Cognitive behavioral markers of neurodevelopmental trajectories in rodents.
Between adolescence and adulthood, the brain critically undergoes maturation and refinement of synaptic and neural circuits that shape cognitive processing. Adolescence also represents a vulnerable period for the onset of symptoms in neurodevelopmental psychiatric disorders. Despite the wide use of rodent models to unravel neurobiological mechanisms underlying neurodevelopmental disorders, there is a surprising paucity of rigorous studies focusing on normal cognitive-developmental trajectories in such models. Here, we sought to behaviorally capture maturational changes in cognitive trajectories during adolescence and into adulthood in male and female mice using distinct behavioral paradigms. C57 BL/6J mice (4.5, 6, and 12 weeks of age) were assessed on three behavioral paradigms: drug-induced locomotor hyperactivity, prepulse inhibition, and a novel validated version of a visuospatial paired-associate learning touchscreen task. We show that the normal maturational trajectories of behavioral performance on these paradigms are dissociable. Responses in drug-induced locomotor hyperactivity and prepulse inhibition both displayed a 'U-shaped' developmental trajectory; lower during mid-adolescence relative to early adolescence and adulthood. In contrast, visuospatial learning and memory, memory retention, and response times indicative of motivational processing progressively improved with age. Our study offers a framework to investigate how insults at different developmental stages might perturb normal trajectories in cognitive development. We provide a brain maturational approach to understand resilience factors of brain plasticity in the face of adversity and to examine pharmacological and non-pharmacological interventions directed at ameliorating or rescuing perturbed trajectories in neurodevelopmental and neuropsychiatric disorders.


Crack arrest and stress dependence of laser-induced surface damage in fused-silica and borosilicate glass.
Results of experiments on stress-inhibited laser-driven crack growth and stress-delayed laser-damage initiation thresholds in fused silica, borosilicate glass (BK-7), and cleaved bulk silica are presented. A numerical model is developed to explain the crack arrest in fused silica. Good agreement is obtained between the model and a finite-element code. The crack arrest is demonstrated to be the result of the breaking of a hoop-stress symmetry that is responsible for crack propagation in fused silica.


Familial multiple epiphyseal dysplasia due to a matrilin-3 mutation: further delineation of the phenotype including 40 years follow-up.
In this study, we followed-up the family with bilateral hereditary micro-epiphyseal dysplasia (BHMED) originally described by Elsbach [1959: J Bone Joint Surg [Br] 41-B:514-523]. Clinical re-examination of all available family members resulted in further delineation of the clinical and radiological phenotype, which is distinct from common multiple epiphyseal dysplasia (MED). Linkage analysis excluded EDM1, EDM2, and EDM3 as candidate genes. Linkage and mutation analysis of matrilin-3 (MATN-3) revealed a new pathogenic mutation confirming that BHMED is indeed a distinct disease entity among MED and MED-like disorders.


Effects of different lipoprotein apheresis methods on serum protein levels.
A total plasma exchange was the first extracorporeal method to treat patients with severe hypercholesterolemia. But in the long run it has several disadvantages. The newer lipoprotein apheresis (LA) methods claim to be more selective with respect to the removal of atherogenic lipoproteins and thus are supposed to avoid an additional protein loss. We wanted to compare the effect of these methods on serum protein concentrations (total serum protein, albumin, proteins measured with electrophoresis, immunoglobulins, fibrinogen, transferrin, and ferritin) which were checked before and after a single LA session in 75 patients. All patients underwent active LA treatment using 6 different LA methods (HELP, TheraSorb(®) LDL, DALI, Lipidfiltration, Liposorber D, MONET). Post-apheresis concentrations were corrected for changes in hematocrit. The slightest impact on total serum protein was observed with the whole-blood methods. Liposorber D showed the least reduction of albumin levels. All LA methods had a small effect on alpha1-globulins and beta-globulins, but alpha2-and gamma-globulins were reduced to a different extent. A major effect was seen on the immunoglobulins when filtration methods were applied. In the patients treated with MONET, both pre- and post-apheresis Immunoglobulin M concentrations were below the normal range. HELP and the filtration methods significantly reduced the fibrinogen concentrations. The filtration methods also decreased ferritin levels but the post-apheresis ferritin levels were still in the normal range. All LA methods had an influence on protein concentrations. At present, these findings will not yield an individualized treatment approach for any selective LA method due to the lack of prospective comparative studies. At minimum, special attention should be paid to protein concentrations in patients suffering from protein deficit.


Sigmoid sinus involvement in middle-ear infection.
It was thought that sigmoid sinus involvement from middle-ear infection would become a rare clinical entity with the introduction of antibiotics. However, this problem is still prevalent. Twelve hundred eighty cases of mastoid surgery were performed at Ghaem Medical Center and the author's private clinic between January 1978 and December 1985 in Mashad, Iran. In sixteen cases, surgically proven sigmoid sinus involvement was due to a bone eroding process of chronic ear infection. The pattern of the clinical picture is different than in the preantibiotic era.


IRAK1 Duplication in MECP2 Duplication Syndrome Does Not Increase Canonical NF-κB-Induced Inflammation.
Besides their developmental and neurological phenotype, most patients with MECP2/IRAK1 duplication syndrome present with recurrent and severe infections, accompanied by strong inflammation. Respiratory infections are the most common cause of death. Standardized pneumological diagnostics, targeted anti-infectious treatment, and knowledge of the underlying pathomechanism that triggers strong inflammation are unmet clinical needs. We investigated the influence of IRAK1 overexpression on the canonical NF-κB signaling as a possible cause for excessive inflammation in these patients. NF-κB signaling was examined by measuring the production of proinflammatory cytokines and evaluating the IRAK1 phosphorylation and degradation as well as the IκBα degradation upon stimulation with IL-1β and TLR agonists in SV40-immortalized fibroblasts, PBMCs, and whole blood of 9 patients with MECP2/IRAK1 duplication syndrome, respectively. Both, MECP2/IRAK1-duplicated patients and healthy controls, showed similar production of IL-6 and IL-8 upon activation with IL-1β and TLR2/6 agonists in immortalized fibroblasts. In PBMCs and whole blood, both patients and controls had a similar response of cytokine production after stimulation with IL-1β and TLR4/2/6 agonists. Patients and controls had equivalent patterns of IRAK1 phosphorylation and degradation as well as IκBα degradation upon stimulation with IL-1β. Patients with MECP2/IRAK1 duplication syndrome do not show increased canonical NF-κB signaling in immortalized fibroblasts, PBMCs, and whole blood. Therefore, we assume that these patients do not benefit from a therapeutic suppression of this pathway.


Nitric oxide pathway activity modulation alters the protective effects of (-)Epigallocatechin-3-gallate on reserpine-induced impairment in rats.
Reserpine (RES) has been reported to increase the brain's neural oxidative stress and cause cognitive dysfunction. Having powerful antioxidative properties, green tea catechins, especially (-)epigallocatechin-3-gallate (EGCG), are able to protect against many oxidative injuries. In this study, we examined the protecting properties of EGCG on RES-induced impairment of short-term memory in three-month-old male Wistar rats. RES (1mg/kg i.p.) induced memory impairment (p<0.001) as evaluated by the social recognition task. EGCG treatment (100mg/kg i.p. for 7days, starting 6days before RES injection) was able to improve the impaired memory caused by RES. RES treatment increased the nitric oxide (NO) level and lipid peroxidation (LPO) production, and decreased the antioxidation power in hippocampi. EGCG treatment was able to counteract the RES-induced NO level and LPO production, as well as enhanced the hippocampal antioxidation power in RES-treated rats. In order to examine the implication of NO pathway activity in RES treatment, either NO precursor (L-arginine; L-A) or NO synthase inhibitor (L-NAME; L-N) was co-pretreated with EGCG; NO precursor treatment eliminated the protective effect of EGCG, in contrast to that NO synthase inhibitor treatment significantly increased the EGCG effects on cognitive and biochemical protection in RES-treated rats. These results suggested that the NO pathway was implicated, at least in part, in the RES-induced impairment, as well as in the protective effect of EGCG in treating RES-induced impairment of memory. The above evidence provides a clinically relevant value for EGCG in preventing RES-induced cognitive dysfunction.


Assessment of efficacy and safety of volanesorsen for treatment of metabolic complications in patients with familial partial lipodystrophy: Results of the BROADEN study: Volanesorsen in FPLD; The BROADEN Study.
Volanesorsen, an antisense oligonucleotide, is designed to inhibit hepatic apolipoprotein C-III synthesis and reduce plasma apolipoprotein C-III and triglyceride concentrations. The present study assessed efficacy and safety of volanesorsen in patients with familial partial lipodystrophy (FPLD) and concomitant hypertriglyceridemia and diabetes. BROADEN was a randomized, placebo-controlled, phase 2/3, 52-week study with open-label extension and post-treatment follow-up periods. Patients received weekly subcutaneous volanesorsen 300 mg or placebo. The primary endpoint was percent change from baseline in fasting triglycerides at 3 months. Secondary endpoints included relative percent change in hepatic fat fraction (HFF), visceral adiposity, and glycated hemoglobin levels. Forty patients (11 men, 29 women) were enrolled, majority of whom were aged <65 years (mean, 47 years) and White. Least squares mean (LSM) percent change in triglycerides from baseline to 3 months was -88% (95% CI, -134 to -43) in the volanesorsen group versus -22% (95% CI, -61 to 18) in the placebo group, with a difference in LSM of -67% (95% CI, -104 to -30; P=0.0009). Volanesorsen induced a significant LSM relative reduction in HFF of 53% at month 12 versus placebo (observed mean [SD]: 9.7 [7.65] vs. 18.0 [8.89]; P=0.0039). No statistically significant changes were noted in body volume measurements (fat, liver, spleen, visceral/subcutaneous adipose tissue) or glycated hemoglobin. Serious adverse events in patients assigned to volanesorsen included 1 case each of sarcoidosis, anaphylactic reaction, and systemic inflammatory response syndrome. In BROADEN, volanesorsen significantly reduced serum triglyceride levels and hepatic steatosis in patients with FPLD.


New developments in reprocessing semicritical items.
Semicritical medical devices are defined as items that come into contact with mucous membranes or nonintact skin (eg, gastrointestinal endoscopes). Such medical devices require minimally high-level disinfection. Because many of these items are temperature sensitive, low-temperature chemical methods must be used rather than steam sterilization. Strict adherence to current guidelines is required because more outbreaks have been linked to inadequately cleaned or disinfected endoscopes undergoing high-level disinfection than any other medical device.


