The role of HIV infection and drug and alcohol dependence in hospital mortality among critically ill patients.
Critical care outcomes among HIV-infected patients have improved because of advances in HIV therapy and general improvements in intensive care unit (ICU) management. There is a high co-occurrence of drug and alcohol dependence among HIV-infected patients, and the independent role of drug and alcohol dependence among patients with and without HIV infection in outcomes of critical illness is unclear. We analyzed a prospectively collected database of 7015 index ICU admissions at 2 teaching hospitals between January 1999 and January 2006. The ICU diagnoses were determined from prospective chart review and classified according to the dictionary of diagnoses developed by the Intensive Care National Audit and Research Council. We used logistic regression to determine the independent association of drug and alcohol dependence as well as HIV infection with in-hospital mortality. Covariates that were adjusted for included acute drug overdose, Acute Physiology and Chronic Health Evaluation II score, age, sex, hospital site, and socioeconomic variables. Of all patients, 4.4% (309 of 7015) were HIV infected; and of these, 56% (173 of 309) had a history of drug and alcohol dependence, whereas only 7.4% (502 of 6706) of the HIV-negative group had a history of drug and alcohol dependence. Drug and alcohol dependence was not independently associated with hospital mortality in either the model including all admissions (adjusted odds ratio [AOR] 0.80; 95% confidence interval [CI] 0.62-1.03) or the model including pneumonia and sepsis admissions only (AOR 0.92; 95% CI 0.59-1.41). Infection with HIV was independently associated with hospital mortality (AOR 2.16; 95% CI 1.60-2.93). Although HIV infection is associated with increased hospital mortality, drug and alcohol dependence is not associated with an increased hospital mortality independent of HIV infection.


European guidelines on perioperative venous thromboembolism prophylaxis: Surgery in the obese patient.
: A systematic literature search was performed and patients were selected as obese patients undergoing bariatric surgery or obese patients undergoing nonbariatric surgical procedures. In addition, patients were stratified according to low risk of venous thromboembolism and high risk of venous thromboembolism (age >55 years, BMI >55 kg m, history of venous thromboembolism, venous disease, sleep apnoea, hypercoagulability or pulmonary hypertension). Prophylaxis of venous thromboembolism was analysed depending on the type of modality: compression devices of the lower extremities (including intermittent pneumatic compression and graduated compression stockings), pharmacological prophylaxis or inferior vena cava filters. Two prospective studies compared mechanical devices and pharmacological prophylaxis vs. a mechanical device alone without significant differences. A few randomised controlled studies and most of the prospective nonrandomised studies showed that low-dose low molecular weight heparin (3000 to 4000 anti-Xa IU 12 h subcutaneously) was acceptable for obese patients with a lower risk of venous thromboembolism, but a higher dose of low molecular weight heparin (4000 to 6000 anti-Xa IU 12 h subcutaneously) should be proposed for obese patients with a higher risk of venous thromboembolism. Extended prophylaxis for 10 to 15 days was well tolerated for obese patients with a high risk of venous thromboembolism in the postdischarge period. The safety and efficacy of inferior vena cava filters in bariatric surgical patients is highly heterogeneous. There were no randomised trials that analysed prophylaxis of venous thromboembolism in obese patients undergoing nonbariatric surgery. Higher doses of anticoagulants could be proposed for obese patients with a BMI more than 40 kg m. The lack of good quality randomised trials with a low risk of bias did not allow us to propose strong recommendations.


[Diagnosing eating disorders: presentation of a new diagnostic test and an initial epidemiological study of eating disorders in adolescents].
Precise diagnosis of eating disorders has long been problematic. First off, although the DSM IV provides clear criteria, these are applicable to a very narrow range of disorders. Subclinical disorders, although well defined in the literature, are difficult to diagnose as no tool has been previously available. These subclinical disorders are particularly important if one considers that they are often precursors to more serious and life-threatening eating disorders. In addition, choice of diagnostic tool for eating disorders has also long been the cause of difficulty for both researchers and clinicians. Although interviews are favored for their in-depth approach, they are sometimes difficult to implement and often too long and costly to use on a regular basis. Most available questionnaires are limited by their approach to one or two diagnostic categories, and again, until now, no tool has fully addressed the issue of subclinical disorders. The goal of this work was to translate and use a new questionnaire, The Questionnaire for Eating Disorders (Q-EDD), which was developed in the United States and based on both DSM IV criteria as well as carefully developed subclinical disorder criteria. The Q-EDD can identify the major eating disorder categories while at the same time distinguishing between different qualities in each (for example restricting versus compensatory anorexia). Moreover, the Q-EDD can identify several subclinical disorder categories, providing useful insight into potentially dangerous evolution of these disorders. In collaboration with one of the original authors, the questionnaire was translated into French with careful attention to DSM IV criteria in order to preserve its original validity. The questionnaire was read by several professionals in psychology as well as lay people to assure its face validity and ease of use. Once the questionnaire was adequately translated and corrected, it was used for an epidemiological study with a large sample of adolescents and young adults (n=1 001) from several Junior High and High Schools in the greater metropolitan area of Toulouse, France. The schools were located in a variety of neighborhoods and represented a wide range of population, some of them being more academic oriented, others being more oriented towards practical training. The population was composed of 703 females and 298 males, with an average age of 17.06 years. In addition, the population included several different ethnic categories, all of which are similarly represented in the general French population. The results from the Q-EDD showed levels of various clinical disorders to replicate data from previous epidemiological studies with 1.5% of the population suffering from a serious clinical DSM IV disorder; 7.9% suffering from DSM IV disorders NOS; and 20.9% suffering subclinical disorders. In addition to this finding of 30% of the population with an eating disorder, it was noted that a large number of these young people fell into the severe underweight and low weight categories. Indeed, nearly 10% of this group were within the weight criteria for anorexia, despite the fact that they did not meet the other criteria. This finding seemed to warrant additional investigation, and as a result, a different cut-off for severe underweight was established using literature references; this cut-off was set at the 10(th) percentile for BMI based on age. Yet, even with this new cut-off, 6% of this population still met a severe underweight criteria suggestive of anorexic pathology. These results led to the formulation of 2 hypotheses to explain this finding, the first of which examines morphological differences, the second of which suggests cultural differences in terms of eating habits and diet. The French version of the Q-EDD appears to follow the psychometric properties of the original version, moreover it provides useful and rich data regarding eating disorders in a format that is simple and efficient.


Estimation of stature from the width of static footprints-insight into an Indian model.
Footprints give an estimate of the height of an individual using gender-dependent models derived for different population and ethnic groups. However, estimation of ethnicity, age and gender from a footprint may not always be possible in forensic case work. The present study is done to develop models for stature (height) estimation from the width of footprints in the Indian population that are independent of the age and gender of individuals. The present research was conducted on 100 young adults from different regions of India. Footprints were obtained from both feet using standard techniques. Stature, and metatarsophalangeal joint (MPJ) Width (distance across the widest part of the forefoot) and calcaneal (Calc) Width (distance across the widest section of the heel) were measured on 200 footprints. Regression models were derived for estimation of stature. A positive correlation is observed between footprint measurements and stature. Regression models derived from the forefoot region give a more accurate estimate of stature than the heel region of the footprint. Multiple linear regression models gave more accurate estimates of stature than the single linear regression models. Regression models derived in the study for Indian population may be valuable in establishing the stature of a footprint in practical scenario when the age and gender are unknown.


The use of total ossicular replacement prosthesis after radical tympanomastoidectomy.
This paper presents our operative method for hearing recovery after the previous radical tympanomasto-idectomy, radical trepanation of the temporal bone (trepanatio radicalis ossis temporalis--TROT) in eight patients submitted to operations for giant cholesteatotoma. All the patients were admitted to our clinic after TROT. There were no signs of cholesteatoma or infection. The patients refused any stent implantations or any hearing aids due to possible aesthetic problems. The described procedure developed in two steps. The first one was to restore the destroyed cavum tympany and to covert with chondroperichondral new membrane with a pin-like "guide" as collumela. The second step was to insert a TORP (total ossicular replacement prosthesis) after guide excision. After the first operation (stage one) there were no infections in the operated area nor chondroperichondral graft rejection. Postoperative audiometry (6 to 8 weeks) was done to demonstrate the improvement of air conduction. Three months following the first, the second (stage two) operation was performed and 2.5 to 3 months after this operation even greater audiometry revealed hearing improvement in air- and bone-conduction. The patients were dismissed from the hospital 2 days after each procedure without any complications. They did not experience any dizziness, vomiting nor a severe pain. Three months after the second operative stage, otoscopic findings were very good. The audiometry findings after a 3-months period (after stage one) and 3 months after final TORP insertion was done for each of the patients. After one year, the audiometric curve was the same. Clinical and audiometry follow up demonstrated a hearing recovery and closure of air bone gap (ABG) to values of 5 to 15 dB. The use of TORP after radical tympanomastoidectomy is feasible. The first step of the procedure is the fixation of a neomembrane. A stabilized neomembrane is essential for light overpressure on the prosthesis and this is important for optimal or better conductivity. A better hearing recovery is confirmed with audiometric findings and ABG reduction to 5-15 dB. This method could be performed in all patients (with good bone-conduction) after radical tympanomastoidectomy for better hearing.


