lipopolysaccharide-induced cystitis rat model.
Therapeutic options for non-Hunner type interstitial cystitis (IC), which is histologically characterized by fibrosis and mast cell infiltration, are limited. We developed a rat model that replicates chronic inflammation and fibrosis and evaluated the therapeutic effect of N-acetylcysteine (NAC), a well-known anti-fibrotic agent, on the model. Intravesical instillation of lipopolysaccharide (LPS, 750 μg) after protamine sulfate (10 mg) was conducted twice per week for five consecutive weeks. One week after final instillation, 200 mg/kg NAC (n = 10, IC + NAC group) or phosphate-buffered saline (n = 10, IC group) was daily injected intraperitoneally once daily for 5 days. LPS instillation induced bladder fibrosis, mast cell infiltration, and apoptotic tissue damage. Functionally, LPS insult led to irregular micturition, decreased inter-contraction intervals, and decreased micturition volume. NAC significantly improved most of the voiding parameters and reversed histological damages including fibrosis. NAC inhibited the induction and nuclear localization of phospho-Smad2 protein in bladder tissues and the upregulation of genes related to fibrosis, such as Tgfb2, Tgfb3, Smad2, Smad3, Cxcl10, and Card10. This is the first study to demonstrate the beneficial effects on NAC in restoring voiding function, relieving tissue fibrosis and related bladder injuries, in the LPS-induced cystitis rat model.


Quick and easy placement of coil spring.
A tooth displaced palatally in an arch often demands placement of an open coil spring for gaining space. Ligation of an archwire with compressed coil spring is a cumbersome process. We have made use of 0.010 supreme AJ Wilcock sectional wire to compress the open coil spring and place it on the required the dental arch.


MYSM1/2A-DUB is an epigenetic regulator in human melanoma and contributes to tumor cell growth.
Histone modifying enzymes, such as histone deacetylases (HDACs) and polycomb repressive complex (PRC) components, have been implicated in regulating tumor growth, epithelial-mesenchymal transition, tumor stem cell maintenance, or repression of tumor suppressor genes - and may be promising targets for combination therapies of melanoma and other cancers. According to recent findings, the histone H2A deubiquitinase 2A-DUB/Mysm1 interacts with the p53-axis in hematopoiesis and tissue differentiation in mice, in part by modulating DNA-damage responses in stem cell and progenitor compartments. Based on the identification of alterations in skin pigmentation and melanocyte specification in Mysm1-deficient mice, we hypothesized that MYSM1 may be involved in melanoma formation. In human melanoma samples, expression of MYSM1 was increased compared with normal skin melanocytes and nevi and co-localized with melanocyte markers such as Melan-A and c-KIT. Similarly, in melanoma cell lines A375 and SK-MEL-28 and in murine skin, expression of the deubiquitinase was detectable at the mRNA and protein level that was inducible by growth factor signals and UVB exposure, respectively. Upon stable silencing of MYSM1 in A375 and SK-MEL-28 melanoma cells by lentivirally-mediated shRNA expression, survival and proliferation were significantly reduced in five MYSM1 shRNA cell lines analyzed compared with control cells. In addition, MYSM1-silenced melanoma cells proliferated less well in softagar assays. In context with our finding that MYSM1 bound to the c-MET promoter region in close vicinity to PAX3 in melanoma cells, our data indicate that MYSM1 is an epigenetic regulator of melanoma growth and potentially promising new target for tumor therapy.


A method for collecting right coronary venous blood samples from conscious dogs.
This report describes for the first time a technique to collect right coronary venous blood samples from conscious dogs. Catheters, prepared from Micro-Renathane tubing, were surgically implanted in right ventricular superficial veins of three anesthetized dogs. Also implanted were an arterial catheter, a right coronary flow transducer, and a right coronary artery constrictor. The coronary catheter was introduced at a venous bifurcation so that its side holes were positioned above the bifurcation; both ends of the catheter were exteriorized. Heparinized saline was continuously infused through the venous catheter by a battery-powered pump. The dogs were maintained for 10-13 days after surgery, and all catheters remained patent. Multiple right coronary venous samples were collected from each dog. These samples were analyzed for venous oxygen tension (PvO2) under baseline conditions, with right coronary pressure reduced to 50 mmHg, and during the reactive hyperemia after release of the right coronary artery constriction. PvO2 was 27.7 +/- 1.0 mmHg at baseline, 23.4 +/- 1.0 mmHg during coronary artery constriction, and 34.3 +/- 1.5 mmHg during reactive hyperemia. These data and the position of the catheter at autopsy demonstrated that coronary venous blood had been sampled.