Inhibition and covalent modification of rape seed (Brassica napus) enoyl ACP reductase by phenylglyoxal.
The NADH-dependent enoyl-ACP reductase from oil seed rape (Brassica napus) was inactivated by treatment with phenylglyoxal, a reagent which specifically modifies arginine residues. The inhibition at various phenylglyoxal concentrations shows pseudo-first-order kinetics, with an apparent second-order rate constant of 14.2 M-1.min-1 for inactivation. The protective ability of several substrates and substrate analogues was investigated in order to ascertain if the inhibition was directed towards the active site of the enzyme. NADH and NAD+ did not protect but acyl carrier protein (ACP) and reduced coenzyme A, along with various derivatives, did protect. 9 microM ACP gave 35% protection from inactivation and 10 mM reduced coenzyme A gave 98% protection. The effectiveness of various subfragments of coenzyme A in protecting against inhibition indicates that the phosphate group is essential for preventing the binding of phenylglyoxal. The idea that phenylglyoxal is inhibiting by binding at the active site is further supported by the observation that the incorporation of 14C-labelled phenylglyoxal is directly related to the loss of activity. Extrapolation of the amount of label incorporated to give total inhibition shows that 4 mol of phenylglyoxal would be incorporated per mol of enzyme. This corresponds to the modification of two arginine side-chains with equal reactiveness towards the reagent. These results are consistent with there being two arginine residues either at the active site of the enzyme or in an environment which is protected from phenylglyoxal by a conformational change induced by coenzyme A binding.


Extraordinary absorption of sound in porous lamella-crystals.
We present the design of a structured material supporting complete absorption of sound with a broadband response and functional for any direction of incident radiation. The structure which is fabricated out of porous lamellas is arranged into a low-density crystal and backed by a reflecting support. Experimental measurements show that strong all-angle sound absorption with almost zero reflectance takes place for a frequency range exceeding two octaves. We demonstrate that lowering the crystal filling fraction increases the wave interaction time and is responsible for the enhancement of intrinsic material dissipation, making the system more absorptive with less material.


Caring for Veteran Women: Collaborative Nursing Approaches to Improve Care.
A strength-based nursing approach to recommendations for interpersonal collaboration and communication is used when caring for Veteran women in health care settings. Four areas are emphasized: (1) using trauma-informed health care practices; (2) acknowledging and affirming the intersectional identities of Veteran women to individualize care and counteract health disparities; (3) engaging strategies to enhance a sense of belonging for Veteran women in health care settings; and (4) encouraging Veteran women to participate in potential research studies to better understand and improve care for this population.


The prognostic significance of the supraclavicular lymph node metastases in breast cancer patients.
To define the patterns of failure and outcome of patients presenting supraclavicular lymph node involvement and the prognostic significance of supraclavicular lymph node involvement. We reviewed the history of 795 breast cancer patients treated at the Department of Radiation Therapy, University of Würzburg between 1978 and 1988. The clinical and pathologic features of 21 patients who had ipsilateral supraclavicular lymph node metastases at primary diagnosis and 38 patients who presented supraclavicular lymph node recurrence during the course of disease were reviewed. These were compared with the features of 20 patients who initially had M1 status at primary diagnosis and 278 patients who had developed distant metastases in the follow-up period. Survival rates were calculated starting from the time of diagnosis of supraclavicular involvement respective of distant metastases. Survival from appearance of supraclavicular lymph node metastases at primary diagnosis or as a recurrence is not different from survival of patients presenting with a primary M1 stage or presenting distant metastases during the course of disease. Two and 5-year survival rates of patients with supraclavicular lymph node involvement at primary diagnosis were 52% and 34% compared to 50% and 16% 2- and 5-year survival rate of patients with supraclavicular lymph node involvement as a recurrence. Patients who presented a primary M1-status had 2- and 5-year survival rates of 56% and 24%. Survival of patients with distant metastases calculated from the onset of metastatic disease was similar to that of the other three groups with a 46% and 16% survival rate at 2 and 5 years. There was no difference in survival rates between the four groups. The prognostic significance of supraclavicular lymph node involvement at primary diagnosis or as a relapse is similar, both have the same significance as the first distant relapse and are characterized by a poor prognosis.


Mechanisms of interaction between persistent organic pollutants (POPs) and CYP2B6: An in silico approach.
Human Cytochrome P450s (CYP450) are a group of heme-containing metalloenzymes responsible for recognition and metabolism of numerous xenobiotics, including drugs and environmental contaminants. CYP2B6, a member of CYP450, is well known for being a highly inducible and polymorphic enzyme and for its important role in the oxidative metabolism of environmental pollutants, such as the Polybrominated Diphenyl Ethers (PBDEs) and Polychlorinated Biphenyls (PCBs). However the mechanisms of interaction of PBDEs and PCBs with CYP2B6 is not entirely known. In this work, a computational approach was carried out to study the interactions of 41 POPs (17 PBDEs, 17 PCBs, and 7 Dioxins) with four CYP2B6 protein structures downloaded from PDB data base (PDB: 3UA5, 3QOA, 3QU8 and 4I91) using molecular docking protocols with AutoDock Vina. The best binding affinity values (kcal/mol) were obtained for PBDE-99 (-8.5), PCB-187 (-9.6), and octachloro-dibenzo-dioxin (-9.8) that can be attributed to the hydrophobic interactions with important residues, such as Phe-363, in the catalytic site of CYP2B6. Molecular docking validation revealed the best values for PDB: 3UA5 (R = 0.622, p = 0.001) demonstrating the reliability of molecular docking predictions. The information obtained in this work can be useful in evaluating the modes of interaction of xenobiotic compounds with the catalytic site of CYP2B6 and provide insights on the important role of these enzymes in the metabolism of potentially toxic compounds in humans.


Dramatically enhanced carbon acidity of the nitrobenzyl fragment in a nickel(II) scorpionate complex.
The -CH(2)- group of the 2-nitrobenzyl pendant arm of the scorpionate complex I deprotonates in basic aqueous solution (pK(a) = 10.6), due to the coordination of the nitronate group to the nickel(II) center. Metal coordination enhances 2-nitrobenzene acidity by 10 orders of magnitude. [reaction: see text]


Chlorhexidine-coated surgical gloves influence the bacterial flora of hands over a period of 3 hours.
The risk of SSI increases in the presence of foreign materials and may be caused by organisms with low pathogenicity, such as skin flora derived from hands of surgical team members in the event of a glove breach. Previously, we were able to demonstrate that a novel antimicrobial surgical glove coated chlorhexidine-digluconate as the active ingredient on its inner surface was able to suppress surgeons' hand flora during operative procedures by a magnitude of 1.7 log10 cfu/mL. Because of the clinical design of that study, we were not able to measure the full magnitude of the possible antibacterial suppression effect of antimicrobial gloves over a full 3 h period. The experimental procedure followed the method for assessment of the 3-h effects of a surgical hand rub's efficacy to reduce the release of hand flora as described in the European Norm EN 12791. Healthy volunteers tested either an antimicrobial surgical glove or non-antimicrobial surgical latex gloves in a standardized laboratory-based experiment over a wear time of 3 h. Wearing antimicrobial surgical glove after a surgical hand rub with 60% (v/v) n-propanol resulted in the highest 3-h reduction factor of 2.67 log10. Non-antimicrobial surgical gloves demonstrated significantly lower (p ≤ 0.01) 3-h reduction factors at 1.96 log10 and 1.68 log10, respectively. Antibacterial surgical gloves are able to maintain a sustainable bacterial reduction on finger tips in a magnitude of almost 3 log10 (log10 2.67 cfu) over 3 h wear time. It was demonstrated that wear of an antibacterial surgical glove coated with chlorhexidine-digluconate is able to suppress resident hand flora significantly over a period of 3-h.


Surgical treatment of patients with hour glass shaped or ruptured membranes prior to the twenty-fifth week of gestation.
The surgical technique of cervical cerclage in patients with bulging membranes prior to the twenty-fourth week of gestation is described. Of the 11 patients, ten had viable births. Ten of the 11 patients had spontaneous rupture of their membranes, lasting from two and one-half to 14 weeks. The only adverse effects of rupture of membranes were preterm labor and fetal growth retardation.


Home testing of urine chloride to estimate dietary sodium intake: evaluation of feasibility and accuracy.
To estimate the utility of quantab chloride titrators, a product of Ames Laboratories, in estimating urine and diet sodium, two study populations were examined. The first consisted of 56 normotensive individuals providing timed, overnight, urine collections and 24-hour food records as part of the baseline assessment for a hypertension prevention study. The second group consisted of 19 study employees, who were instructed to maintain a low sodium diet, and to self-assess diet sodium and urine chloride at home. Results showed that urine chloride measured by quantab was highly correlated with urine sodium. Neither urine chloride nor urine sodium correlated highly with the previous day's intake of dietary sodium as measured by food record. It is estimated that five overnight urine samples would be required to estimate food record sodium to within +/- 25 mEq in individuals with relatively stable diets. Home assessment of urine chloride is feasible. It seems likely that clinical procedures which combine self-monitoring of dietary sodium intake by food record and home measurement of urine chloride concentration would be an effective way of providing persons prescribed sodium restricted diets with continuous and convergent feedback about their success in dietary adherence.


Effects of cyclic nucleotides on midgut infections and maturation of T. b. brucei in G. m. morsitans.
Cyclic nucleotide signalling through cyclic adenosine monophosphate (cAMP) is thought to play an important role in the transformation of the long slender (dividing) form to the short-stumpy (arrested) form in the mammalian bloodstream but the role of cyclic nucleotides in the tsetse-based part of the trypanosome life cycle is unknown. In a series of in vivo experiments, it was found that cyclic guanosine monophosphate (cGMP) but not cAMP could induce significantly higher rates of midgut infection in tsetse. Continuous feeding of either cGMP or cAMP to tsetse had no effect on rates of maturation of established midgut infections suggesting that these two parts of the life cycle in tsetse are not linked.