Can repeated fertilizer applications to young Norway spruce enhance avian diversity in intensively managed forests?
Repeated fertilization of forests to increase biomass production is an environmentally controversial proposal, the effects of which we assessed on breeding birds in stands of young Norway spruce (Picea abies), in an intensively managed forest area in southern Sweden. Our results show that fertilized stands had 38% more species and 21% more individuals than unfertilized stands. Compared with stands under traditional management, the further intensification of forestry by repeated applications of fertilizers thus seemed to enhance species richness and abundance of forest birds. We cannot conclude at this stage whether the response in the bird community was caused by changes in food resources or increased structural complexity in the forest canopy due to the skid roads used for the application of the fertilizers. Future studies should focus on structural and compositional effects of fertilization processes during the entire rotation period and at assessing its effects in a landscape


Public implementation of a web-based program for veterans with risky alcohol use and PTSD: A RE-AIM evaluation of VetChange.
Evidence-based web and mobile interventions are available for a range of mental health concerns. Little is known about how self-administered web interventions are used outside of controlled research trials, and there is a critical need to empirically examine real-world public implementation of such programs. To this end, the aim of the current study was to evaluate and describe outcomes of a nationwide public implementation of VetChange, a self-administered web intervention for veterans with problematic alcohol use and symptoms of PTSD. The study used the RE-AIM framework to organize outcomes along five key dimensions: reach, effectiveness, adoption, implementation, and maintenance. This naturalistic observation study included program use information for all who registered an account with VetChange during the 2-year study period and who self-identified as a returning veteran. We collected program use data automatically via normal website operation; a subset of program users provided additional self-report outcome data. The study used linear multilevel mixed modeling to evaluate changes in alcohol use and PTSD symptoms over a six-month postregistration period. VetChange successfully reached a large, geographically diverse sample of returning veterans with risky drinking and PTSD symptoms. Despite variable, overall modest, rates of intervention use over time, registered users demonstrated significant improvements in drinking, PTSD, and quality of life, and participants maintained these outcomes at a six-month follow-up. Given the observed low cost per acquisition, positive clinical outcomes, and the potential to produce long-term cost savings through reduced health care burden associated with chronic alcohol use disorder and PTSD, this study demonstrates how web-based interventions can provide public health benefits and reduce long-term health care costs.


hSulf-1 gene exhibits anticancer efficacy through negatively regulating VEGFR-2 signaling in human cancers.
Human sulfatase 1 (hSulf-1) is a heparin-degrading endosulfatase that desulfates cell surface heparan sulfate proteoglycans (HSPGs) in extracellular matrix and negatively modulates heparin-binding growth factor and cytokine signaling in cell proliferation. But hSulf-1 function is more complicated, and its molecular mechanism has not been well known. To further investigate the functions of hSulf-1 gene in regulating the vascular endothelial growth factor receptor (VEGFR) signaling, a series of vectors expressing hSulf-1, hSulf-1 small hairpin RNA (shRNA) and VEGFR-2 shRNA were generated. hSulf-1 re-expression could downregualte the VEGFR-2 phosphorylation and inhibit cancer cell proliferation both in ovarian and hepatocellular cancer cell lines. Knockdown of hSulf-1 expression by hSulf-1 shRNA enhanced the recovery of high levels of phosphorylated VEGFR-2, and knockdown of VEGFR-2 expression by VEGFR-2 shRNA inhibited the proliferation activity of cancer cells in vitro to some extent. In human cancer xenografts in nude mice, tumor growth was inhibited markedly after injections of adenovirus expressing hSulf-1, with the tumor inhibition rates of 46.19% and 49.56% in ovarian and hepatocellular tumor models, respectively. hSulf-1 expression significantly reduced tumor microvessel density. The results demonstrated that hSulf-1 re-expression both in ovarian and hepatocellular cancer cells induces antitumor efficacy by attenuating the phosphorylation of VEGFR-2 and suppressing angiogenesis. Therefore, hSulf-1-mediated antiproliferation and antiangiogenesis could be a reasonable approach for cancer therapy.


Ectopic fat storage, insulin resistance, and hypertension.
Obesity, insulin resistance, glucose intolerance/type 2 diabetes and hypertension are clustered in the metabolic syndrome representing critical risk factors for increased incidence cardio-cerebro-vascular diseases, kidney failure and cancer. Ectopic fat accumulation, i.e., accumulation in the mediastinum, liver and the abdomen, as well as generalized fat accumulation are associated with arterial hypertension, either systolic or diastolic. Several mechanisms including insulin resistance, sub-inflammatory state, increased Renin- Angiotensin-Aldosterone System (RAAS) system activity, oxidative stress, autonomic dysregulation as well as mechanical compression on the kidneys are all activated by obesity. Interestingly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ATII) receptor blockers, while correcting arterial hypertension, also have a positive effect on glucose metabolism and diabetes prevention, in high risk patients. The implementation of dietary, medical and surgical strategies to prevent and treat obesity, are cornerstones for the primary prevention as well as treatment of arterial hypertension.


Human Escherichia coli O157:H7 infection associated with the consumption of unpasteurized goat's milk.
A cluster of four cases of haemolytic uraemic syndrome in children occurred in Northern Bohemia, Czech Republic, between 15 June and 7 July, 1995. All the cases had significantly elevated titres of anti-O157 lipopolysaccharide (LPS) antibodies as detected by the indirect haemagglutination assay. All but one of them had drunk unpasteurized goat's milk from the same farm within the week before the disease. Evidence of E. coli O157 infection was subsequently found in 5 of 15 regular drinkers of the farm's raw goat's milk; four of them were asymptomatic, 1 had mild diarrhoea at the end of June. Verocytotoxin 2-producing E. coli O157:H7 strains of phage type 2 and of identical pulsed-field gel electrophoresis patterns were isolated from 1 of 2 farm goats and from 1 of the asymptomatic goat's milk drinkers. The frequency of anti-O157 LPS antibodies found among regular drinkers of the farm's raw goat's milk (33%; 5 of 15) was significantly higher than that found in control population (0%; none of 45) (P = 0.0005; Fisher's exact test). Our findings indicate that goats may be a reservoir of E. coli O157:H7 and a source of the infection for humans; raw goat's milk may serve as a vehicle of the pathogen transmission.


The aryl hydrocarbon receptor controls mesenchymal stromal cell-mediated immunomodulation via ubiquitination of eukaryotic elongation factor-2 kinase.
Mesenchymal stem cells (MSCs) have great therapeutic advantages due to their immunosuppressive properties. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose signaling plays an important role in the immune system. AHR may be involved in the regulation of MSC-associated immunomodulatory functions. However, the mechanisms by which AHR controls the immunosuppressive functions of MSCs are not well understood. Here, we report that Ahr-deficient MSCs show decreased therapeutic efficacy against graft-versus-host disease (GVHD) compared to wild-type (WT)-MSCs. This was probably due to decreased iNOS protein expression, which is a key regulatory enzyme in MSC immunomodulation. The expression of eukaryotic elongation factor 2 kinase (eEF2K), which inhibits the elongation stage of protein synthesis, is significantly increased in the Ahr-deficient MSCs. Inhibition of eEF2K restored iNOS protein expression. AHR is known to act as an E3 ligase together with CUL4B. We observed constitutive binding of AHR to eEF2K. Consequently, ubiquitination and degradation of eEF2K were inhibited in Ahr-deficient MSCs and by the AHR antagonist CH223191 in WT-MSCs. In summary, AHR regulates the immunomodulatory functions of MSCs through ubiquitination of eEF2K, thereby controlling iNOS protein synthesis and its product, nitric oxide levels.


Sulfur Oxidation State and Substituents Influenced Multifunctional Organic Luminophores in BTP Core for OLEDs: A Computational Study on RTP, TADF Emitter and Sensitizer.
The exploration of triplet excitons in thermally activated delayed fluorescence (TADF) and room-temperature phosphorescence (RTP) molecules has become a subject of significant attention and interest in recent studies. This study employed density functional theory (DFT) and time-dependent DFT theoretical methods to delve into the intricate relationship between the molecular structure and properties of molecules designed with the oxidation of sulfur atoms (S, SO, and SO2) in benzothiazinophenothiazine (BTP) core units. The calculations revealed that as the oxidation state of the sulfur atom increased, the BTP derivatives exhibited elevated ionization potentials (IPs), electron affinities (EAs), and triplet energies (ET), accompanied by reduced reorganization energies (λ), singlet energies (ES), and a S1-T1 energy gap (ΔEST). Additionally, the decrease in the exchange energy prompts a shift in the excited-state properties of molecules, transitioning them from hybridized local and charge transfer (HLCT) to charge transfer (CT) in the S1 state while maintaining their HLCT character in the T1 state. The sulfur oxidation process systematically decreases spin-orbit coupling magnitudes in the S1-T1 and T1-S0 pathways while increasing the KRISC rate, signifying a reduced propensity for phosphorescence radiative decay in oxidized molecules. Thorough investigations have explored the screening effect and orbital mixing of lone pair electrons in sulfur atoms, satisfying the desired criteria for a multifunctional RTP, TADF emitter and sensitizer.


Cationization of catalase, peroxidase, and superoxide dismutase. Effect of improved intraarticular retention on experimental arthritis in mice.
Several enzymes and other proteins were made cationic either by coupling to polylysine or by shielding of anionic sites. These cationic proteins, all having an isoelectric point greater than 8.5 exhibited excellent retention in articular structures when injected in mouse knee joints. Autoradiography and histochemistry showed that cationic forms of catalase, superoxide dismutase, and horseradish peroxidase were firmly retained by synovial and cartilaginous tissues. The half-life of these enzymes in the joint is thus significantly extended compared with native enzymes. The native enzymes and their cationic derivatives were tested for antiinflammatory properties in mice, using antigen-induced arthritis and zymosan-induced arthritis. It was found that injection of cationic catalase or peroxidase induced a marked suppression of some parameters of the inflammatory response in both types of arthritis, as measured by 99m technetium pertechnetate uptake and leakage of 125I-labeled albumin. Native catalase and peroxidase were less, or not at all effective. Cationic superoxide dismutase or cationic nonenzyme proteins did not suppress inflammation. The observed suppression of two different types of inflammation (an immune and a nonimmune arthritis) by catalase and peroxidase suggests that elimination of peroxides contributes to the suppression of an inflammatory response. We would hypothesize that cationic enzymes offer the possibility for investigating the mechanisms of inflammation and, in addition, might be interesting from a therapeutical point of view.


Comparing Injecting Risk Behaviors of Long-Term Injectors with New Injectors in Tehran, Iran.
Global estimates suggest there are 15.6 million people who inject drugs (PWID) of whom 17.8% are living with HIV.Few studies have characterized newly-onset injectors with long-term injectors and its association with injecting risk behaviors. We examined the relationship between length of injection and risk behaviors among people who inject drugs (PWID) in Tehran, Iran. A cross-sectional study was conducted among PWID, from March to August 2016 in Tehran, Iran. PWID were recruited by convenience and snowball sampling from five Drop-in Centers (DIC) located in the south of Tehran. Our primary independent variable was length of injecting career, defined as the number of months since injecting initiation. Those defined as new injectors (were injecting for less than 18 months), and long-term injectors (as injecting drugs for more than 18 months). We reported the adjusted odds ratio (aOR) point estimate and 95% confidence interval (CI95%) as the effect measure. The level of significance used in multiple logistic regression model was 0.05. We used STATA v. 11 for all analyzes. The analytical sample comprised of 500 participants (100% male). Mean (±SD) age of PWID with a length of injection history was 31.2 ± 7.2 years. Overall, 270 (54%) (CI95%: 49.6%, 58.4%) of participants were long-term injectors. The average age of drug use initiation among long-term injectors group was lower as compared to new injectors group (31.2 vs. 29.4, p < 0.001). The odds of distributive syringe sharing among new injectors were two times higher than long-term injectors (AOR = 2.1, 95% CI 1.4-4.7). The odds of receptive syringe sharing were lower among new injectors group (AOR = 0.7, CI95% 0.2-0.87), compared to long-term injectors. New injectors had higher odds of reusing their own syringes (OR = 2.8, 95% CI: 1.4-5.7; p = 0.01). Improvements in harm reduction service provision can occur through taregted risk reduction education for new injectors focusing on reducing distributive syringe sharing among them.