Hypothesis: apoptosis caused by cytotoxins represents a defensive response that evolved to combat intracellular pathogens.
1. Over 100 different agents have been shown, under certain circumstances, to cause apoptosis, a form of cell death with characteristic morphology. In most cases, the mechanism of cell death is likely to be the same, as expression of the cell death inhibitory gene bcl-2 can frequently prevent apoptotic changes and/or delay cell death. 2. These observations raise the question of how and why cells detect these agents and why they respond by implementing the suicide mechanism that bcl-2 can control. Our hypothesis is that apoptosis is used as an anti-viral strategy, and that cells interpret any metabolic disturbance as evidence of infection by a virus and thereby kill themselves in response to these toxins before they are killed by the action of the toxin itself. 3. Experiments on the effect of sodium azide upon growth factor-dependent cells support this idea. Bcl-2 can delay cell death caused by azide, and inhibit apoptotic changes seen by electron microscopy, but cannot prevent the eventual death of the cells. 4. These ideas suggest that drugs designed to regulate cell death may be useful for the treatment of ischaemic or neoplastic diseases. For example, human cells may activate a suicide pathway in response to sub-lethal amounts of anoxia following a stroke or heart attack and so blocking apoptosis may be a useful therapy to limit tissue damage. On the other hand, increasing the propensity of cells to activate their physiological cell death mechanisms may enhance the effectiveness of toxins designed to kill tumour cells.


Genome-wide data reveal cryptic diversity and genetic introgression in an Oriental cynopterine fruit bat radiation.
The Oriental fruit bat genus Cynopterus, with several geographically overlapping species, presents an interesting case study to evaluate the evolutionary significance of coexistence versus isolation. We examined the morphological and genetic variability of congeneric fruit bats Cynopterus sphinx and C. brachyotis using 405 samples from two natural contact zones and 17 allopatric locations in the Indian subcontinent; and investigated the population differentiation patterns, evolutionary history, and the possibility of cryptic diversity in this species pair. Analysis of microsatellites, cytochrome b gene sequences, and restriction digestion based genome-wide data revealed that C. sphinx and C. brachyotis do not hybridize in contact zones. However, cytochrome b gene sequences and genome-wide SNP data helped uncover a cryptic, hitherto unrecognized cynopterine lineage in northeastern India coexisting with C. sphinx. Further analyses of shared variation of SNPs using Patterson's D statistics suggest introgression between this lineage and C. sphinx. Multivariate analyses of morphology using genetically classified grouping confirmed substantial morphological overlap between C. sphinx and C. brachyotis, specifically in the high elevation contact zones in southern India. Our results uncover novel diversity and detect a pattern of genetic introgression in a cryptic radiation of bats, demonstrating the complicated nature of lineage diversification in this poorly understood taxonomic group. Our results highlight the importance of genome-wide data to study evolutionary processes of morphologically similar species pairs. Our approach represents a significant step forward in evolutionary research on young radiations of non-model species that may retain the ability of interspecific gene flow.