Stakeholders involvement by HTA Organisations: why is so different?
To investigate stakeholder involvement by Health Technology Assessment Organisations (HTAOs) in France, Spain, England and Wales, Germany, Sweden, and The Netherlands and to examine whether this involvement depends on (i) the administrative tradition and the relevant conception of the relationship between state and society (contractarian and corporative vs. organic), (ii) the general structure of the healthcare system (HCS) (Bismarckian vs. Beveridgian system), and (iii) the role of Health Technology Assessment (HTA) and HTAOs in the HCS. Given the exploratory nature of the study, we considered interviews based on semi-structured questionnaires the most appropriate data-gathering technique. The interviews were administered to 16 key personnel in the HTAOs concerned. We have also carried out a literature review on HTAOs and stakeholders (1999-2011) using PubMed, Ebsco, JSTOR and Wiley Science. In contractarian and (to a lesser extent) Bismarckian models, stakeholders are more involved. The administrative tradition and the HCS appear less important when the HTA is binding and used for regulatory purposes. In such situations, stakeholders are more intensively involved because their participation provides an opportunity for HTAOs to achieve consensus and legitimacy in advance. Despite the limitations of the research (we did not conduct multiple interviews for each HTAO, and key informants were not always available) and its exploratory nature, we can conclude that models of stakeholders involvement cannot easily be transferred from one country to another due to the importance of national administrative traditions and the characteristics of HCSs.


Associations between PFAS concentrations and the oxidative status in a free-living songbird (Parus major) near a fluorochemical facility.
For the past 7 decades, PFAS have been used in many different products and applications, which has led to a widespread contamination of these compounds. Nevertheless at present, little is known about the effects of these compounds on avian wildlife. Therefore, this study investigated associations between PFAS concentrations in the plasma and the oxidative status (i.e. non-enzymatic antioxidants and biomarkers of oxidative stress) in great tits at two sites near a fluorochemical manufacturing facility. Different PFAS were detected in the blood plasma with a mean ΣPFAS of 16062 pg/μL at the site closest to the facility. The PFAS profile in the plasma consisted mainly of PFOS, PFOA, PFDA and PFDoDA, where concentrations were higher for these compounds at the site closest to the plant. Our results show a clear link between PFAS and the antioxidant status of the birds; total antioxidant capacity and peroxidase activity were higher near the plant site, while the glutaredoxin activity was higher further away. Additionally, positive associations were found between PFDoDA and glutathione-S-transferase activity, between PFOS and glutathione-S-transferase activity, between PFDA and peroxidase activity, and between PFOS and peroxidase activity. Lastly, a negative association was found between plasma PFDA concentrations and the total polyphenol content. Interestingly, malondialdehyde levels did not differ between sites, suggesting lipid peroxidation was not affected. Although our results suggest that great tits with elevated PFAS concentrations did not suffer oxidative damage, the antioxidant defence responses were significantly triggered by PFAS exposure. This implies that the great tits have managed to defend themselves against the possible oxidative damage coming from PFAS contamination, although the upregulated antioxidant defences may have fitness costs. Further, experiments are needed to investigate the specific mechanisms by which PFAS induce oxidative stress in avian species.


Comparison of the SF6D, the EQ5D, and the oswestry disability index in patients with chronic low back pain and degenerative disc disease.
The need for cost effectiveness analyses in randomized controlled trials that compare treatment options is increasing. The selection of the optimal utility measure is important, and a central question is whether the two most commonly used indexes - the EuroQuol 5D (EQ5D) and the Short Form 6D (SF6D) - can be used interchangeably. The aim of the present study was to compare change scores of the EQ5D and SF6D utility indexes in terms of some important measurement properties. The psychometric properties of the two utility indexes were compared to a disease-specific instrument, the Oswestry Disability Index (ODI), in the setting of a randomized controlled trial for degenerative disc disease. In a randomized controlled multicentre trial, 172 patients who had experienced low back pain for an average of 6 years were randomized to either treatment with an intensive back rehabilitation program or surgery to insert disc prostheses. Patients filled out the ODI, EQ5D, and SF-36 at baseline and two-year follow up. The utility indexes was compared with respect to measurement error, structural validity, criterion validity, responsiveness, and interpretability according to the COSMIN taxonomy. At follow up, 113 patients had change score values for all three instruments. The SF6D had better similarity with the disease-specific instrument (ODI) regarding sensitivity, specificity, and responsiveness. Measurement error was lower for the SF6D (0.056) compared to the EQ5D (0.155). The minimal important change score value was 0.031 for SF6D and 0.173 for EQ5D. The minimal detectable change score value at a 95% confidence level were 0.157 for SF6D and 0.429 for EQ5D, and the difference in mean change score values (SD) between them was 0.23 (0.29) and so exceeded the clinical significant change score value for both instruments. Analysis of psychometric properties indicated that the indexes are unidimensional when considered separately, but that they do not exactly measure the same underlying construct. This study indicates that the difference in important measurement properties between EQ5D and SF6D is too large to consider them interchangeable. Since the similarity with the "gold standard" (the disease-specific instrument) was quite different, this could indicate that the choice of index should be determined by the diagnosis.


Impact of curcumin loading on the physicochemical, mechanical and antimicrobial properties of a methacrylate-based experimental dental resin.
Oral biofilms are directly linked to one of the most common chronic human diseases, dental caries. Resin-based dental materials have significant potential to replace amalgam, however they lack sufficient antimicrobial power. This innovative study investigates a curcumin-loaded dental resin which can be utilized in an antimicrobial photodynamic therapy (aPDT) approach. The study evaluated the effects of curcumin loading on resin physicochemical, mechanical, and adhesive properties, as well as the antimicrobial response associated with blue light activation. Preliminary tests involving degree of conversion (DC) and sample integrity determined the optimal loading of curcumin to be restricted to 0.05 and 0.10 wt%. These optimal loadings were tested for flexural strength (FS), water sorption (WS) and solubility (SL), shear bond strength to dentin (SBS), and viability of Streptococcus mutans under 14.6 J/cm2 blue light or dark conditions, in 6 h and 24 h biofilms. The results demonstrated that 0.10 wt% curcumin had minimal impact on either FS or SBS, but detectably increased WS and SL. A 2 log10 (CFU/mL) reduction in S. mutans after light application in both 6 h and 24 h biofilms were corroborated by CLSM imaging and highlighted the significant potential of this novel aPDT approach with resin-based dental materials.


Laparoscopic pancreatectomy for solid pseudo-papillary tumors of the pancreas is a suitable technique; our experience with long-term follow-up and review of the literature.
Solid pseudopapillary tumors (SPTs) are rare pancreatic neoplasms of low malignant potential that occur mainly in young women. Only 17 cases of SPT treated laparoscopically have been published in the literature and long-term follow-up data are still lacking. Retrospective analysis of ten patients (8 women, 2 men; mean age, 25.4 years) (DS: 12.1; minimum 11, maximum 51) who underwent laparoscopic distal pancreatectomy with a definitive histological diagnosis of SPT. Long-term follow-up data were collected. The average tumor size was 43.8 mm (minimum 20, maximum 65 mm). The mean operative time was 177.5 minutes (DS: 53.7; minimum 120, maximum 255). In all, five patients underwent distal splenopancreatectomy; five patients underwent spleen-preserving distal pancreatectomy of whom three with splenic vessel preservation and two with the Warshaw technique. The conversion rate was nil and no case of perioperative mortality was recorded. The mean hospital stay was 7 days (DS: 2.7; minimum 4, maximum 12). Six patients had an uneventful postoperative course and four had postoperative complications. Two of them underwent reoperation, and the other two had nonsurgical complications. After a median follow-up of 47 (range, 5-98) months, all patients were alive and disease-free. Laparoscopic pancreatic resection is a safe and feasible procedure that could become the treatment of choice for patients affected by pancreatic SPT. Distal pancreatectomy should be performed, if possible, with spleen-preserving technique, especially in young patients. To avoid metastatic spread, laparoscopic or laparotomic biopsy should not be performed in patients affected by SPT.


Excitotoxic effect of kainic acid on chicken cochlear afferent neurons.
The excitotoxic effects of kainic acid, a glutamate analog, on the auditory neurons in the chicken cochlea were assessed by light and transmission electron microscopy. Kainic acid was directly applied onto the round window of adult chickens and their cochleas were harvested 3 h after application. Transverse microscopic sections of the basilar papilla revealed swelling of afferent dendrites without any morphological changes in efferent endings. The regions of the basilar papilla damaged by kainic acid were localized in the apical 80% and primarily on the neural side where tall hair cells are located. The basal, abneural short hair cell region was devoid of damage. These results imply that glutamate is a primary neurotransmitter in chicken auditory afferent neurons that synapse on tall hair cells.


Role of bile acid receptor FXR in development and function of brown adipose tissue.
Bile acids act as signalling molecules that contribute to maintenance of energy homeostasis in mice and humans. Activation of G-protein-coupled bile acid receptor TGR5 induces energy expenditure in brown adipose tissue (BAT). However, a role for the nuclear bile acid receptor Farnesoid X receptor (FXR) in BAT has remained ambiguous. We aimed to study the potential role of FXR in BAT development and functioning. Here we demonstrate low yet detectable expression of the α1/2 isoforms of FXR in murine BAT that markedly decreases upon cold exposure. Moderate adipose tissue-specific FXR overexpression in mice induces pronounced BAT whitening, presenting with large intracellular lipid droplets and extracellular collagen deposition. Expression of thermogenic marker genes including the target of Tgr5, Dio2, was significantly lower in BAT of chow-fed aP2-hFXR mice compared to wild-type controls. Transcriptomic analysis revealed marked up-regulation of extracellular matrix formation and down-regulation of mitochondrial functions in BAT from aP2-hFXR mice. In addition, markers of cell type lineages deriving from the dermomyotome, such as myocytes, as well as markers of cellular senescence were strongly induced. The response to cold and β3-adrenergic receptor agonism was blunted in these mice, yet resolved BAT whitening. Newborn cholestatic Cyp2c70-/- mice with a human-like bile acid profile also showed distinct BAT whitening and upregulation of myocyte-specific genes, while thermogenic markers were down-regulated. Ucp1 expression inversely correlated with plasma bile acid levels. Therefore, bile acid signalling via FXR has a role in BAT function already early in tissue development. Functionally, FXR activation appears to oppose TGR5-mediated thermogenesis.