Gaining Insight into Exclusive and Common Transcriptomic Features Linked to Drought and Salinity Responses across Fruit Tree Crops.
The present study aimed at identifying and mapping key genes expressed in root tissues involved in drought and salinity tolerance/resistance conserved among different fruit tree species. Twenty-six RNA-Seq samples were analyzed from six published studies in five plant species (Olea europaea, Vitis riparia Michx, Prunus mahaleb, Prunus persica, Phoenix dactylifera). This meta-analysis used a bioinformatic pipeline identifying 750 genes that were commonly modulated in three salinity studies and 683 genes that were commonly regulated among three drought studies, implying their conserved role in resistance/tolerance/response to these environmental stresses. A comparison was done on the genes that were in common among both salinity and drought resulted in 82 genes, of which 39 were commonly regulated with the same trend of expression (23 were upregulated and 16 were downregulated). Gene set enrichment and pathway analysis pointed out that pathways encoding regulation of defense response, drug transmembrane transport, and metal ion binding are general key molecular responses to these two abiotic stress responses. Furthermore, hormonal molecular crosstalk plays an essential role in the fine-tuning of plant responses to drought and salinity. Drought and salinity induced a different molecular "hormonal fingerprint". Dehydration stress specifically enhanced multiple genes responsive to abscisic acid, gibberellin, brassinosteroids, and the ethylene-activated signaling pathway. Salt stress mostly repressed genes encoding for key enzymes in signaling proteins in auxin-, gibberellin-(gibberellin 2 oxidase 8), and abscisic acid-related pathways (aldehyde oxidase 4, abscisic acid-responsive element-binding protein 3). Abiotic stress-related genes were mapped into the chromosome to identify molecular markers usable for the improvement of these complex quantitative traits. This meta-analysis identified genes that serve as potential targets to develop cultivars with enhanced drought and salinity resistance and/or tolerance across different fruit tree crops in a biotechnological sustainable way.


An assessment of the malaria-related knowledge and practices of Tanzania's drug retailers: exploring the impact of drug store accreditation.
Since 2003 Tanzania has upgraded its approximately 7000 drug stores to Accredited Drug Dispensing Outlets (ADDOs), involving dispenser training, introduction of record keeping and enhanced regulation. Prior to accreditation, drug stores could officially stock over-the-counter medicines only, though many stocked prescription-only antimalarials. ADDOs are permitted to stock 49 prescription-only medicines, including artemisinin combination therapies and one form of quinine injectable. Oral artemisinin monotherapies and other injectables were not permitted at any time. By late 2011 conversion was complete in 14 of 21 regions. We explored variation in malaria-related knowledge and practices of drug retailers in ADDO and non-ADDO regions. Data were collected as part of the Independent Evaluation of the Affordable Medicines Facility - malaria (AMFm), involving a nationally representative survey of antimalarial retailers in October-December 2011. We randomly selected 49 wards and interviewed all drug stores stocking antimalarials. We compare ADDO and non-ADDO regions, excluding the largest city, Dar es Salaam, due to the unique characteristics of its market. Interviews were conducted in 133 drug stores in ADDO regions and 119 in non-ADDO regions. Staff qualifications were very similar in both areas. There was no significant difference in the availability of the first line antimalarial (68.9% in ADDO regions and 65.2% in non-ADDO regions); both areas had over 98% availability of non-artemisinin therapies and below 3.0% of artemisinin monotherapies. Staff in ADDO regions had better knowledge of the first line antimalarial than non-ADDO regions (99.5% and 91.5%, p = 0.001). There was weak evidence of a lower price and higher market share of the first line antimalarial in ADDO regions. Drug stores in ADDO regions were more likely to stock ADDO-certified injectables than those in non-ADDO regions (23.0% and 3.9%, p = 0.005). ADDO conversion is frequently cited as a model for improving retail sector drug provision. Drug stores in ADDO regions performed better on some indicators, possibly indicating some small benefits from ADDO conversion, but also weaknesses in ADDO regulation and high staff turnover. More evidence is needed on the value-added and value for money of the ADDO roll out to inform retail policy in Tanzania and elsewhere.


Epstein-Barr virus with heterogeneous DNA disrupts latency.
By cloning the HR-1 Burkitt lymphoma line, we previously uncovered two distinct biological variants of nontransforming Epstein-Barr virus (EBV). The most commonly cloned variant has a low rate of spontaneous viral synthesis and is unable to induce early antigen in Raji cells (EAI-). A rare variant spontaneously releases virus which is capable of inducing early antigen in Raji cells (EAI+). Since EAI- virus lacks heterogeneous DNA (het-) and EAI+ virus contains heterogeneous DNA (het+), we suggested that spontaneous viral synthesis and induction of early antigen are biological properties which correlate with the presence of het sequences. The present experiments provide three new lines of experimental evidence in favor of this hypothesis. (i) Revertant subclones of the EAI+ het+ variant which have lost the het DNA concomitantly lost EAI ability. Thus, het DNA is not stably associated with the cells as are the episomes. (ii) het DNA was acquired by two het- subclones of the HR-1 line after superinfection with EAI+ virus. After superinfection, these clones synthesized EAI+ het+ virus. Thus, het DNA may be maintained in the HR-1 line by cell-to-cell spread. (iii) Virus with het DNA activated full expression of endogenous latent EBV of the transforming phenotype in a line of immortalized neonatal lymphocytes designated X50-7. By use of restriction endonuclease polymorphisms unique to both the superinfecting and endogenous genomes, we show that the genome of the activated virus resembles that of the virus which was endogenous to X50-7 cells. This result suggests that het sequences result in transactivation of the latent EBV. het DNA had homology with EBV sequences which are not normally contiguous on the physical map of the genome. het DNA was always accompanied by the presence of DNA of nonheterogenous HR-1. Thus, het DNA is a form of "defective" EBV DNA. However, the biological effect of this defective DNA is to enhance rather than to interfere with EBV replication. This is a novel property of defective virus.


Xanthogranuloma in the heavily irradiated low neck in a patient with head and neck cancer.
Head and neck cancer is often managed with a combination of surgery, radiation therapy, and chemotherapy, and skin toxicity is not uncommon. Xanthogranuloma is a pathological finding resulting from an inflammatory reaction that has not been previously reported following head and neck radiation therapy. A patient with squamous cell carcinoma of the oropharynx, treated with definitive chemoradiation and hyperthermia, presented at eight-month follow-up with an in-field cutaneous lesion in the low neck, initially concerning for recurrent tumor. Biopsy showed xanthogranuloma and the patient underwent complete resection with congruent surgical pathology. The patient remained free of malignancy but continued to experience wound healing difficulties at the resection site which resolved with specialized wound care and hyperbaric oxygen. Skin toxicity is not uncommon in patients with head and neck cancer treated with radiation therapy. Awareness of unusual pathologic sequelae, such as xanthogranuloma, is needed to provide patient counseling while continuing appropriate surveillance for recurrent malignancy.


Persistent growth of a human plasma-derived hepatitis C virus genotype 1b isolate in cell culture.
HCV (hepatitis C virus) research, including therapeutics and vaccine development, has been hampered by the lack of suitable tissue culture models. Development of cell culture systems for the growth of the most drug-resistant HCV genotype (1b) as well as natural isolates has remained a challenge. Transfection of cultured cells with adenovirus-associated RNA(I) (VA RNA(I)), a known interferon (IFN) antagonist and inhibitor of dsRNA-mediated antiviral pathways, enhanced the growth of plasma-derived HCV genotype 1b. Furthermore, persistent viral growth was achieved after passaging through IFN-alpha/beta-deficient VeroE6 cells for 2 years. Persistently infected cells were maintained in culture for an additional 4 years, and the virus rescued from these cells induced strong cytopathic effect (CPE). Using a CPE-based assay, we measured inhibition of viral production by anti-HCV specific inhibitors, including 2'-C-Methyl-D-Adenosine, demonstrating its utility for the evaluation of HCV antivirals. This virus constitutes a novel tool for the study of one of the most relevant strains of HCV, genotype 1b, which will now be available for HCV life cycle research and useful for the development of new therapeutics.


Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial.
Patients with resected stage IIB/C melanoma have high recurrence risk, similar to those with resected stage IIIA/B disease. The phase 3, double-blind CheckMate 76K trial assessed 790 patients with resected stage IIB/C melanoma randomized 2:1 (stratified by tumor category) to nivolumab 480 mg or placebo every 4 weeks for 12 months. The primary endpoint was investigator-assessed recurrence-free survival (RFS). Secondary endpoints included distant metastasis-free survival (DMFS) and safety. At 7.8 months of minimum follow-up, nivolumab significantly improved RFS versus placebo (hazard ratio (HR) = 0.42; 95% confidence interval (CI): 0.30-0.59; P < 0.0001), with 12-month RFS of 89.0% versus 79.4% and benefit observed across subgroups; DMFS was also improved (HR = 0.47; 95% CI: 0.30-0.72). Treatment-related grade 3/4 adverse events occurred in 10.3% (nivolumab) and 2.3% (placebo) of patients. One treatment-related death (0.2%) occurred with nivolumab. Nivolumab is an effective and generally well-tolerated adjuvant treatment in patients with resected stage IIB/C melanoma. ClinicalTrials.gov identifier: NCT04099251 .