[The history of healing; beriberi: 'kind of paralysis'].
Beriberi began to attract increasing attention in the second half of the 19th century, mostly due to the large numbers of victims among Dutch military personnel in the Netherlands East Indies. A study, carried out in Atjeh in 1886 by the Japanese Sugenoya and F. J. Cornelissen, led to the conclusion that there existed a beriberi bacillus which they could make visible in stained microscopical preparations. An extensive disinfection campaign in all barracks followed, but its benefits were a matter of debate. Inadequate nutrition in the investigators' eyes was only a predisposing factor. A.G. Vorderman (1844-1902) assumed a connection between rice feeding and beriberi in prisoners; he reported that the disease coincided with a diet of polished white rice. Beriberi could be prevented by providing the prisoners with 'red rice' (unpolished rice). However, red rice was regarded as inferior and status-lowering so that substitution of red for white rice in the rations was impossible. The concept of a 'lacking substance' (thiamine, vitamin B1) was hesitatingly accepted in the Netherlands. C. Winkler and C. Eijkman, for instance, refused until the early twenties of this century to exclude the possibility of a bacterial infection as the cause. As known, Eijkman in 1929 was awarded the Nobel prize for his contribution to vitamin research.


Toward Unified Flavor Quantitation in Cocoa-Based Products.
Because food flavor is perceived through a combination of odor and taste, an analytical method that covers both dimensions would be very beneficial for mapping the consistent product quality over the entirety of a manufacturing process. Such a method, so-called "unified flavor quantitation", has been successfully applied to several different food products in recent years. The simultaneous detection of aroma and taste compounds by means of ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) enables the analysis and quantification of an enormously large number of compounds in a single run. To evaluate the limits of this method, chocolate, a high-fat, complex matrix, was selected. In 38 distinct commercial chocolate samples, 20 flavor-active acids, aldehydes, and sugars were analyzed after a simple, rapid extraction step followed by derivatization with 3-nitrophenylhydrazine using a single UHPLC-MS/MS method. The results obtained highlight the great potential of the "unified flavor quantitation" approach and demonstrate the possibility of high-throughput quantitation of key aroma- and taste-active molecules in a single assay.


Bereavement among widowed Latinos in the United States: A systematic review of methodology and findings.
This study systematically reviewed the methodology and findings of 19 peer-reviewed studies on the experience of bereavement among widowed Latinos, including risk and protective factors to the health of this vulnerable population. Of these studies, 10 included quantitative data, 3 were qualitative studies, and 6 were narrative reviews. Results emphasized the relevance of cultural beliefs about death, rituals, religion, and Latino values (i.e., familismo, respeto, simpatía, personalismo) as common themes in the included studies, along with expressions of grief (e.g., Ataque de nervios, somatization) that vary by gender and acculturation. Risk factors associated with diminished well-being in this population included being a male, financial strain, cultural stressors, having an undocumented legal status, experiencing widowhood at a younger age, and having poor physical health. Effective coping strategies identified included having adequate social support primarily from family, religion and religious practices, the use of folk medicine, volunteering, and the use of emotional release strategies. Moreover, the results highlight that researches informing the health needs of widowed Latinos in the US is limited, and studies with enhanced methodological rigor are needed to better understand the complex needs of this vulnerable population.


Modelling the interplay between hypoxia and proliferation in radiotherapy tumour response.
A tumour control probability computational model for fractionated radiotherapy was developed, with the goal of incorporating the fundamental interplay between hypoxia and proliferation, including reoxygenation over a course of radiotherapy. The fundamental idea is that the local delivery of oxygen and glucose limits the amount of proliferation and metabolically-supported cell survival a tumour sub-volume can support. The model has three compartments: a proliferating compartment of cells receiving oxygen and glucose; an intermediate, metabolically-active compartment receiving glucose; and a highly hypoxic compartment of starving cells. Following the post-mitotic cell death of proliferating cells, intermediate cells move into the proliferative compartment and hypoxic cells move into the intermediate compartment. A key advantage of the proposed model is that the initial compartmental cell distribution is uniquely determined from the assumed local growth fraction (GF) and volume doubling time (TD) values. Varying initial cell state distributions, based on the local (voxel) GF and TD, were simulated. Tumour response was simulated for head and neck squamous cell carcinoma using relevant parameter values based on published sources. The tumour dose required to achieve a 50% local control rate (TCD50) was found for various GFs and TD's, and the effect of fraction size on TCD50 was also evaluated. Due to the advantage of reoxygenation over a course of radiotherapy, conventional fraction sizes (2-2.4 Gy fx(-1)) were predicted to result in smaller TCD50's than larger fraction sizes (4-5 Gy fx(-1)) for a 10 cc tumour with GFs of around 0.15. The time to eliminate hypoxic cells (the reoxygenation time) was estimated for a given GF and decreased as GF increased. The extra dose required to overcome accelerated stem cell accumulation in longer treatment schedules was estimated to be 0.68 Gy/day (in EQD26.6), similar to published values derived from clinical data. The model predicts, for a 2 Gy/weekday fractionation, that increased initial proliferation (high GF) should, surprisingly, lead to moderately higher local control values. Tumour hypoxia is predicted to increase the required dose for local control by approximately 30%. Predicted tumour regression patterns are consistent with clinical observations. This simple yet flexible model shows how the local competition for chemical resources might impact local control rates under varying fractionation conditions.