The polymorphic metabolism of dextromethorphan.
The ability of healthy male volunteers to metabolize a 30-mg oral dose of dextromethorphan (DM) was studied in 252 Americans. Two blood samples were collected at four and 24 hours after administration of the dose. The resulting plasma was analyzed for unchanged DM. The volunteers were classified as slow, intermediate, or fast metabolizers on the basis of plasma concentrations of DM. Further differentiation of slow and intermediate metabolizers was achieved by comparing the two-point estimates of elimination-rate constants. In the population studied, 84.3% were fast DM metabolizers, 6.8% were intermediate metabolizers, and 8.8% were slow metabolizers. Previous reports have related the slow DM metabolizers to slow debrisoquin metabolizers, but no such correlations have been achieved with intermediate DM metabolizers. These intermediate DM metabolizers may suggest a new polymorphism not related to debrisoquin or may suggest that "debrisoquin gene" regulation is more complex than originally suggested.


Health Must Be Recognized as the Human Right It Is: Héctor Javier Sánchez MD MSSenior Researcher, Department of Society, Culture and HealthEl Colegio de la Frontera Sur (ECOSUR), Chiapas, Mexico.
Dr Héctor Javier Sánchez specializes in public health and research methodology and holds a master's degree in epidemiology. He is a senior researcher in the Society, Culture and Health Department at El Colegio de la Frontera Sur, Mexico. The Colegio is a public research institu-tion concentrating on environmental, economic and social issues related to a sustainable future for Mexico's southern border area, and belongs to the National Council of Science and Technol-ogy (CONACYT). In Chiapas State, the country's poorest region and home to many indigenous peoples, Dr Sánchez has carried out studies on TB, poverty and health, domestic violence, hu-man rights, maternal-child health and the effect of agrochemicals on human health.


Together we stand: genes cluster to coordinate regulation.
Although most eukaryotic genomes lack operons, occasionally clusters of genes are discovered that are related in function. Now, a metabolic operon-like gene cluster has been described in Arabidopsis thaliana, that is needed for triterpene synthesis.


Fusion of multislice computed tomography imaging with three-dimensional electroanatomic mapping to guide radiofrequency catheter ablation procedures.
The outcome of catheter ablation procedures of cardiac arrhythmias depends on the ability to evaluate the underlying mechanism and to depict target sites for ablation. Fusion of different imaging modalities within one system may improve electroanatomic modeling and facilitate ablation procedures. The purpose of this study was to study the feasibility of fusion of multislice computed tomography (MSCT) with electroanatomic mapping to guide radiofrequency catheter ablation of atrial arrhythmias. Sixteen patients (15 men, age 54 +/- 7 years) with drug-refractory atrial fibrillation (AF) underwent 64-slice MSCT within 2 days before radiofrequency catheter ablation. MSCT data were imported to the Carto electroanatomic mapping system. Using the new CartoMerge Image Integration Module, the MSCT images and the electroanatomic map were aligned. A statistical algorithm provided information about the accuracy of the fusion process. In all patients, MSCT images could be fused with the electroanatomic map. Mean distance between the mapping points and the MSCT surface ranged from 1.7 +/- 1.2 mm to 2.8 +/- 1.8 mm. This resulted in an average of 2.1 +/- 0.2 mm for the patient group as a whole. MSCT images can be fused with the three-dimensional electroanatomic mapping system in an accurate manner. Anatomy-based catheter ablation procedures for atrial arrhythmias may be facilitated by integration of different imaging modalities.


The segmental origin of preganglionic axons in the upper thoracic rami of the cat.
Sympathetic preganglionic neurones have been identified in the thoracic spinal cord of cats after selective application of horseradish peroxidase (HRP) to the cut axons of the individual white rami of T1 to T3. The labelled neurones were restricted rostrocaudally to the length of a single segment, although this did not correspond exactly with the point of exit of the corresponding spinal root. The results do not support the concept of an intraspinal pathway of preganglionic axons in this region and one possible explanation for the difference between these data and those of others is discussed.


Identification of a high affinity FcgammaRIIA-binding peptide that distinguishes FcgammaRIIA from FcgammaRIIB and exploits FcgammaRIIA-mediated phagocytosis and degradation.
FcgammaRIIA is a key activating receptor linking immune complex formation with cellular effector functions. FcgammaRIIA has 93% identity with an inhibitory receptor, FcgammaRIIB, which negatively regulates FcgammaRIIA. FcgammaRIIA is important in the therapeutic action of several monoclonal antibodies. Binding molecules that discriminate FcgammaRIIA from FcgammaRIIB may optimize receptor activity and serve as a lead for development of therapeutics with FcgammaRIIA as a key target. Here we report the use of phage display libraries to select short peptides with distinct FcgammaRIIA binding properties. An 11-mer peptide (WAWVWLTETAV) was characterized that bound FcgammaRIIA with a K(d) of 500 nm. It mediated cell internalization and degradation of a model antigen. The peptide-binding site on FcgammaRIIA was shown to involve Phe(163) and the IgG binding amino acids Trp(90) and Trp(113). It is thus overlapping but not identical to that of IgG. Neither activating receptors FcgammaRI and FcgammaRIII, nor FcgammaRIIB, all of which lack Phe(163), bound the peptide.


Studies on alkaline phosphatase, catalase and z-galactosidase in Vibrio el tor under normal and rifampicin resistant conditions.
Alkaline phosphate, catalase and beta-galactosidase activities of Vibrio et tor were decreased after acquisition of resistance towards rifampicin. Zn2+, Mn2+ and EDTA inhibited alkaline phosphatase which is most active with p-nitrophenylphosphate as substrate while Mg2+ was found to suppress alkaline phosphatase activity. Removal of EDTA however, restores the original activity. Rifampicin could not induce mutation of lactose nonfermenting Vibrio el for cells allowing them to grow on lactose as sole carbon source, z-galactosidase which is a constitutive enzyme in this case is repressed by glucose. This repression is overcome by cAMP.


[Reconstruction of the branches of the trigeminal nerve using microsurgery methods].
The cause and pathomechanism of injuries of the n. trigeminus branches are described. The diagnostics and prognostics of the injuries are discussed in detail and a system of classification employed by the author is disclosed. After describing the microsurgical technique employed for treating the injuries successful treatment of 210 patients is reported on.


Neurocysticercosis: an exotic disease presenting in Australian immigrants.
Two cases of neurocysticercosis which occurred in migrant women are reported. This disease, produced from the larval form of the pig tapeworm, Taenia solium, is not endemic in Australia. It is prevalent in Latin America, India, parts of Africa and eastern Europe and some Mediterranean areas. Where the possibility of exposure to this parasite exists, neurocysticercosis should be considered in the differential diagnosis of late-onset epilepsy, hydrocephalus, focal fits, progressive dementia, and in spinal cord tumours.


Factors influencing coronary vascular resistance during hypothermia.
Factors influencing total coronary vascular resistance (CVR) during hypothermia were studied in 30 mongrel dogs. Complete isolation of the heart in situ was achieved by transection of all cardiac neural and vascular connections in 15 dogs (denervated, Group I). Cardiac innervation was maintained in the other 15 dogs using systemic normothermic cardiopulmonary bypass (innervated, Group II). The aortic root was perfused with heparinized oxygenated blood at a constant flow rate at variable myocardial temperatures. Electromechanical arrest was achieved using potassium chloride (KCl) (25 meq/liter) added to the coronary perfusate. In each group, 5 dogs were maintained at a flow rate of 10 cc/kg/min without KCl and allowed to beat spontaneously, another 5 at a flow rate of 10 cc/kg/min and arrested with KCl, and the remaining 5 at a flow rate of 5 cc/kg/min with KCl. Total coronary vascular resistance was calculated from aortic root pressure, right atrial pressure, and flow rate and expressed in units per 100 grams of cardiac tissue. At 37 degrees C, resistance was lower in the denervated arrested (1.3 +/- 0.2) than in the innervated arrested hearts (2.1 +/- 0.2) (P less than 0.001). Preservation of spontaneous electromechanical activity in the innervated hearts resulted in a lower resistance (0.4 +/- 0.1) (P less than 0.001). A progressive decrease in myocardial temperature to 15 degrees C resulted in a corresponding decrease in coronary vascular resistance to a plateau value (0.5 to 0.7 U) in all arrested groups. The data suggest that at normothermia, innervation increases vascular tone in the coronary vascular bed, while electromechanical activity decreases it.(ABSTRACT TRUNCATED AT 250 WORDS)


A focus on natural products for preventing and cure of mitochondrial dysfunction in Parkinson's disease.
Mitochondria are considered the only source of energy production within cells. This organelle is vital for neural function and survival by producing energy (adenosine triphosphate (ATP)) and regulating intracellular calcium. Mitochondrial dysfunction, which significantly contributes to both idiopathic and familial types of Parkinson's disease (PD), depletes cellular energy, disrupts homeostasis, and induces oxidative stress, leading to cell death. In recent years several natural products have been discovered to be protective against mitochondrial dysfunction. This review discusses the role of mitochondria in the progression of PD to define the path for using natural products to prevent and/or cure PD.


Drug hepatotoxicity from a regulatory perspective.
This article summarizes problems of drug-induced liver injury (DILI), as seen from the perspective of the Food and Drug Administration (FDA). After brief consideration of the scope of FDA activities and processes of new drug development and review for possible approval of products for clinical use and marketing, some of the perceived current problems in detection, confirmation, close observation, differential diagnosis, and follow-up of cases of possible DILI in controlled clinical trials are described. Readers are invited to consider possible solutions to the many problems of DILI, propose ways to support research in the field, and keep abreast of progress by visiting the web site at www.fda.gov/cder/livertox.


Simultaneous surgical management of aortic and renovascular disease.
The results of simultaneous elective infrarenal aortic reconstruction and renovascular surgery were retrospectively reviewed in 102 patients who consecutively underwent operation. The perioperative mortality rate (0 to 54 days) was 5% (5 of 102). Renal function had returned to baseline or was improved at discharge in 89 of 97 (92%) surviving patients. The intraoperative use of renal hypothermia was an independent predictor of improved postoperative renal function, by multivariate analysis. Twenty-five of 29 (86%) patients with severe hypertension had improvement in their blood pressure on the same or fewer medications postoperatively (p = 0.0005). A retroperitoneal incision was associated with less intraoperative crystalloid fluid administration (p = 0.03), more rapid postoperative resumption of an oral diet (p = 0.04), and better long-term survival (p = 0.02) when compared with a transperitoneal incision. We conclude that the simultaneous repair of infrarenal aortic pathology and renovascular lesions is associated with an acceptable perioperative morbidity and preserves or improves renal function in the majority of patients. The frequent use of renal hypothermia and careful consideration of the route of operative exposure will lead to optimal results.