Characterization of placenta-derived mesenchymal stem cells cultured in autologous human cord blood serum.
Human placenta-derived mesenchymal stem cells (P-MSCs) have drawn increasing attention in the field of stem cell research due to their potential in clinical applications as well as their rich and easy to procure cell source. While studies demonstrating the potential of P-MSCs for therapeutic transplantations have been documented, a clinically compliant procedure for P-MSC expansion in vitro has yet to be established. To this end, previous studies have demonstrated that MSCs of bone marrow and cord blood origins cultured in human cord blood serum (hCBS) are comparable to those cultured in fetal bovine serum (FBS), indicating that hCBS may be an alternative to FBS for the development of in vitro cell expansion procedures free of animal components. However, stem cells from origins other than bone marrow or cord blood, particularly from human placental tissues, which have demonstrated a good potential for clinical applications, have not been characterized under similar conditions. In this study, in an attempt to define a clinically compliant protocol for P-MSC expansion in vitro, we examined the effects of human hCBS as a replacement for FBS on cell proliferation capacity, differentiation potential, MSC-specific phenotypic expression and the genetic stability of P-MSCs in cultures. P-MSCs expanded in vitro in autologous hCBS maintained the capacity of self‑renewal and expressed surface antigens characteristic of bone marrow-derived mesenchymal stem cells. Under differentiation conditions, the P-MSCs expanded in hCBS developed into adipogenic, osteogenic and neurogenic cell phenotypes. Chromosomal karyotyping and single cell gel electrophoresis analysis demonstrated that P-MSCs cultured in autologous hCBS were genetically stable. These results suggest that autologous hCBS may be used as an alternative to FBS for the in vitro expansion of P-MSCs for clinical applications.


[Characteristics of chronic alcoholism in patients with sensitive premorbid states].
Overall 69 patients with sensitive traits of character not reaching the degree of psychopathy, suffering from stage II chronic alcoholism were examined on a clinical basis. In the given patients' group, alcoholism manifested itself atypically. The initial lack of the protective nauseous and vomiting reflex and high tolerance, relative preservation of the quantitative control, no amnesia during drunkenness, temporal break between the formation of compulsive addiction and the abstinent syndrome, manifestation of compulsive addiction only in a state of alcoholic intoxication were recorded. At the same time attention should be drawn to the frequently occurring depressive forms of drunkenness, early appearance of the asthenic state, the lack of marked personality changes by the alcoholic type, relative preservation of a critical attitude towards the disease, and to the abortive abstinent syndrome, characterized sometimes by an elevated attitude of mind resembling the hypomaniacal state. Alcoholism tends towards a moderate progredient course, which is often not realized because of the influence of psychic trauma and in that case alcoholism takes a malignant course.


Regenerative Dentistry and Stem Cells: A Multilineage Differentiation as a Safe and Useful Alternative Way of Harvesting and Selection Adipose Derived Mesenchymal Stem Cells.
This review aims to address procedures and indications for the application of the adipose-derived stem cells (ADSCs) for regenerative dentistry. ADSCs have rarely been used in this particular field; conversely, experience from other clinical fields and basic research seems to recommend the suitability of this application. We reviewed 32 out of 193 articles on Medline sorted by the relevance option. The main purpose of this paper is to perform a short review of the application of stem cells in regenerative dentistry, describing a multilineage differentiation as a safe and useful alternative way of harvesting and selection of ADSCs. The most common derivation of stem cells for regenerative dentistry is from the adipose tissue. There are conditions in which the levy adipose cannot be easily achieved, or where large amount of grafting is not needed. For this purpose, the possibility of selecting stromal stem cells directly from the lax subcutaneous connective tissue, preferably of the head region, would allow a technical simplification.


Serum Apelin and Asymmetric Dimethylarginine Levels in Patients With Exfoliation Syndrome or Exfoliative Glaucoma.
PRéCIS:: Apelin and asymmetric dimethylarginine (ADMA) concentrations, affecting the nitric oxide pathway, were different in the patient group compared with the control subjects. These 2 molecules may have potential effects in vascular pathologies and their possible role in predisposition to vascular comorbidities in exfoliation syndrome (XFS) or exfoliative glaucoma (XFG). To evaluate apelin and ADMA levels in serum samples from patients with XFS or XFG compared with healthy control subjects. Serum ADMA and apelin concentrations were evaluated from 36 and 32 XFS patients; 27 and 24 XFG patients; and 34 and 30 healthy controls, respectively. Subjects without systemic disease (including diabetes mellitus, hypertension, coronary artery disease, obesity) were included in the study and body mass index was calculated in all participants. An enzyme-linked immunosorbent assay and high-performance liquid chromatography were used to determine serum apelin and ADMA concentrations. Independent sample t test, χ test, analysis of variance test, and Pearson test were used for statistical analysis. Mean serum apelin levels of XFG, XFS, and control group were 1063.3±373.4, 1196.7±433.7, and 1343.3±405.1 ng/mL, respectively. Patients with XFG demonstrated significantly lower level of apelin versus controls (P=0.034). Mean serum ADMA concentration was significantly greater in XFS subjects (2.05±0.98 µmol/L) compared with normal controls (1.57±0.58 µmol/L) (P=0.042). No association was detected between ADMA and apelin concentrations and age, sex, and body mass index for both XFS and XFG groups. Significant alterations in serum levels of apelin and ADMA may suggest potential effects in vascular pathologies and a possible role in predisposition to vascular comorbidities in XFS/XFG.


Effect of LH on progesterone and oestradiol production in vivo and in vitro by preovulatory rat follicles.
Temporal changes in follicular oestradiol production induced in vitro and in vivo by LH were studied. In-vitro changes were measured by incubating preovulatory rat follicles for 12 h, changing the medium every 2 h. Follicles isolated at various intervals after an injection of 10 i.u. hCG were incubated for 2 h to measure changes in oestradiol production in vivo. In both studies there was an increase in oestradiol production lasting 4 h followed by a sharp decline. Progesterone production was also increased by LH in vitro or hCG in vivo, but remained high. A second exposure to LH did not raise oestradiol synthesis, but increased progesterone synthesis in vitro only. The decline in oestradiol production is most probably due to a decrease in C17-20 lyase activity, because addition of testosterone, but not of 17 alpha-hydroxyprogesterone, increased oestradiol production. Incubation of preovulatory follicles in the absence of LH or incubation of follicles derived from animals in which the spontaneous LH surge was blocked by an injection of pentobarbitone sodium also resulted in a decrease of oestradiol and an increase in progesterone production. This oestrogen-progesterone shift was also caused by a decrease in C17-20 lyase activity. The results demonstrate that the changes in steroid production in vivo and in vitro are similar and occur in the presence and absence of LH. It is concluded that the decrease in oestradiol production is dependent on the decrease in the activity of enzymes converting progesterone to aromatizable androgens.


Effects of various handle shapes and surface profiles on the hand-arm responses and comfort during short-term exposure to handle vibration.
The magnitude of hand- (HTV) and wrist- (WTV) transmitted vibration can negatively impact upper limb responses even during short-term exposure. This study aimed to establish the effects of various handle-grip designs on the harmful impacts of vibration, sustained grip exertion, and unnatural posture. The primary focus was to investigate how using a handle grip and how three shapes with two surface profiles affect HTV, WTV, and forearm muscle activities during exposure. The secondary goal was to evaluate the immediate effects on fundamental hand functions, perceived discomfort/comfort, and perceived vibration level after exposure. The final objective was to assess which of the handle designs had the least harmful effects. Fourteen young male adults were recruited and asked to consistently grip a vibrating handle structure for 2 min while the primary parameters were recorded. Pre- and post-task measurements of secondary parameters were recorded on the six design conditions and one control condition (no handle grip). The study found that implementing a regular circular-smooth handle resulted in lower transmitted vibrations, leading to lower upper-limb discomfort, higher grip comfort, and lower perceived vibration. Additionally, shape significantly affected HTV, resulting in grip strength reduction, while surface profile did not influence transmitted vibrations but significantly impacted ring and small finger sensitivity, finger and hand discomfort, and grip comfort. Finally, forearm muscle activities were unaffected, and no significant interaction effects were observed. Circular handles also had the least negative impacts, and elliptic handles had the most negative impacts on the upper extremity because of the level of hand-handle contact stress and hand-grip effort. Meanwhile, the uneven distribution of vibration on the fingers and palm imposed by the rounded spikes on the patterned surface led to decreased finger sensitivity, higher discomfort, and lower grip comfort. Therefore, when machine operation involves moderate grip exertion, pronated forearm posture, and short-term handle vibration exposure, implementing a hard-solid handle with less hand-handle contact area, less grip effort, and even texture is recommended.


Synchrotron radiation X-ray fluorescence microscopy reveals a spatial association of copper on elastic laminae in rat aortic media.
Copper, an essential trace metal in humans, plays an important role in elastic formation. However, little is known about the spatial association between copper, elastin, and elastin producing cells. The aorta is the largest artery; the aortic media is primarily composed of the elastic lamellae and vascular smooth muscle cells, which makes it a good model to address this issue. Synchrotron radiation X-ray fluorescence microscopy (SRXRF) is a new generation technique to investigate the spatial topography of trace metals in biological samples. Recently, we utilized this technique to determine the topography of copper as well as other trace elements in aortic media of Sprague Dawley rats. A standard rat diet was used to feed Sprague Dawley rats, which contains the normal dietary requirements of copper and zinc. Paraffin embedded segments (4 μm of thickness) of thoracic aorta were analyzed using a 10 keV incident monochromatic X-ray beam focusing on a spot size of 0.3 μm × 0.2 μm (horizontal × vertical). The X-ray spectrum was measured using an energy-dispersive silicon drift detector for elemental topography. Our results showed that phosphorus, sulfur, and zinc are predominately distributed in the vascular smooth muscle cells, whereas copper is dramatically accumulated in elastic laminae, indicating a preferential spatial association of copper on elastic laminae in aortic media. This finding sheds new light on the role of copper in elastic formation. Our studies also demonstrate that SRXRF allows for the visualization of trace elements in tissues and cells of rodent aorta with high spatial resolution and provides an opportunity to study the role of trace elements in vasculature.


A comparison of paper-and-pencil and computerized forms of Line Orientation and Enhanced Cued Recall Tests.
The purpose of this study was to assess whether a computerized battery of neuropsychological tests could produce similar results as the conventional forms. Comparisons on 77 volunteer undergraduates were carried out with two neuropsychological tests: Line Orientation Test and Enhanced Cued Recall Test. Firstly, students were assigned randomly across the test medium (paper-and-pencil versus computerized). Secondly, the groups were given the same test in the other medium after a 30-day interval between tests. Results showed that the Enhanced Cued Recall Test-Computer-based did not correlate with the Enhanced Cued Recall Test-Paper-and-pencil results. Line Orientation Test-Computer-based scores, on the other hand, did correlate significantly with the Line Orientation Test-Paper-and-pencil version. In both tests, scores were higher on paper-and-pencil tests compared to computer-based tests. Total score difference between modalities was statistically significant for both Enhanced Cued Recall Tests and for the Line Orientation Test. In both computer-based tests, it took less time for participants to complete the tests.