A randomized trial of chemotherapy with or without estrogenic recruitment in locally advanced breast cancer. North-West Oncology Group (GONO) Study, Italy.
The present phase III trial was carried out to verify whether a kinetic recruitment induced by low doses of diethylstilbestrol (DES) could increase the killing efficacy of chemotherapy in patients with locally advanced breast cancer. One-hundred and seventeen untreated patients with locally advanced breast cancer (stage IIIA/IIIB) were randomized to receive 3 courses of primary chemotherapy consisting of cyclophosphamide (600 mg/m2 i.v.), doxorubicin (50 mg/m2 i.v.) and fluorouracil (600 mg/m2 i.v.) (CAF) on day 1, or DES-CAF (DES, 1 mg orally days 1-3, CAF on day 4). The courses were repeated every 3 weeks. The patients who achieved an objective response were submitted to mastectomy followed by 3 courses of CAF alternated with 3 courses of CMF (cyclophosphamide, 600 mg/m2 i.v.; methotrexate, 40 mg/m2 i.v.; fluorouracil, 600 mg/m2 i.v.), with or without DES. The two treatment arms were well balanced in terms of clinical and pathologic features. There was no significant difference in response rates to induction chemotherapy between the two treatment arms (objective response rate, 63.3% for CAF and 56.1% for DES-CAF). Median overall survival was 49 and 47 months and median progression-free survival was 24 and 21 months for CAF and DES-CAF patients, respectively. Toxicity was not significantly different in the two groups, with the exception of leukopenia: DES chemotherapy was significantly more myelotoxic than the standard treatment, which resulted in a significant reduction in the actual dose intensity. In spite of the attractive experimental evidence, we conclude that so far there is no clinical advantage in the combination of estrogen and chemotherapy. Further research is needed to investigate different schedules of chemotherapy and hormones, or to test the possibility of combining various mitogens.


Severe chondrolysis after shoulder arthroscopy: a case series.
Chondrolysis has been observed after shoulder arthroscopy and results in severe glenohumeral complications. Twenty three cases of post-arthroscopic glenohumeral chondrolysis, occurring between 2005-2006, are reported following a variety of arthroscopic shoulder procedures. Presenting complaints, signs and symptoms, associated operative findings, and potential etiological factors are reviewed. Management options are summarized. Of the 23 cases of chondrolysis identified in our practice over a two year period, 14 occurred in patients following labral repair using a bioabsorbable device. Seventeen of the 23 patients used a high volume intra-articular pain pump for 48 hours after surgery. Seven of the 23 cases had documented use of a thermal probe. Four cases occurred in shoulders with no reported use of fixation anchors, pain pumps, or thermal probes. All cases had at least a 20 cc intra-articular bolus injection of 0.25% bupivicaine with epinephrine. This case series identifies several common factors that could be responsible for post-arthroscopic glenohumeral chondrolysis. No single mechanism can be implicated based on the results of this study. Although strong concerns are raised over the use of intra-articular local anesthetics, glenohumeral chondrolysis appears to be an unfortunate convergence of multiple factors that may initiate rapid dissolution of articular cartilage and degenerative changes. Chondrolysis is a devastating complication of arthroscopic shoulder surgery that can result in long-term disabling consequences. Further research is required to specifically identify causative factors. Until this is a available, we strongly advise against the use of large doses of intra-articular placement of local anesthetics.