Neuronal differentiation reporter mice as a new methodology for detecting in vivo developmental neurotoxicity.
Current in vivo developmental neurotoxicity (DNT) tests are not performed routinely for chemical risk assessment because they are time and resource intensive and require many animals. Therefore, new methodologies are required that can detect and evaluate the DNT potential of chemicals in a more simple, quantitative, and objective manner. Toward this end, we generated transgenic mice expressing reporter genes (luciferase and lacZ) under the control of the rat synapsin 1 promoter (Syn-Rep mice) and evaluated their usefulness as a DNT detection tool. Brain luciferase expression levels in Syn-Rep mice increased dramatically from just before to after birth, peaked early in the postnatal period, subsequently decreased sharply, and then remained low after weaning. This pattern is analogous to the generally recognized temporal changes in synapse numbers in the developing mammal brain. To evaluate further the responsiveness of Syn-Rep mice during DNT induction, we administered valproic acid (VPA), a reference DNT-inducing chemical, to pregnant mice and evaluated its effect on reporter gene expression in the developing brains of Syn-Rep pups. In vivo luminescence in the brains of VPA-exposed pups was significantly lower than in controls from postnatal days 4 to 13. Moreover, luciferase activity in the prefrontal cortexes of 8-week-old VPA-exposed offspring was significantly lower than in controls, reflecting the reduced number of neurons in the prefrontal cortex. These results suggest that the Syn-Rep mice are potentially useful tools for streamlined detection of chemical-induced DNT in the developing mammalian brain.


Atherogenic index of plasma and the risk of advanced subclinical coronary artery disease beyond traditional risk factors: An observational cohort study.
Atherogenic lipoprotein profile of plasma is an important risk factor for atherosclerosis. The atherogenic index of plasma (AIP) has been suggested as a novel marker for atherosclerosis. AIP is a useful marker of advanced subclinical coronary artery disease (CAD) in subjects without overt renal dysfunction. A total of 6928 subjects with estimated glomerular filtration rate > 60 mL/minutes/1.73 m2 evaluated by coronary computed tomography angiography (CCTA) for health check-up were included. The relation of AIP to advanced CAD (heavy coronary calcification, defined as coronary artery calcium score [CACS] >100 or obstructive coronary plaque [OCP], defined as plaque with >50% stenosis) was evaluated. All participants were stratified into four groups based on AIP quartiles. The prevalence of CACS >100 (group I [lowest] 4.7% vs group II 7.0% vs group III 8.8% vs group IV 10.0%) and OCP (group I 3.7% vs group II 6.4% vs group III 8.8% vs group IV 10.9%) (all P < .001) increased with elevating AIP quartiles. Higher AIP (per 0.1 unit increase) was associated with an increased risk of CACS >100 (odds ratio [OR] 1.057, 95% confidence interval (CI) 1.010 to 1.106, P = .017; relative risk (RR) 1.048, 95% CI 1.009-1.089, and P = .015) and OCP (OR 1.079, 95% CI 1.033-1.127, P = .001; RR 1.069, 95% CI 1.031-1.108, P < .001) after adjusting for age > 60 years, male sex, hypertension, diabetes mellitus, dyslipidaemia, obesity, and proteinuria. AIP is independently associated with advanced subclinical CAD beyond traditional risk factors.


Developmental endothelial locus-1 (Del-1) mediates clearance of platelet microparticles by the endothelium.
Phosphatidylserine-expressing microparticles circulate in blood with a short half-life of <10 minutes. We tested the role of an endothelium-derived phosphatidylserine-binding opsonin, developmental endothelial locus-1 (Del-1), in the uptake of platelet microparticles. Cultured human umbilical vein and microvascular endothelial cells avidly engulf BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)-maleimide-labeled platelet microparticles. Microparticle uptake was inhibited by a monoclonal antibody to Del-1 (P=0.027) and by annexin A5 (P=0.027), abciximab (P=0.027), a monoclonal antibody to integrin αVβ3 (P=0.027), and chlorpromazine (P=0.027). These results suggest that Del-1 mediates phosphatidylserine- and integrin-dependent endothelial uptake of microparticles by endocytosis. To assess the in vivo significance, we infused fluorescent platelet microparticles into the inferior vena cava of mice and harvested endothelial cells from the pulmonary and systemic circulation. Compared with their wild-type littermates, Del-1-deficient mice had decreased uptake in endothelial cells in lung (3.07±1.9 versus 1.09±1.3, P=0.02) and liver (2.85±1.1 versus 1.35±0.92, P=0.01). Furthermore, after endotoxin administration, Del-1-deficient mice displayed an increase in the level of microparticles compared with wild-type mice (P=0.02). These studies show a physiological role for Del-1 in the clearance of phosphatidylserine-expressing microparticles by endothelium.


Liver stiffness measurement predicts long-term survival and complications in non-alcoholic fatty liver disease.
In non-alcoholic fatty liver disease (NAFLD), fibrosis is the strongest prognostic factor and can be assessed by non-invasive methods. We evaluated the ability of liver stiffness measurement (LSM) to predict overall survival and liver, cardiovascular and oncologic complications. We prospectively collected data on 2251 consecutive NAFLD patients (mean age 59 years, male 53%, mean body mass index 28 kg/m2 ) in two centres. At inclusion, all patients had LSM, clinical and biological evaluation. During follow-up, we recorded cardiovascular events, cancers, liver complications, liver transplantation and death. The primary endpoint was overall survival. Survival curves according to LSM were first performed using Kaplan-Meier method for the primary endpoint, and Aalen-Johansen method for secondary outcomes to take into account competitive risks. In a second step, a Cox proportional hazard model analysis was done to identify independent predictors of overall survival. Median follow-up was 27 months [IQR: 25-38]. Fifty-five patients died and three patients had liver transplantation. Overall survival significantly decreased as baseline LSM increased. Twenty-one patients (0.9%) had a liver event, 142 (6.3%) developed cancer (excluding HCC) and 151 (6.7%) had a cardiovascular event during follow-up. By multivariable analysis, independent predictors of overall survival were as follows: baseline LSM (adjusted HR (aHR) = 2.85 [1.65-4.92], P = .0002), age (aHR = 1.11 [1.08-1.13], P < .0001) and male sex (aHR = 2.05 [1.17-3.57], P = .012). Patients with elevated LSM were also more likely to develop cardiovascular, and liver events but not other cancers. LSM can be used to predict survival, cardiovascular and liver complications in NAFLD patients.


[Rupture of sinus of valsalva aneurysm. Differentiation from cardiac contusion (author's transl)].
The diagnostic aspects of rupture sinus of Valsalva aneurysm are discussed. The indication for corrective surgery can only be derived by angiocardiography. Important is the demonstration of pathophysiological hemodynamics, due to the cardiovascular anomaly. The importance of echocardiographic findings in an early phase of the clinical examination is stressed.


Impact of surgical treatment of pectus carinatum on cardiopulmonary function: a prospective study.
The frequency of sternochondroplasty in cases of pectus carinatum (PC) has increased due to greater surgeon experience and modified surgical techniques. PC deformity does not usually cause cardiopulmonary malfunction or impairment. However, whether cardiopulmonary function changes after surgical repair remains a matter of controversy. The aim of our prospective study was to determine if surgery changes preoperative cardiopulmonary function. Nineteen patients (16 males, 3 females) were enrolled in a prospective, open-label, single-arm, single-centre clinical trial (Impact of Surgical Treatments of Thoracic Deformation on Cardiopulmonary Function) (NCT02163265) between July 2013 and January 2017. All patients underwent PC repair via a modified Ravitch procedure and wore a lightweight, patient-controlled chest brace for 8 weeks postoperatively (the Innsbruck protocol). The average follow-up surgical examination was 8.3 months after surgery. In all enrolled patients, before surgery and not before 6 months postoperatively chest X-ray, 3-dimensional volume-rendered computed tomography thorax imaging, cardiopulmonary function tests with stepwise cycle spiroergometry (sitting and supine position) and Doppler echocardiography were performed; questionnaires about daily physical activity were also completed. Fourteen patients (aged 16.3 ± 2.6 years at study entry) completed the study. Changes in submaximal and peak power output were not detected during sitting, or when in the supine position. Also, no clinically relevant postoperative changes in spirometry or echocardiography were noted. Our findings confirm that surgical correction of PC does not impair cardiopulmonary function at rest or during physical exercise. clinicaltrials.gov NCT02163265.


Tobacco smoke and the pulmonary alveolar macrophage.
Our results indicate that tobacco smoke exposure to varying duration causes morphological, biochemical and functional alterations in pulmonary alveolar macrophages. The results of these changes is a population of alveolar macrophages made up of larger cells, with a reduced nucleus-cytoplasmic ratio, which are heavily loaded with heterolysosomes containing lipid. Though their fractional complement of mitochondria remains the same, an increase in the inner mitochondrial membrane surface area may be related to an enhanced oxidative metabolism. The cell is biochemically activated particularly following chronic exposure and is functionally impaired with respect to phagocytosis.


Influence of spatial characteristics of green spaces on microclimate in Suzhou Industrial Park of China.
Continuous urban development leads to urban heat island effects. Research suggests that urban green spaces can help effectively reduce urban heat island effects in the summer. Previous studies have mainly focused on the influence of different underlying surfaces on air cooling and humidification. There is a lack of in-depth research on the relationship between park structure and microclimatic effects. Here, we examined the main landscape parameters of green spaces in 15 parks located in Suzhou Industrial Park (SIP) with a subtropical maritime monsoon climate zone during the summer to analyze their influence on the microclimate. We adopted a multiple regression method to perform a quantitative analysis of the correlation between the factors and the cooling and humidifying effects. We used one-way ANOVA (analysis of variance) and multiple linear regression statistical analysis methods to study the influence of woodland density and water bodies on the microclimatic effect of the green areas. The result shows that the average cooling and humidifying effect of medium-size green spaces was most significant during high-temperature hours in the daytime. Also, the result shows that the shape and size of water areas within a green space have a significant influence on local cooling and humidification.