Psoriasin (S100A7) is a novel biomarker for lung squamous cell carcinoma in humans.
Psoriasin (S100A7) plays a role in the malignant potential of several epithelial cancers, and could candidate diagnostic marker or therapeutic target. Nuclear factor kappa B (NF-κB) regulates cancer cell growth and is modulated by phospholipase activity in many cancer cells. In the present study, we first evaluate the involvement of S100A7 in lung squamous cell carcinoma and its clinical usefulness for diagnosis. We then study whether knockdown of S100A7 in lung squamous cell carcinoma cells would reduce cell proliferation and NF-κB activity in vitro and attenuate tumor growth in vivo. We examined S100A7 expression in lung squamous cell carcinoma tissues by immunohistology. The human lung squamous cell carcinoma cell line NCI-H520 were transduced with short hairpin RNA targeting S100A7. Quantitative reverse transcriptase-polymerase chain reaction and immunoblotting confirmed knockdown of S100A7 messenger RNA and protein, respectively. Cell proliferation was evaluated by the MTT assay. NF-κB phosphorylation was assayed by western blot. 1 × 10(6) of NCI-H520/S100A7 knockdown cells were injected into the left flanks of nude mice (aged 6 to 8 weeks). Tumors were followed for 35 days, then removed and stained with hematoxylin and eosin, stained with Ki-67, and analyzed for S100A7 protein expression. S100A7 protein levels were significantly higher in carcinoma specimens than in nonneoplastic tissues. S100A7 might be a useful marker for diagnosis of lung squamous cell carcinoma. In vitro data showed that inhibition of S100A7 decreased proliferation of NCI-H520 cells. S100A7 knockdown reduced NF-κB phosphorylation and tumor growth in vivo and vivo. Explanted knockdown tumors maintained lower S100A7 levels compared with wild-type, confirmed by immunohistology. Ki-67 staining was more prominent throughout the wild-type tumors compared with knockdown tumors. Our present results suggest that S100A7 level is a promising tool for diagnosis of lung squamous cell carcinoma. Knockdown of S100A7 suppresses lung cancer growth in part by attenuating NF-κB activity. S100A7 may be a promising therapeutic target for lung squamous cell carcinoma.


A Kinetic Analysis of the Thermal Degradation Behaviours of Some Bio-Based Substrates.
In the present paper, we report on a detailed study regarding the thermal degradation behaviours of some bio-sourced substrates. These were previously identified as the base materials in the formulations for fireproofing wood plaques through our investigations. The substrates included: β-cyclodextrin, dextran, potato starch, agar-agar, tamarind kernel powder and chitosan. For deducing the Arrhenius parameters from thermograms obtained through routine thermogravimetric analyses (TGA), we used the standard Flynn-Wall-Ozawa (FWO) method and employed an in-house developed proprietary software. In the former case, five different heating rates were used, whereas in the latter case, the data from one dynamic heating regime were utilized. Given that the FWO method is essentially based on a model-free approach that also makes use of multiple heating rates, it can be considered in the present context as superior to the one that is dependent on a single heating rate. It is also relevant to note here that the values of energy of activation (Ea) obtained in each case should only be considered as apparent values at best. Furthermore, some useful, but limited, correlations were identified between the Ea values and the relevant parameters obtained earlier by us from pyrolysis combustion flow calorimetry (PCFC).


Connexin 30 expression inhibits growth of human malignant gliomas but protects them against radiation therapy.
Glioblastomas remain ominous tumors that almost invariably escape treatment. Connexins are a family of transmembrane, gap junction-forming proteins, some members of which were reported to act as tumor suppressors and to modulate cellular metabolism in response to cytotoxic stress. We analyzed the copy number and expression of the connexin (Cx)30 gene gap junction beta-6 (GJB6), as well as of its protein immunoreactivity in several public and proprietary repositories of glioblastomas, and their influence on patient survival. We evaluated the effect of the expression of this gap junction protein on the growth, DNA repair and energy metabolism, and treatment resistance of these tumors. The GJB6 gene was deleted in 25.8% of 751 analyzed tumors and mutated in 15.8% of 158 tumors. Cx30 immunoreactivity was absent in 28.9% of 145 tumors. Restoration of Cx30 expression in human glioblastoma cells reduced their growth in vitro and as xenografts in the striatum of immunodeficient mice. Cx30 immunoreactivity was, however, found to adversely affect survival in 2 independent retrospective cohorts of glioblastoma patients. Cx30 was found in clonogenic assays to protect glioblastoma cells against radiation-induced mortality and to decrease radiation-induced DNA damage. This radioprotection correlated with a heat shock protein 90-dependent mitochondrial translocation of Cx30 following radiation and an improved ATP production following this genotoxic stress. These results underline the complex relationship between potential tumor suppressors and treatment resistance in glioblastomas and single out GJB6/Cx30 as a potential biomarker and target for therapeutic intervention in these tumors.


Genotypes of erythrovirus B19, their geographical distribution & circulation in cases with various clinical manifestations.
Erythrovirus B19 (B19V) is one of the erythroviruses known to be pathogenic in humans. B19V is classified into three distinct genotypes; 1, 2 and 3, differing from each other by 2-13 per cent. Genotype 1 consists of the prototype B19V isolates, genotype 2 comprises the A6, LaLi and their related isolates while genotype 3 includes the V9- and V9-related isolates. The classification of genotype 1 into two subtypes (1A and 1B) and genotype 3 into two subtypes (3a and 3b) with an estimated nucleotide difference of about 5 per cent has been done. Predominance of genotype 1 across all the continents is seen followed by genotypes 2 and 3. There are no disease-specific genotypes. All the three genotypes have been found in symptomatic as well as asymptomatic individuals and have been reported from several countries across the world. The prevalence of genotype 2 in older populations and its absence from current circulation in Northern Europe has also been reported. The present review focuses on geographic distribution and association of genotypes of B19V with different clinical manifestations.


Singlet and triplet excitation management in a bichromophoric near-infrared-phosphorescent BODIPY-benzoporphyrin platinum complex.
Multichromophoric arrays provide one strategy for assembling molecules with intense absorptions across the visible spectrum but are generally focused on systems that efficiently produce and manipulate singlet excitations and therefore are burdened by the restrictions of (a) unidirectional energy transfer and (b) limited tunability of the lowest molecular excited state. In contrast, we present here a multichromophoric array based on four boron dipyrrins (BODIPY) bound to a platinum benzoporphyrin scaffold that exhibits intense panchromatic absorption and efficiently generates triplets. The spectral complementarity of the BODIPY and porphryin units allows the direct observation of fast bidirectional singlet and triplet energy transfer processes (k(ST)((1)BDP→(1)Por) = 7.8 × 10(11) s(-1), k(TT)((3)Por→(3)BDP) = 1.0 × 10(10) s(-1), k(TT)((3)BDP→(3)Por) = 1.6 × 10(10) s(-1)), leading to a long-lived equilibrated [(3)BDP][Por]⇌[BDP][(3)Por] state. This equilibrated state contains approximately isoenergetic porphyrin and BODIPY triplets and exhibits efficient near-infrared phosphorescence (λ(em) = 772 nm, Φ = 0.26). Taken together, these studies show that appropriately designed triplet-utilizing arrays may overcome fundamental limitations typically associated with core-shell chromophores by tunable redistribution of energy from the core back onto the antennae.


SLC22A2 is associated with tubular creatinine secretion and bias of estimated GFR in renal transplantation.
Genome-wide association studies reported SLC22A2 variants to be associated with serum creatinine. As SLC22A2 encodes the organic cation transporter 2 (OCT2), the association might be due to an effect on tubular creatinine handling. To test this hypothesis we studied the association of SLC22A2 polymorphisms with phenotypes of net tubular creatinine secretion: fractional creatinine excretion (FEcreat) and bias of estimated glomerular filtration rate (eGFR). We also studied the association with end-stage renal disease (ESRD) and graft failure (GF) in renal transplant recipients. SLC22A2 single nucleotide polymorphisms (SNPs), rs3127573 and rs316009, were genotyped in 1,142 ESRD patients receiving renal transplantation and 1,186 kidney donors as controls. GFR was measured with (125)I-iothalamate clearance. Creatinine clearance was also assessed. FEcreat was calculated from the simultaneous clearances of creatinine and (125)I-iothalamate. Donor rs316009 was associated with FEcreat (beta -0.053, P = 0.024) and with estimated [modification of diet in renal disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] but not measured GFR. In line with this, donor rs316009 was associated with bias of the MDRD and CKD-EPI but not the Cockroft-Gault equation. Both SNPs were associated with ESRD: odds ratios [95% CI] 1.39 [1.16-1.67], P = 0.00065, and 1.23 [1.02-1.48], P = 0.042, for rs3127573 and rs316009, respectively. Neither SNP was associated with GF. Thus, SLC22A2 is associated with phenotypes of net tubular creatinine secretion and ESRD.


Trends in inequalities in child stunting in South Asia.
We analysed socio-economic inequalities in stunting in South Asia and investigated disparities associated with factors at the individual, caregiver, and household levels (poor dietary diversity, low maternal education, and household poverty). We used time-series analysis of data from 55,459 children ages 6-23 months from Demographic and Health Surveys in Bangladesh, India, Nepal, and Pakistan (1991-2014). Logistic regression models, adjusted for age, sex, birth order, and place of residency, examined associations between stunting and multiple types of socio-economic disadvantage. All countries had high stunting rates. Bangladesh and Nepal recorded the largest reductions-2.9 and 4.1 percentage points per year, respectively-compared to 1.3 and 0.6 percentage points in India and Pakistan, respectively. Socio-economic adversity was associated with increased risk of stunting, regardless of disadvantage type. Poor children with inadequate diets and with poorly educated mothers experienced greater risk of stunting. Although stunting rates declined in the most deprived groups, socio-economic differences were largely preserved over time and in some cases worsened, namely, between wealth quintiles. The disproportionate burden of stunting experienced by the most disadvantaged children and the worsening inequalities between socio-economic groups are of concern in countries with substantial stunting burdens. Closing the gap between best and worst performing countries, and between most and least disadvantaged groups within countries, would yield substantial improvements in stunting rates in South Asia. To do so, greater attention needs to be paid to addressing the social, economic, and political drivers of stunting with targeted efforts towards the populations experiencing the greatest disadvantage and child growth faltering.