Failure of normal osteoclasts to resorb calcified cartilage from osteosclerotic (oc/oc) mice in vitro.
Osteosclerosis is an osteopetrotic mutation in the mouse characterized by reduced bone resorption, numerous small osteoclasts lacking elaborate ruffled borders, and resistance to cure by bone marrow transplants from normal littermates. The failure of osteosclerotic mice to be cured by bone marrow transplants could be due to the production of bone that is not resorbable by normal osteoclasts. We tested this hypothesis using a modification of the metatarsal organ culture system of Burger et al. (1982), in which metatarsals are cultured with various tissues that act as sources of osteoclast precursors. Metatarsals from neonatal mutants were isolated, and live bone rudiments were cultured with small cubes of liver or spleen from normal littermates for 7 days. Controls included normal and mutant metatarsals cultured alone or with spleen or liver from littermates of the same or different genotype. Mutant metatarsals cultured alone or with mutant tissue had small osteoclasts, no marrow spaces, and no evidence of bone resorption. Mutant metatarsals cultured with normal liver or spleen had larger osteoclasts, evidence of resorption of bone but not cartilage, and no marrow spaces because the calcified cartilage cores of metaphyseal trabeculae persisted. Normal metatarsals cultured with normal liver had large osteoclasts, bone resorption, and marrow spaces. By transmission EM, mutant trabeculae contained a layer of amorphous material between the central core of calcified cartilage and the surrounding bone matrix. This material was not present in normal metatarsals.(ABSTRACT TRUNCATED AT 250 WORDS)


Dual Mechanism of a New SMN1 Variant (c.835G>C, p.Gly279Arg) by Interrupting Exon 7 Skipping and YG Oligomerization in Causation of Spinal Muscular Atrophy.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by deletion or subtle variant of survival motor neuron 1 (SMN1) gene. By multiplex ligation-dependent probe amplification, genomic sequencing, and T-A cloning on cDNA level, we identified one novel SMN1 subtle variant c.835G>C (p.Gly279Arg) in a non-homozygous patient with type 1 SMA. Full-length SMN1 (fl-SMN1) transcripts in the peripheral bloods of the patient were significantly decreased compared with those in healthy individuals and the carries (p < 0.05). And two fragments of SMN1 transcripts including fl-SMN1 and △7-SMN1 were observed by RT-PCR, which indicated Exon 7 skipping of SMN1 gene. To further evaluate its splicing effects on Exon 7, we performed ex vivo splicing analysis, which showed that the mutant mini gene with c.835G>C reduced Exon 7 inclusion to 54%. In addition, self-oligomerization between mutant SMN protein with the c.835G>C (p.Gly279Arg) and wild SMN was decreased in self-interaction assays. Our study clearly demonstrates that the c.835G>C (p.Gly279Arg) variant can lead to a decrease in fl-SMN1 transcripts by interrupting correct splicing of SMN1. What is more, the variant also affects SMN self-oligomerization via amino acid substitution from Gly to Arg at amino acid position of 279. This work presents the first evidence that it does exit double-hit events for the novel variant, which is crucial to understanding a severe SMA phenotype (type 1).


Loneliness in monkeys: Neuroimmune mechanisms.
Loneliness, or perceived social isolation, may be evident in any group-living species, although its assessment in nonhumans provides some measurement challenges. It is well-known that loneliness in humans confers significant risk for morbidity and mortality, although mechanisms remain unclear. The authors describe a naturally-occurring model of loneliness in adult male rhesus monkeys that shows many parallels with the phenomenon in humans. Lonely monkeys (those that display high frequencies of social initiations but low frequencies of complex interaction) show elevated sympathetic nervous system activity and down regulated Type I interferon responses. Analysis of data from simian immunodeficiency virus-infected monkeys indicates that these physiological changes have functional consequences. Use of this animal model can help identify mechanisms by which loneliness impacts health.


Simple and rapid instrumental characterization of sensory attributes of virgin olive oil based on the direct coupling headspace-mass spectrometry.
A methodology for obtaining reliable qualitative and quantitative information about negative (fusty, muddy sediment, musty, rancid and vinegary) and positive (fruity) sensory attributes of virgin olive oils (lampante and extra) has been developed. The procedure implies the joint use of a headspace autosampler, a mass spectrometer and an adequate chemometric data treatment. For this purpose, soft independent modelling of class analogy (SIMCA) and partial least squares (PLS) regression approaches were used for attribute identification and quantification, respectively. InStep application was employed to generate a decision tree by the combination of both models in order to provide the joint prediction of the sensory attributes of a given virgin olive oil and their respective intensities by means of a single output result. The good prediction results obtained when the decision tree generated were applied to a new set of virgin olive oil samples (viz, a specificity of 100%, an average sensitivity of 86% and a RMSEP<0.8% in the quantification task) reveals its potential applicability in routine analysis.


Amide side chain amphiphilic polymers disrupt surface established bacterial bio-films and protect mice from chronic Acinetobacter baumannii infection.
Bacterial biofilms represent the root-cause of chronic or persistent infections in humans. Gram-negative bacterial infections due to nosocomial and opportunistic pathogens such as Acinetobacter baumannii are more difficult to treat because of their inherent and rapidly acquiring resistance to antibiotics. Due to biofilm formation, A. baumannii has been noted for its apparent ability to survive on artificial surfaces for an extended period of time, therefore allowing it to persist in the hospital environment. Here we report, maleic anhydride based novel cationic polymers appended with amide side chains that disrupt surface established multi-drug resistant A. baumannii biofilms. More importantly, these polymers significantly (p < 0.0001) decrease the bacterial burden in mice with chronic A. baumannii burn wound infection. The polymers also show potent antibacterial efficacy against methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococci (VRE) and multi-drug resistant clinical isolates of A. baumannii with minimal toxicity to mammalian cells. We observe that optimal hydrophobicity dependent on the side chain chemical structure of these polymers dictate the selective toxicity to bacteria. Polymers interact with the bacterial cell membranes by causing membrane depolarization, permeabilization and energy depletion. Bacteria develop rapid resistance to erythromycin and colistin whereas no detectable development of resistance occurs against these polymers even after several passages. These results suggest the potential use of these polymeric biomaterials in disinfecting biomedical device surfaces after the infection has become established and also for the topical treatment of chronic bacterial infections.


Successful venous repair and reconstruction for oncologic resections.
We report our institutional experience of various venous reconstruction methods during oncologic resections, especially examining the patency of venous reconstructions and the conduits used. All patients undergoing venous repair or reconstruction for oncologic resections between 2008 and 2014 were identified by a retrospective search of a prospectively maintained database at a single university hospital. Extent and manner of venous reconstruction and conduit or patch material were recorded. Need for intraoperative venovenous bypass or cardiopulmonary bypass was also recorded. Whereas no prescribed follow-up protocol has been instituted, patency and survival data as available were analyzed. During the study period, 127 patients were identified. Five patients had primary ligations, without limb loss. Of the remaining 122 patients, 77 (63%) underwent primary repairs, 23 (19%) had patch repair, and 22 (18%) had bypasses. Of these, 27 (22%) were for portal vein reconstruction during a Whipple procedure, 47 (39%) were for caval repair during caval thrombectomy in the setting of renal cell cancer, and 28 (23%) were for caval repair during resection for other abdominal malignant neoplasms. Venovenous bypass was used in 16 repairs and cardiopulmonary bypass in 10. The 1-year patency rates were 100% for primary and patch repairs and 86% for bypass graft reconstructions. Occlusions were suffered only in the prosthetic grafts group. There was no limb loss or significant long-term morbidity in patients with occluded grafts. Rate of infection was 0%, and there was no evidence of an increased infection rate in prosthetic or bioprosthetic conduits or patches. Perioperative mortality was 5.5%. Overall, venous reconstruction for oncologic resection can be done safely with very low complication rates and low perioperative mortality. Prosthetic grafts can be used for most reconstructions with no infections and good patency rates.


Chromosome aberrations in workers at a tannery in Iraq.
Blood samples were collected from 17 healthy chromium-exposed workers at a tanning plant near Baghdad city and 13 controls matched for age, period of service and social background. For each individual more than 100 lymphocyte metaphases were examined. The results showed no significant differences in the per cell frequencies of chromatid and isochromatid gaps, single chromatid breaks, various chromosome-type aberrations and all aberrations combined. However, smoking workers exhibited statistically higher frequency of chromosome-type aberrations than non-smoking workers and smoking controls.


In vitro natural killer activity against progressive and regressive variants of a rat colon adenocarcinoma. Effect of treatments with anti-asialo GM1 plus complement.
In a previous work, a cell line (DHD/K12) was established from a colon adenocarcinoma induced in a BDIX rat by 1,2-dimethylhydrazine. From this line, two cloned sublines, PROb and REGb, were then isolated. When subcutaneously inoculated into syngeneic rats, PROb cells yield progressive tumors, whereas REGb cells yield tumors which regress. In this study, in a 16-h 51Cr release assay, natural cytotoxicity mediated by BDIX splenic nonadherent lymphoid cells (NK cells) was shown to be much higher against REGb cells than against PROb cells. Whatever the target cells, NK cytotoxicity was always higher when the effector cells were obtained from males rather than from females. Treatment of BDIX splenic lymphocytes by anti-asGM1 serum plus complement revealed that both anti-asGM1 sensitive and non-sensitive NK cells exist. The activity of anti-asGM1 non-sensitive NK cells appeared to be minor and to be detected only when the level of cytotoxicity before treatment was sufficiently high. The difference between PROb and REGb tumor growth appears to be linked, at least in part, to a higher sensitivity of REGb cells to NK cells and especially to anti-asGM1-sensitive NK cells.


Patients With Suspected Severe Adverse Reactions to COVID-19 Vaccination Admitted to Intensive Care Unit: A Case Report.
Several cases of adverse reactions following vaccination for coronavirus disease 2019 (COVID-19) with adenoviral vector vaccines or mRNA-based vaccines have been reported to date. The underlying syndrome has been named "vaccine-induced immune thrombotic thrombocytopenia" (VITT) or "thrombosis with thrombocytopenia syndrome (TTS)" with different clinical manifestations. We report the clinical course of five patients who had severe adverse reactions to COVID-19 vaccines, either with VITT/TTS, abdominal or pulmonary thrombosis after adenoviral vaccines, or Stevens' Johnson syndrome because of mRNA vaccination, all of whom required admission to the intensive care unit (ICU). All patients with severe or life-threatening suspected reaction to different types of COVID-19 vaccination required ICU admission. A prompt evaluation of early symptoms and individualized clinical management is needed to improve outcomes.