Production and characterization of recombinant perdeuterated cholesterol oxidase.
Cholesterol oxidase (CO) is a FAD (flavin adenine dinucleotide) containing enzyme that catalyzes the oxidization and isomerization of cholesterol. Studies directed toward elucidating the catalytic mechanism of CO will provide an important general understanding of Flavin-assisted redox catalysis. Hydrogen atoms play an important role in enzyme catalysis; however, they are not readily visualized in protein X-ray diffraction structures. Neutron crystallography is an ideal method for directly visualizing hydrogen positions at moderate resolutions because hydrogen and deuterium have comparable neutron scattering lengths to other heavy atoms present in proteins. The negative coherent and large incoherent scattering lengths of hydrogen atoms in neutron diffraction experiments can be circumvented by replacing hydrogen atoms with its isotope, deuterium. The perdeuterated form of CO was successfully expressed from minimal medium, purified, and crystallized. X-ray crystallographic structures of the enzyme in the perdeuterated and hydrogenated states confirm that there are no apparent structural differences between the two enzyme forms. Kinetic assays demonstrate that perdeuterated and hydrogenated enzymes are functionally identical. Together, structural and functional studies indicate that the perdeuterated protein is suitable for structural studies by neutron crystallography directed at understanding the role of hydrogen atoms in enzyme catalysis.


[Perianal cutaneous amebiasis. Report of two cases].
Perianal cutaneous amebiasis is a rare entity, with 0.03% to 0.07% reported incidence. We present two cases of perianal cutaneous amebiasis, both in male patients. Diagnosis was established by biopsy, with demonstration of Entamoeba histolytica trophozoites. Treatment with metronidazol was performed with good outcome. Although incidence of perianal cutaneous amebiasis is low, this entity must be kept in mind when painful atypical ulcers appear in this region. Diagnosis must be confirmed by identification of the parasite and treatment must be established with antiamebic extra-luminal drugs.


STUDIES ON GASTRIN.
These three papers present studies on gastrin. The first paper describes a method of biological assay using the rat. The second paper demonstrates that the highest concentration of gastrin-like activity occurs in the antral mucosa, with a clear gradient of concentration of activity down the gut. However, it is to be noted that the total amount of extractable activity is greatest in the duodenum, although the concentration there is less than in the antrum. No activity was detected in the pancreas. The third paper studies the contents of gastrin-like activity in patients with duodenal ulcer and demonstrates higher figures when stenosis is present. Patients with benign gastric ulcer and carcinomata showed results equal to or greater than in those with the average uncomplicated duodenal ulcer. It was noted that two patients with dilated antra both had very low total gastrin-like activity. There was no correlation between total activity and maximal histamine-stimulated output of acid. There was, however, a positive correlation between the insulin-stimulated acid secretion and the total gastrin-like activity in the cases of uncomplicated duodenal ulcers. The clinical studies are still tentative in view of the several variables present, but it seems likely that they will in due course clarify the role of gastrin in the ulcer problem.


Role of taste in the microstructure of quinine ingestion by rats.
The microstructure of the licking behavior of water-deprived rats presented with either water or quinine during 45-min single-bottle tests was analyzed. The chorda tympani (CT) and glossopharyngeal (GL) nerves, which innervate the taste buds of the tongue, were transected in deeply anesthetized rats to discern their contribution to the behavioral pattern of quinine drinking. Rats were presurgically habituated to the testing protocol and postsurgically tested first with water and then novel 0.2 mM quinine-HCl in a subsequent session. The substantial decrease in intake observed in sham-operated controls (n = 16) when quinine was the stimulus was entirely a function of a decrease in lick volume and burst size (a run of licks with interlick intervals <1 s). Contrary to the intake-suppressing effects of quinine, pause duration decreased and burst number increased. Combined transection of the CT and GL (n = 6) strikingly opposed all of these quinine-induced behavioral changes, whereas CT transection (n = 7) was without effect and GL transection (n = 8) had an intermediate influence. These results suggest that taste acts more on neural circuits governing burst termination as opposed to burst initiation, which, in turn, appears to be more sensitive to signals related to physiological state. These findings are discussed in terms of other known nerve transection effects on quinine responsiveness, and the implications of the microstructural results are considered with respect to probabilistic as opposed to deterministic control of licking behavior.


Reappraisal of the biological role of epidermal growth factor receptor in transitional cell carcinoma.
Retrospective immunohistochemical and flow cytometric DNA analyses were performed on 56 cases of transitional cell carcinoma (TCC) to examine the biologic implications of epidermal growth factor receptor (EGFR) expression. A total of 28 (50%) cases were reactive for EGFR immunostaining. The receptor expression increased from 41.7 to 56.3% with tumor stage. There was a significant association between EGFR expression and tumor stage (p < 0.0005), but not tumor grade. The flow DNA content and the Ki-67 proliferating index had no relation to the status of EGFR (p = 1, respectively). For those receptor-positive tumors (n = 28), there was a significant association (p < 0.0001) between receptor expression and tumor proliferation. Interestingly, the DNA content was not correlated with EGFR expression (p = 0.69). We support the possible role of EGFR in cell proliferation and the potential significance for tumor growth in TCCs. However, the biology of TCC in half the cases could not be explained by this mechanism. The interaction between EGFR and DNA ploidy status necessitates further evaluation.


Selective Knockdowns in Maize by Sequence-Specific Protein Aggregation.
Protein aggregation is determined by 5-15 amino acids peptides of the target protein sequence, so-called aggregation-prone regions (APRs) that specifically self-associate to form β-structured inclusions. The presence of APRs in a target protein can be predicted by a dedicated algorithm, such as TANGO. Synthetic aggregation-prone proteins are designed by expressing specific APRs fused to a fluorescent carrier for stability and visualization. Previously, the stable expression of these proteins in Zea mays (maize) has been demonstrated to induce aggregation of target proteins with specific localization, such as the starch-degrading enzyme α-glucan water dikinase, giving rise to plants displaying knockdown phenotypes. Here, we describe how to design synthetic aggregation-prone proteins to harness the sequence specificity of APRs to generate aggregation-associated phenotypes in a targeted manner and in different subcellular compartments. This method points toward the application of induced targeted aggregation as a useful tool to knock down protein functions in maize and to generate crops with improved traits.


Clinical efficacy of the mulligan maneuver for cervicogenic headache: a randomized controlled trial.
Cervicogenic headache is an often observed secondary headache in clinical settings, with patients who endure prolonged and persistent pain being particularly susceptible to mood changes. Currently, the Mulligan is one of the effective methods for CEH. However, there is a lack of evaluation about the strength and frequency of headaches, as well as the assessment of pain-induced emotions, in individuals with CEH using this particular procedure. Herein, we aimed to evaluate the effectiveness of the Mulligan maneuver from a multidimensional perspective of pain intensity and mood. A total of forty patients diagnosed with CEH who satisfied the specified inclusion criteria were recruited and allocated randomly into two groups: the control group and the treatment group, with each group consisting of twenty cases. The control group received health education, while the treatment group received the Mulligan maneuver once daily over a course of 10 treatment sessions.The clinical outcome of patients with CEH in two groups was assessed using the Visual Analog Scale (VAS), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD). Resting-state functional magnetic resonance imaging was employed to examine variations in brain function activities between the two CEH groups. Brain regions showing differences were identified as regions of interest and subsequently correlated with clinical behavioral measures using Pearson's correlation analysis. The differences in VAS, HAMA and HAMD between the two groups of CEH patients were also statistically significant. The brain regions that showed differences in the ReHo scores between the two groups of CEH patients included the left cerebellum, the frontal gyrus, and the middle temporal gyrus. There was a positive correlation between the left frontal gyrus and VAS, HAMA and HAMD. The left middle temporal gyrus had a negative correlation with VAS, HAMA, and HAMD and the left cerebellum had a positive correlation with VAS correlation. The Mulligan maneuver may improve pain levels and have a moderating effect on pain-related negative emotions by regulating the function of relevant brain regions in CEH patients.


Expression of DNA cytosine deaminase APOBEC3 proteins, a potential source for producing mutations, in gastric, colorectal and prostate cancers.
APOBEC3B is a deaminase that possesses DNA C-to-T editing activity. A recent report showed that APOBEC3B mRNA was overexpressed in breast cancer and that its expression was responsible for the high C-to-T mutation spectrum in breast cancer, suggesting that APOBEC3B could serve as a source for producing mutations. To see whether APOBEC3B is overexpressed in other common cancers at the protein level, we investigated APOBEC3 protein expression in 100 gastric, 103 colorectal and 107 prostate cancer tissues as well as in 10 breast cancers by immunohistochemistry using antibody that could detect APOBEC3B, APOBEC3F and APOBEC3D proteins. In the cancers, APOBEC3 expression was detected in 100% of breast cancers, 67% of gastric, 84% of colorectal and 67% of prostate cancer. Also, it was expressed in 100% of normal breast, 90% of normal stomach, 82% of normal colon and 93% of normal prostate tissues. In contrast to earlier data that showed an increased APOBEC3B expression in breast cancer cells compared to normal breast cells, APOBEC3 expression in cancers was lower than in normal tissues (gastric and prostate cancer) or was not different from normal tissues (colorectal and breast cancer). There was no significant association of APOBEC3 expression with clinocopathological parameters, including histology, metastasis and stage. Our data indicate that APOBEC3 overexpression might not be restricted to specific cancer types. Also, APOBEC3 expression in many normal epithelial cells suggests that there might be a mutation unrelated function of APOBEC3 in the normal cells.


Evaluation of the Success of High-Throughput Physiologically Based Pharmacokinetic (HT-PBPK) Modeling Predictions to Inform Early Drug Discovery.
Minimizing in vitro and in vivo testing in early drug discovery with the use of physiologically based pharmacokinetic (PBPK) modeling and machine learning (ML) approaches has the potential to reduce discovery cycle times and animal experimentation. However, the prediction success of such an approach has not been shown for a larger and diverse set of compounds representative of a lead optimization pipeline. In this study, the prediction success of the oral (PO) and intravenous (IV) pharmacokinetics (PK) parameters in rats was assessed using a "bottom-up" approach, combining in vitro and ML inputs with a PBPK model. More than 240 compounds for which all of the necessary inputs and PK data were available were used for this assessment. Different clearance scaling approaches were assessed, using hepatocyte intrinsic clearance and protein binding as inputs. In addition, a novel high-throughput PBPK (HT-PBPK) approach was evaluated to assess the scalability of PBPK predictions for a larger number of compounds in drug discovery. The results showed that bottom-up PBPK modeling was able to predict the rat IV and PO PK parameters for the majority of compounds within a 2- to 3-fold error range, using both direct scaling and dilution methods for clearance predictions. The use of only ML-predicted inputs from the structure did not perform well when using in vitro inputs, likely due to clearance miss predictions. The HT-PBPK approach produced comparable results to the full PBPK modeling approach but reduced the simulation time from hours to seconds. In conclusion, a bottom-up PBPK and HT-PBPK approach can successfully predict the PK parameters and guide early discovery by informing compound prioritization, provided that good in vitro assays are in place for key parameters such as clearance.


[Prevention and treatment of postoperative nausea and vomiting with 5-HT3-receptor blockers].
Since there continues to be a high incidence of postoperative nausea and vomiting associated with many types of surgery, and the standard antiemetics often do not achieve satisfactory results, there have been attempts to use the 5-HT3 antagonists. This group of substances is relatively new, but has already been used successfully as an antiemetic during chemotherapy. To date, results are on hand for four different 5-HT3 receptor blockers: ondansetron, tropisetron, granisetron and dolasetron. Applied intravenously, all four have been effective both in prophylaxis and also as therapy for postoperative emesis. Except for ondansetron, there is so far no definitely clear knowledge about the lowest possible effective dosage. The entire group is well tolerated: only occasional and minor side effects have been reported. Even though not all the hopes originally set in the 5-HT3 group of antagonists have been fulfilled, progress has nevertheless been achieved. Especially noteworthy points are a positive cost-effectiveness relationship of these drugs and their appropriate use in case of the proper indications.


A unique element in the cytoplasmic tail of the type II transforming growth factor-beta receptor controls basolateral delivery.
Transforming growth factor (TGF)-beta receptors stimulate diverse signaling processes that control a wide range of biological responses. In polarized epithelia, the TGFbeta type II receptor (T2R) is localized at the basolateral membranes. Sequential cytoplasmic truncations resulted in receptor missorting to apical surfaces, and they indicated an essential targeting element(s) near the receptor's C terminus. Point mutations in the full-length receptor confirmed this prediction, and a unique basolateral-targeting region was elucidated between residues 529 and 538 (LTAxxVAxxR) that was distinct, but colocalized within a clinically significant signaling domain essential for TGFbeta-dependent activation of the Smad2/3 cascade. Transfer of a terminal 84 amino-acid fragment, containing the LTAxxVAxxR element, to the apically sorted influenza hemagglutinin (HA) protein was dominant and directed basolateral HA expression. Although delivery to the basolateral surfaces was direct and independent of any detectable transient apical localization, fluorescence recovery after photobleaching demonstrated similar mobility for the wild-type receptor and a missorted mutant lacking the targeting motif. This latter finding excludes the possibility that the domain acts as a cell membrane retention signal, and it supports the hypothesis that T2R sorting occurs from an intracellular compartment.


Clinical aspects of pulmonary and pleural carcinoma in Nigeria.
Carcinoma of the lung may not be uncommon in Nigeria and other parts of tropical Africa. Twenty-seven cases of pulmonary and pleural carcinoma seen at UNTH Enugu, are reviewed; 20 were primary and 7 were secondary. The 20 patients with primary carcinoma were aged 35-75 years (mean 51.8 years); there were 14 males and 6 females. Cigarette smoking was the possible aetiological factor in 10 cases while exposure to asbestos products was elicited in a case of mesothelioma. Massive pleura effusion was present in 60% of cases. Different histological cell types were represented but squamous cell and adenocarcinoma were predominating. Resection could be achieved in only 3 cases. Mean survival period was 103.5 days for the primary carcinoma, and 80.8 days for the secondary carcinomas. With increasing industrialisation, atmospheric pollution and cigarette smoking in Nigeria, the incidence and problems of bronchopulmonary carcinoma would be expected to rise.


First record of Aedes albopictus (Skuse) from Argentina.
Aedes albopictus was collected in San Antonio City, Misiones Province, Argentina, near the border with Brazil in March, 1998. Collected material included 12 pupae, 1 recently emerged adult female, and a few larvae, which were found in a dish, a plough disk, and a tin pot. From the collected pupae, 5 males and 4 females emerged in the laboratory.


Can a serotonin type 3 (5-HT3) receptor antagonist reduce experimentally-induced itch?
Serotonin type 3 (5-HT3) receptor antagonists have been reported to be a novel therapeutic principle for the treatment of cholestatic and uremic pruritus. To determine the antipruritic effect of a 5-HT3 receptor antagonist (tropisetron) on histamine and serotonin-induced itch under experimental conditions in comparison to native skin and after pretreatment with an orally applied antihistamine (cetirizine). Histamine and serotonin were iontophoretically applied in 10 healthy volunteers. Wheals and flares were planimetrically evaluated. Itching and burning sensations were entered on a scale over 24 min. The examination also comprised alloknesis, elicitation of perifocal itch sensation by usually non-itching (e.g. mechanical) stimuli. Tropisetron did not have any significant influence on histamine-induced reactions but could significantly reduce serotonin-induced flares. Cetirizine led to a significant reduction of all histamine-induced parameters and abolished serotonin-induced wheals. Serotonin has an own pruritic potency and does not only act over histamine containing mast cells. The antipruritic effect of tropisetron reported in cholestatic and uremic pruritus could not be verified in healthy persons under experimental conditions.


Issues in renovascular disease and ischemic nephropathy: beyond ASTRAL.
Whereas atherosclerotic renal artery stenosis is recognized to accelerate hypertension and threaten kidney function, recent trials indicate that many patients can be managed primarily with antihypertensive drug therapy without renal revascularization. These trials have been criticized for many reasons, including inclusion of large groups with only minor vascular occlusive disease. Although moderate stenosis is associated with preserved oxygenation within both cortex and medulla, severe disease is demonstrably associated with reduced oxygenation that can be identified using blood oxygen level-dependent magnetic resonance. Fewer clinical procedures to revascularize stenotic kidneys likely will be followed by advanced occlusion with loss of function. Experimental studies confirm that poststenotic microvascular injury is magnified in the presence of atherosclerosis, activating local inflammatory and fibrogenic pathways in the kidney. Even without restoring renal blood flow, experimental studies with endothelial progenitor cells indicate that recovery of renal vascular structures and function may be possible. The short-term prospective trials to date remain at odds with observational studies indicating improved blood pressure, stabilization of renal function, and improved management of some patients with congestive heart failure. Nephrologists will need to balance optimizing medical therapy for complex patients with renovascular disease and identifying those most likely to benefit from renal revascularization on an individualized basis.


CDK4/6 inhibition suppresses tumour growth and enhances the effect of temozolomide in glioma cells.
In adults, glioma is the most commonly occurring and invasive brain tumour. For malignant gliomas, the current advanced chemotherapy includes TMZ (temozolomide). However, a sizeable number of gliomas are unyielding to TMZ, hence, giving rise to an urgent need for more efficient treatment choices. Here, we report that cyclin-dependent kinases 4 (CDK4) is expressed at significantly high levels in glioma cell lines and tissues. CDK4 overexpression enhances colony formation and proliferation of glioma cells and extends resistance to inhibition of TMZ-mediated cell proliferation and induction of apoptosis. However, CDK4 knockdown impedes colony formation and cell proliferation, and enhances sensitivity of glioma cells to TMZ. The selective inhibition of CDK4/6 impedes glioma cell proliferation and induces apoptotic induction. The selective inhibitors of CDK4/6 may enhance glioma cell sensitivity to TMZ. We further showed the possible role of RB phosphorylation mediated by CDK4 for its oncogenic function in glioma. The growth of glioma xenografts was inhibited in vivo, through combination treatment, and corresponded to enhanced p-RB levels, reduced staining of Ki-67 and enhanced activation of caspase 3. Therefore, CDK4 inhibition may be a favourable strategy for glioma treatment and overcomes TMZ resistance.


Comparison of humoral immune responses in dairy heifers vaccinated with 3 different commercial vaccines against bovine viral diarrhea virus and bovine herpesvirus-1.
A randomized clinical trial was conducted to compare the humoral immune response to 3 different commercial vaccines in dairy heifers housed in 3 different dairy farms in Quebec. All heifers were seronegative to type 1 bovine viral diarrhea virus (BVDV) (Singer strain), type 2 BVDV (NVSL 125c strain), and bovine herpesvirus-1 (BHV-1) at the beginning of the trial. In addition, control heifers in group 1 remained seronegative to the 2 viruses till the end of the trial. Significant differences in humoral immune responses occurred among the 3 commercial vaccines at 4 weeks and 6 months following vaccination. The vaccine in group 2 elicited higher mean antibody titers and seroconversion rates to both type 1 and type 2 BVDV than that in groups 3 or 4. Vaccines in groups 2 and 3 induced higher mean antibody titers to BHV-1 than did the vaccine in group 4.


The etiologies, pathophysiology, and alternative/complementary treatment of asthma.
A chronic inflammatory disorder of the respiratory airways, asthma is characterized by bronchial airway inflammation resulting in increased mucus production and airway hyper-responsiveness. The resultant symptomatology includes episodes of wheezing, coughing, and shortness of breath. Asthma is a multifactorial disease process with genetic, allergic, environmental, infectious, emotional, and nutritional components. The underlying pathophysiology of asthma is airway inflammation. The underlying process driving and maintaining the asthmatic inflammatory process appears to be an abnormal or inadequately regulated CD4+ T-cell immune response. The T-helper 2 (Th2) subset produces cytokines including interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10, and IL-13, which stimulate the growth, differentiation, and recruitment of mast cells, basophils, eosinophils, and B-cells, all of which are involved in humoral immunity, inflammation, and the allergic response. In asthma, this arm of the immune response is overactive, while Th1 activity, generally corresponding more to cell-mediated immunity, is dampened. It is not yet known why asthmatics have this out-of-balance immune activity, but genetics, viruses, fungi, heavy metals, nutrition, and pollution all can be contributors. A plant lipid preparation containing sterols and sterolins has been shown to dampen Th2 activity. Antioxidant nutrients, especially vitamins C and E, selenium, and zinc appear to be necessary in asthma treatment. Vitamins B6 and B12 also may be helpful. Omega-3 fatty acids from fish, the flavonoid quercetin, and botanicals Tylophora asthmatica, Boswellia serrata and Petasites hybridus address the inflammatory component. Physical modalities, including yoga, massage, biofeedback, acupuncture, and chiropractic can also be of help.