Nucleotide sequence of complementary DNA encoding for quaking protein of cow, horse and pig.
Complementary DNA (cDNA) for bovine quaking gene (Bqk), equine quaking gene (Eqk) and porcine quaking gene (Pqk), which are homologous to mouse quaking gene (qkI), were isolated, and their nucleotide sequences were determined. cDNA sequences of Bqk, Eqk and Pqk showed very high homology to that of qkI at nucleotide level; 94.2, 95.7 and 95.6%, respectively. Deduced amino acid sequences for Bqk, Eqk and Pqk perfectly matched to that of qkI. These findings suggest that the quaking gene family is highly conserved during mammalian evolution, and that Bqk, Eqk and Pqk are likely to have important biological functions also in cow, horse and pig.


Mast cells have no impact on cutaneous leishmaniasis severity and related Th2 differentiation in resistant and susceptible mice.
The genus leishmania comprises different protozoan parasites which are causative agents of muco-cutaneous and systemic, potentially lethal diseases. After infection with the species Leishmania major, resistant mice expand Th1 cells which stimulate macrophages for Leishmania destruction. In contrast, susceptible mice generate Th2 cells which deactivate macrophages, leading to systemic spread of the pathogens. Th-cell differentiation is determined within the first days, and Th2 cell differentiation requires IL-4, whereby the initial IL-4 source is often unknown. Mast cells are potential sources of IL-4, and hence their role in murine leishmaniasis has previously been studied in mast cell-deficient Kit mutant mice, although these mice display immunological phenotypes beyond mast cell deficiency. We therefore readdressed this question by infecting Kit-independent mast cell-deficient mice that are Th1 (C57BL/6 Cpa(Cre) ) or Th2 (BALB/c Cpa(Cre) ) prone with L. major. Using different parasite doses and intra- or subcutaneous infection routes, the results demonstrate no role of mast cells on lesion size development, parasite load, immune cell phenotypes expanding in draining lymph nodes, and cytokine production during murine cutaneous leishmaniasis. Thus, other cell types such as ILCs or T cells have to be considered as primary source of Th2-driving IL-4.


Limitaciones de los estudiantes en el curso de cirugía de pregrado durante la pandemia de COVID-19.
To know the limitations that the students encountered during the undergraduate surgery course during COVID-19 pandemic. Through an online questionnaire, students were asked about the evaluation of the undergraduate surgery course, the limitations encountered during the course, both those perceived by themselves, and the limitations they perceived in teachers. Questions were asked about the total evaluation of the surgery course and the clinical part of the course. 63 students of the subject of surgery were included. The most mentioned limitations of the students were the availability of schedule and teaching material. The most mentioned limitation in relation to the teachers was the lack of technical knowledge. A relationship was found between the evaluation of the course and the interaction between the teacher and the student. The medical education have undergone great changes, especially the clinical part. There are several limitations in this process that can be improved by teachers and students and the perception of the quality of the course is related to the degree of interaction that teachers had with the students.


The effect of taurine on chronic heart failure: actions of taurine against catecholamine and angiotensin II.
Taurine, a ubiquitous endogenous sulfur-containing amino acid, possesses numerous pharmacological and physiological actions, including antioxidant activity, modulation of calcium homeostasis and antiapoptotic effects. There is mounting evidence supporting the utility of taurine as a pharmacological agent against heart disease, including chronic heart failure (CHF). In the past decade, angiotensin II blockade and β-adrenergic inhibition have served as the mainstay in the treatment of CHF. Both groups of pharmaceutical agents decrease mortality and improve the quality of life, a testament to the critical role of the sympathetic nervous system and the renin--angiotensin system in the development of CHF. Taurine has also attracted attention because it has beneficial actions in CHF, in part by its demonstrated inhibition of the harmful actions of the neurohumoral factors. In this review, we summarize the beneficial actions of taurine in CHF, focusing on its antagonism of the catecholamines and angiotensin II.


Development and internal validation of a nomogram for predicting stone-free status after flexible ureteroscopy for renal stones.
To develop and internally validate a preoperative nomogram for predicting stone-free status (SF) after flexible ureteroscopy (fURS) for renal stones, as there is a need to predict the outcome of fURS for the treatment of renal stone disease. We retrospectively analysed 310 fURS procedures for renal stone removal performed between December 2009 and April 2013. Final outcome of fURS was determined by computed tomography 3 months after the last fURS session. Assessed preoperative factors included stone volume and number, age, sex, presence of hydronephrosis and lower pole calculi, and ureteric stent placement. Multivariate logistic regression analysis with backward selection was used to model the relationship between preoperative factors and SF after fURS. Bootstrapping was used to internally validate the nomogram. Five independent predictors of SF after fURS were identified: stone volume (P < 0.001), presence of lower pole calculi (P = 0.001), operator with experience of >50 fURS (P = 0.026), stone number (P = 0.075), and presence of hydronephrosis (P = 0.047). We developed a nomogram to predict SF after fURS using these five preoperative characteristics. Total nomogram score (maximum 25) was derived from summing individual scores of each predictive variable; a high total score was predictive of successful fURS outcome, whereas a low total score was predictive of unsuccessful outcome. The area under the receiver operating characteristics for nomogram predictions was 0.87. The nomogram can be used to reliably predict SF based on patient characteristics after fURS treatment of renal stone disease.


Quantitative analysis of cefquinome considering different matrix compositions of bovine colostrum and raw milk.
A robust liquid chromatography-tandem mass spectrometry method was developed and comprehensively validated for the quantification of cefquinome considering the changing matrix composition from bovine colostrum to raw milk. Sample preparation consisted of addition of isotopically labeled cefquinome internal standard prior to protein precipitation of 2 g colostrum or milk followed by solid-phase extraction. A wide concentration range from 1 to 5000 ng cefquinome per gram of colostrum or milk was quantified using a 3200 QTRAP tandem mass spectrometer in positive ionization mode with electrospray ionization. Validation was performed according to the European Commission Decision 2002/657/EC guidelines. Matrix-comprehensive in-house validation included analytical limits CCα and CCβ, recovery, precision and calibration curves with prediction intervals, storage conditions, and evaluation of robustness based on factorial effect analysis. The detection limit was 0.2 ng cefquinome per gram of colostrum or milk. Recovery was between 98.4 and 99.4% for cefquinome concentrations from 4 to 240 ng/g. None of the investigated validation factors (matrix, storage of extracts, lot of SPE cartridges, and operators) exerted an influence higher than ± 3.2%, indicating that these factors make relatively low contributions to the respective combined measurement uncertainties. The comprehensively validated method enables routine residue control purposes and to monitor the pharmacokinetics of cefquinome in bovine colostrum and raw milk. In particular, residue depletion curves of cefquinome from high concentrations in first milking after treatment to concentrations far below the maximum residue limit can be measured.


Identification of valid endogenous control genes for determining gene expression in C6 glioma cell line treated with conditioned medium from adipose-derived stem cell.
There is growing evidence that mesenchymal stem cells (MSCs) can be important players in the tumor microenvironment. They can affect the glioma progression through the modulation of different genes. This modulation can be evaluated through a very useful model, treating the tumor cells with MSC-conditioned medium. However, for an accurate and reliable gene expression analysis, normalization of gene expression data against reference genes is a prerequisite. We performed a systematic review in an attempt to find a reference gene to use when analyzing gene expression in C6 glioma cells lines. Considering that we were not able to find a reference gene originated by an appropriate validation, in this study we evaluated candidate genes to be used as reference gene in C6 cells under different treatments with adipose-derived stem cells conditioned medium (CM-ADSCs). β-actin (ACTB); glyceraldehyde-3-phosphate dehydrogenase (GAPDH); hypoxanthine-guanine phosphoribosyltransferase I (HPRT-1); TATA box binding protein (TBP) and beta-2-microglobulin (B2M) were evaluated by real-time reverse transcription PCR (RT-qPCR). The mean Cq, the maximum fold change (MFC) and NormFinder software were used for reference gene evaluation and selection. The GAPDH and ACTB genes have been the most widely used reference genes to normalize among the different investigated genes in our review, however, controversially these genes underwent a substantial variability among the genes evaluated in the present work. Individually, TBP gene was more stable when compared with other genes analyzed and the combination of TBP and HPRT-1 was even more stable. These results evidence the importance of appropriate validation of reference genes before performing qPCR experiments. Besides, our data will contribute with researchers that work analyzing the role of ADSCs in glioma microenvironment through gene expression.


Healthcare utilization and outcomes of spinal cord injured veterans with stage 3-4 pressure injuries.
Pressure injuries (PI) are a significant source of morbidity for individuals with spinal cord injury/disease (SCI/D). They are also associated with significant healthcare resource utilization including prolonged hospitalizations. However, the long-term outcomes in terms of wound recurrence-free survival, hospital readmission rates, and all-cause mortality in this population remain largely unknown. To examine the clinical characteristics, healthcare utilization and outcomes of SCI Veterans hospitalized at the VA North Texas Health Care System (VANTHCS) SCI inpatient unit with stage 3 and 4 PI, and compare these between those who received a myocutaneous flap surgery (flap patients (FP)) and those treated medically (non-flap patients (NFP)). A retrospective chart review was conducted of all adult patients admitted to the VANTHCS SCI/D unit with stage 3 or 4 pelvic PI between 1/1/2013 and 12/31/2018. Healthcare utilization and outcome information was extracted for pre-specified time points. 78 patients met criteria (113 hospitalizations; 27 FP; 51 NFP). Average length of stay (LOS) was 122 days; FP had a significantly higher LOS than NFP (P = 0.01). Average number of consults was 24. Estimated cost per hospitalization was $175,198. Readmission rate within 30 days was 12.39%. The mortality rate within 1 year of discharge was 21.57% for NFP, as opposed to 3.70% in the FP group. Only 5.00% of NFP wounds were healed at discharged with sustained healing at 1 year, significantly less than FP wounds (55.26%, P < 0.01). Despite the high investment in terms of healthcare utilization, outcomes in terms of wound healing are poor. Additionally, nearly 22% of NFP died within one year of discharge. This calls into question the utility of prolonged hospitalizations for PI in the SCI/D population in terms of wound treatment efficacy, healthcare costs, and patient morbidity/mortality.