Influence of bay-region methyl group on formation of 5-methylchrysene dihydrodiol epoxide:DNA adducts in mouse skin.
The binding of tritium-labeled 5-methylchrysene to DNA of CD-1 mouse skin 24 hr after treatment has been studied. DNA was isolated from the treated skin areas of mice and hydrolyzed enzymatically to deoxyribonucleosides, and the hydrolysate was chromatographed on a Sephadex LH-20 column using a methanol:water gradient. The major adducts eluted between 70 and 100 ml (Peak 1), 470 and 590 ml (Peaks 2A to C), and 750 and 850 ml (peak 3). For identification of these products, markers were prepared from 5-methylchrysene bay-region dihydrodiol epoxides. [5-14C]1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene and [5-14C]7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-5-methylchrysene were synthesized by reacting the corresponding metabolically formed [5-14C]1,2-dihydro-1,2-dihydroxy-5-methylchrysene and [5-14C]7,8-dihydro-7,8-dihydroxy-5-methylchrysene with m-chloroperoxybenzoic acid. The structures of the dihydrodiol epoxides were established by their mass spectra and by hydrolysis to tetrols. Peak 2B was chromatographically indistinguishable, both on Sephadex LH-20 and reverse-phase high-pressure liquid chromatography, from the adduct formed when [5-14C]1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene was reacted with salmon sperm DNA in solution. Similarly, Peak 2A was chromatographically inseparable from the [5-14C]7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-5-methylchrysene:DNA adduct. Adduct 2B was formed to a greater extent than adduct 2A by the ratio of 2.7 to 1. These data indicate that 5-methylchrysene preferentially forms DNA adducts from the bay-region dihydrodiol epoxide adjacent to the methyl group.


Effects of clove oil-phospholipid mixtures on rheology of gum tragacanth - possible application for surfactant action on mucus gel simulants.
The present study evaluates the effectiveness of specialised biomaterials consisting of clove oil- phospholipid mixtures as possible substitute surfactants in diseases of altered mucus viscosity by studying their effect on the viscosity of mucus gel simulants in vitro. Test surfactants consisting of phospholipid-clove oil mixtures in the ratio of 1 part of oil to 9 parts of phospholipid were prepared. The phospholipids used were dipalmitoyl phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) and binary mixtures of PC: PE and PC: PG in the ratio of 2 parts of PC to 3 parts of PE or PG. The effects of the phospholipid-clove oil mixtures on the viscosity of mucus gel simulant (MGS: a polymeric gel consisting predominantly of gum tragacanth and simulating respiratory mucus), was studied by application of steady shear rates ranging from 0.512 to 51.2/s in a concentric cylinder viscometer at 37 degrees C. The change in MGS viscosity, after incubation with surfactants, was found to have a non-Newtonian character and to follow the power law model with R2 values >0.8. The addition of clove oil-phospholipid mixtures caused a decrease in the MGS viscosity when compared with the effect of the phospholipid alone at low shear rates in case of PC, PG and PCPG. The combination of PC : PG with clove oil caused ratios of change in MGS viscosity < 1 i.e., caused a decrease in the MGS viscosity. PC: PG with clove oil was capable of lowering MGS viscosity and should be further researched as possible therapies for diseases of altered mucus rheology.


Comparison of Risk-Standardized Readmission Rates of Surgical Patients at Safety-Net and Non-Safety-Net Hospitals Using Agency for Healthcare Research and Quality and American Hospital Association Data.
Medical patients discharged from safety-net hospitals (SNHs) experience higher readmission rates compared with those discharged from non-SNHs. However, little is known about whether this association persists for surgical patients. To examine differences in readmission rates between SNHs and non-SNHs among surgical patients after discharge and determine whether hospital characteristics might account for some of the variation. This observational retrospective study linked the Healthcare Cost and Utilization Project State Inpatient Databases of the Agency for Healthcare Research and Quality from January 1, 2011, through December 31, 2014, for 4 states (New York, Florida, Iowa, and Washington) with data from the 2014 American Hospital Association annual survey. After identifying surgical discharges, SNHs were defined as those with the top quartile of inpatient stays paid by Medicaid or self-paid. Hospital-level risk-standardized readmission rates (RSRRs) for surgical discharges were calculated. The association between hospital RSRRs and hospital characteristics was evaluated with bivariate analyses. An estimated multivariable hierarchical linear regression model was used to examine variation in hospital RSRRs, adjusting for hospital characteristics, state, year, and SNH status. Data were analyzed from June 1, 2017, through March 1, 2018. Surgical care at an SNH. Readmission after an index surgical admission. A total of 1 252 505 patients across all 4 years and states were included in the analysis (51.7% women; mean [SD] age, 52.7 [18.1] years). Bivariate analyses found that SNHs had higher mean (SD) surgical RSRRs compared with non-SNHs; significant differences were found for New York (9.6 [0.1] vs 10.9 [0.1]; P < .001) and Florida (11.6 [0.1] vs 12.1 [0.1]; P = .001). The SNHs also had higher RSRRs in these 2 states when stratified by hospital funding (nonfederal government SNHs in New York, 11.9 [0.2]; for-profit, private SNHs in Florida, 13.1 [0.2]; P < .001 for both); however, bed size was a significant factor for higher mean (SD) RSRRs only for New York (200 to 399 beds, 12.0 [0.4]; P = .006). Similar results were found for multivariable linear regression models; RSRRs were 1.02% higher for SNHs compared with non-SNHs (95% CI, 0.75%-1.29%; P < .001). Increased RSRRs were observed for hospitals in New York and Florida, teaching hospitals, and investor-owned hospitals. Factors associated with reduced RSRRs included presence of an ambulatory surgery center, cardiac catheterization capabilities, and high surgical volume. According to results of this study, surgical patients treated at SNHs experienced slightly higher RSRRs compared with those treated at non-SNHs. This association persisted after adjusting for year, state, and hospital factors, including teaching status, hospital bed size, and hospital volume.


Comparison of serotonin and dopamine release in substantia nigra and ventral tegmental area: region and species differences.
In this study, we compare the electrically evoked, somatodendritic release of dopamine (DA) with axonal release of serotonin (5-HT) in the substantia nigra (SN) and ventral tegmental area (VTA) in vitro by using fast-scan cyclic voltammetry with carbon-fibre microelectrodes. Furthermore, we have examined transmitter release in these regions in guinea-pig compared with rat. Somatodendritic DA was released, as shown previously, in guinea-pig VTA, SN pars compacta (SNc), and occasionally in SN pars reticulata (SNr). 5-HT was rarely released, except in SNr, where nonetheless it only contributed to <30% of amine signals. In rat midbrain, somatodendritic DA release was evoked to a similar extent as in guinea-pig. However, a clear species difference was apparent; i.e., 5-HT and DA were detected equally in rat SNc, whereas in rat SNr, 5-HT was the predominant transmitter detected. Nevertheless, electrically evoked extracellular concentrations of 5-HT in SNc and SNr were, respectively, seven- and fourfold less than DA in SNc. 5-HT release was low in all regions in neonatal rat slices before the maturation of 5-HT terminals. Hence, axonal 5-HT transmission in midbrain exhibits both species and site selectivity. Moreover, whereas somatodendritic DA release is conventionally regarded as modest compared with axon terminal release in striatum, somatodendritic DA release can result in significantly greater extracellular levels than a transmitter released from axon terminals in the same locality.


[Influenza vaccine stimulation of antibodies to different variants of influenza A virus].
The capacity of live influenza type A (H3N2) vaccines to produce antihemagglutinins and antineuraminidase antibody to drift variants of a given serosubtype emerging later than the vaccine strain was studied. For this purpose, a wider set of antigens was used to examine retrospectively by the HI and virus elution from erythrocyte inhibition tests the paired sera from the subjects immunized in 1975 and 1976 with live vaccine virus strains similar to A/Port Chalmers/1/73 (H3N2) and A/Victoria/3/75. These vaccines were shown to actively stimulate antibody production in titres of 1:40 or higher to strains forestolling the vaccine strain by 1 (antihemagglutinins) and 2 (antineuraminidase antibody) degrees of the antigenic hierarchy. The intensity of production of both kinds of antibody to similar future strains depended on the intensity of immune response to the vaccine virus. By increasing the dose and frequency of administration of the virus serosubtype A (H3N2) to animals it was possible to intensify the production of antihemagglutinins and antineuraminidase antibodies to later drift variants of this agent with respect to the virus-immunogen. Volunteers immunized in 1983 with a commercial inactivated chromatographic bivaccine prepared from the strains similar to A/Bangkok/1/79 (H3N2) and A/Brazil/14/78 (H1N1) were found to intensively produce antihemagglutinins in titres of 1:40 or higher to viruses A/Philippines/2/84 (H3N2), A/Leningrad/167/83 (H3N2), A/Leningrad/3/82 (H1N1) but not to A/Dunedin/27/83 (H1N1) virus.


Is (1→3)-β-D-glucan the missing link from bedside assessment to pre-emptive therapy of invasive candidiasis?
Invasive candidiasis is a frequent life-threatening complication in critically ill patients. Early diagnosis followed by prompt treatment aimed at improving outcome by minimizing unnecessary antifungal use remains a major challenge in the ICU setting. Timely patient selection thus plays a key role for clinically efficient and cost-effective management. Approaches combining clinical risk factors and Candida colonization data have improved our ability to identify such patients early. While the negative predictive value of scores and predicting rules is up to 95 to 99%, the positive predictive value is much lower, ranging between 10 and 60%. Accordingly, if a positive score or rule is used to guide the start of antifungal therapy, many patients may be treated unnecessarily. Candida biomarkers display higher positive predictive values; however, they lack sensitivity and are thus not able to identify all cases of invasive candidiasis. The (1→3)-β-D-glucan (BG) assay, a panfungal antigen test, is recommended as a complementary tool for the diagnosis of invasive mycoses in high-risk hemato-oncological patients. Its role in the more heterogeneous ICU population remains to be defined. More efficient clinical selection strategies combined with performant laboratory tools are needed in order to treat the right patients at the right time by keeping costs of screening and therapy as low as possible. The new approach proposed by Posteraro and colleagues in the previous issue of Critical Care meets these requirements. A single positive BG value in medical patients admitted to the ICU with sepsis and expected to stay for more than 5 days preceded the documentation of candidemia by 1 to 3 days with an unprecedented diagnostic accuracy. Applying this one-point fungal screening on a selected subset of ICU patients with an estimated 15 to 20% risk of developing candidemia is an appealing and potentially cost-effective approach. If confirmed by multicenter investigations, and extended to surgical patients at high risk of invasive candidiasis after abdominal surgery, this bayesian-based risk stratification approach aimed at maximizing clinical efficiency by minimizing health care resource utilization may substantially simplify the management of critically ill patients at risk of invasive candidiasis.