The POSH/JIP-1 scaffold network regulates TCR-mediated JNK1 signals and effector function in CD8(+) T cells.
Signals from the T-cell recognition of antigen program effector functions are necessary to clear infections and tumors. The JNK pathway is critically important in regulating this process. In T lymphocytes, JNK1 and JNK2 have distinct functions depending on their maturation state and cell-type. However, the mechanisms that regulate their isoform-specific activity and function are still unclear. Here, we identify plenty of SH3 (POSH) and JNK-interacting protein 1 (JIP-1) as a multiprotein scaffold network for TCR-mediated JNK1 activation in CD8(+) T cells. Disruption of the POSH/JIP-1 complex led to profound defects in the activation of JNK1, as well as deficient activation or induction of the transcription factors c-Jun, T-bet, and Eomesodermin. Furthermore, disruption of the POSH/JIP complex in CD8(+) T cells resulted in impaired proliferation, decreased cytokine expression, and the inability to control tumors. Collectively, these data identify a mechanism for the specific regulation of TCR-dependent JNK1 activation and function that is key for CD8(+) T-cell responses.


Development of the Prevent for Work Questionnaire (P4Wq) for the assessment of musculoskeletal risk factors in the workplace: part 2-pilot study for questionnaire development and validation.
The aim of this study was to develop a multifactorial, self-report questionnaire: Prevent for Work Questionnaire (P4Wq). The questionnaire is intended for screening for risk factors in work-related musculoskeletal disorders (WMSDs). Data were collected from otherwise healthy workers employed in three service areas at a specialist hospital in Italy: healthcare, administration and ancillary services. In all, 115 participants were enrolled (67% women; average age 41.5±9.94 years). The content of the tool for WMSDs was derived from three participation rounds of analysis involving a select group of experts who identified the questionnaire domains and items. Participants responded to 89 items in addition to the EuroQol 5 Dimensions Questionnaire (EQ-5D-5L), Fear-Avoidance Beliefs Questionnaire (FABq) and Oswestry Disability Index (ODI). The proportion of missing data and the distribution of responses were analysed for each item. Items with a discrimination index >0.40 and an interitem correlation <0.80 were retained. Factor analysis was performed using the VARIMAX rotation method, factor extraction, and identification, assignment of items to subscales, and assignment of scores to items. Internal consistency, reliability, construct validity and face validity were also assessed. A total of 52 items were included in the factor analysis and four subscales identified: Physical Stress Subscore (six items); Mental Stress Subscore (six items); Job Satisfaction Subscore (four items) and Kinesiophobia/Catastrophizing Subscore (four items). The items in the final questionnaire version had a factor loading >0.7. The questionnaire consisted of 20 items with good internal consistency (Cronbach's alpha 0.81-0.91), reliability (weighted kappa coefficient 0.617-1.00), good construct validity (EQ-5D-5L, r=-0.549, p<0.001; ODI, r=0.549, p<0.001; FABq work, r=0.688, p<0.001) and satisfactory face validity (universal validity index 96.04%). The P4Wq is a 20-item, multifactorial self-report risk assessment questionnaire. It may provide a useful tool for screening for WMSDs by specifically addressing back disorders. It investigates risks for individual workers and may inform educational programmes and preventive strategies tailored to a worker's needs. NCT04192604.


Cancer as a complex genetic trait: tumor susceptibility in humans and mouse models.
Cancer directly affects at least one-third of the human population, but the inherited genetic determinants of cancer risk remain largely unknown. Mouse models of human cancer are helping us to understand this disease as a complex genetic trait and thus to identify the multiple genetic variant alleles involved in pathways that affect individual cancer susceptibility.


Respiratory depression in a patient receiving oral methadone for cancer pain.
Methadone is a synthetic opioid with excellent oral bioavailability, variable, but long duration of action and extremely low cost. Our group has found that methadone is well tolerated in patients with difficult pain syndromes who are receiving high dose opioids. However, because of high interpersonal variation in bioavailability and the long duration of action of this drug, treatments should be highly personalized. We report on a 61 year old cancer patient who was switched from 84 mg/day of subcutaneous hydromorphone to 90 mg/day of oral methadone. On this dose, she developed respiratory depression and non-cardiogenic pulmonary edema that responded to subcutaneous naloxone and methadone discontinuation. Our findings suggest that standard equalanalgesic tables are unreliable for methadone titration. Switchovers should take place slowly and in a personalized fashion.


Massachusetts Substance Use Disorder Treatment Organizations' Perspectives on the Affordable Care Act: Changes in Payment, Services, and System Design.
The Affordable Care Act (ACA) expanded insurance benefits and coverage for substance use disorder (SUD) treatment and encouraged delivery and payment reforms. Massachusetts passed a similar reform in 2006. This study aims to assess Massachusetts SUD treatment organizations' responses to the ACA. Organizational interviews addressing challenges of and responses to the ACA were conducted in person June-December 2014 with 31 leaders at 12 treatment organizations across Massachusetts. Many organizations were affiliated with medical or social services and offered a range of SUD services. Sampling was based on services offered (detoxification only, detoxification and outpatient, outpatient only). Framework analysis was used. Challenges identified were considered similar to ongoing challenges, not unique to the ACA. Organizations experienced insurance expansions in 2006 and faced new challenges, including insurance coverage, payment arrangements, expansion of services, and system design. System design efforts included care coordination/integration, workforce development, and health information technology. Differences in responses related to connections with medical and social service organizations. Many organizations engaged in efforts to respond to changing policies by expanding capacity and services. Offering a range of SUD treatment (e.g., detoxification and outpatient) and affiliating with a medical organization could enable organizations to respond to new insurance, delivery, and payment reforms.


Cross-reactive immune responses to monkeypox virus induced by MVA vaccination in mice.
Mpox (monkeypox) infection cases increased recently in non-Mpox outbreak areas, potentially causing an international threat. The desire to defend against a potential outbreak has led to renewed efforts to develop Mpox vaccines. In this report, mice were immunized with various doses of modified vaccinia virus Ankara (MVA) to evaluate the cross-reactive immune response of MVA immunization against protective antigens of the current monkeypox virus. We demonstrated that MVA induced specific antibodies against protective antigens (A29, A35, B6, M1, H3, and I1), mediating the neutralization abilities against the MVA and the monkeypox virus (MPXV). Moreover, recombinant protective antigens of the MPXV elicited cross-binding and cross-neutralizing activities for MVA. Hence, the MVA induced cross-reactive immune responses, which may guide future efforts to develop vaccines against the recent MPXV. Notably, compared to the other protective antigens, the predominant A29 and M1 antigens mediated higher cross-neutralizing immune responses against the MVA, which could serve as antigen targets for novel orthologous orthopoxvirus vaccine.


Environmental Risk Factors of Pediatric-Onset Primary Sclerosing Cholangitis and Autoimmune Hepatitis.
The aim of this population-based observational case-control questionnaire study was to investigate the possible role of environmental risk factors associated with pediatric-onset autoimmune liver diseases. Seventy-one patients with autoimmune liver diseases (<16 years) received a questionnaire with 22 items, evaluating contact with environmental factors (eg, family manners, type of housing, pets) before the diagnosis. Two age- and sex-matched control groups were used: inflammatory bowel disease (IBD; n = 91) and healthy subjects (n = 716; matched also for place of residence at birth). Univariate analysis (odds ratio [OR] and 95% confidence interval) for all variables was calculated. Fisher exact test was performed to depict associations between variables and the multivariate logistic regression to test their interactions. In the final analyses, the responses of 51 autoimmune liver diseases cases (n = 51/71, 72%), 59 IBD controls (n = 59/91, 65%), and 292 healthy controls (n = 292/716, 41%) were investigated. In univariate analysis only having a cat, a dog, and a cat or a dog were risk factors of autoimmune liver diseases (OR varying between 2.6-3.4); no other significant associations (eg, place of residence, number of siblings, family manners) were found. Multivariate logistic regression analyses showed that especially living with a cat in block of flats was a risk factor (OR 3.6, 1.2-10.8). Living in a close contact with a pet (especially a cat) was a risk factor of autoimmune liver diseases. This finding may suggest an involvement of an unidentified agent (ie, toxin/microbe) among the triggers of these diseases.


A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stage IA1 with LVSI, IA2): study protocol of the LAUNCH 1 trial.
A retrospective study and a randomized controlled trial published in a high quality journal in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology, therefore this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stage IA1 with LVSI, IA2) patient survival under stringent operation standards and consistent tumor-free technique. This paper reports the rationale, design, and implementation of the trial. This is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 690 patients with stage IA1 (with intravascular), and IA2 cervical cancer will be enrolled over a period of three years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed-up for at least five years. The primary endpoint will be 5-year progression-free survival. Secondary endpoints will include 5-year overall survival rates, recurrence rates, operation time, intraoperative blood loss, surgery-related complications, and quality of life. The results of the trial will provide valuable evidence for guiding clinical decision of choosing appropriate treatment strategies for stage IA1 (LVSI) and stage IA2 cervical cancer patients. ClinicalTrials.gov ( NCT04934982 , Registered on 22 June 2021).


Osseous choristoma of an extraocular muscle.
Osseous choristoma is a benign lesion defined as normal osseous proliferative tissue in an ectopic site. We report what we believe to be the first osseous choristoma to replace extraocular muscle.


Comparison of various serological assays for novel SARS-COV-2.
Coronavirus disease-19 (COVID19), the novel respiratory illness caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), is associated with severe morbidity and mortality. The aim of our study was to compare different immunoassays. We evaluated three immunochromatographic test (The StrongStep®SARS-CoV-2 IgG/IgM kit, AllTest COV-19 IgG/IgM kit, and Wondfo® SARS-CoV-2 Antibody) and two chemiluminescence immunoassays (CMIA) (Covid-19 VIRCLIA® IgM+IgA/IgG monotest and the Abbott SARS-CoV-2 IgG assay) in COVID-19 patients. The assays were performed using serum samples of three group patients, i.e., healthy controls, patients with SARS-CoV-2 PCR positive, and patients with SARS-CoV-2 PCR negative clinically diagnosed of COVID-19 infection. The detection percentages of IgG with the StrongStep® SARS-CoV-2 IgG/IgM kit and AllTest COV-19 IgG/IgM kit were similar in both groups (83.3% and 80.6%, respectively in group 2, p = 0.766) and (42.9% and 50.0%, respectively in group 3, p = 0.706). There were some differences on IgM detection between StrongStep® SARS-CoV-2 IgG/IgM kit and AllTest COV-19 IgG/IgM kit (11.1% and 30.6%, respectively in group 2, p = 0.042 and 0.0% and 28.6%, respectively in group 3, p = 0.031). The positive rate of IgG in group 2 is higher compared to group 3 with the two immunoassays tested. We observe the same positive rates of IgG with the two CMIA. Our study shows excellent performance of CMIA compared to immunochromatographic test and confirms its potential use in the diagnosis of the new SARS-CoV-2.