Setting performance-based financing in the health sector agenda: a case study in Cameroon.
More than 30 countries in sub-Saharan Africa have introduced performance-based financing (PBF) in their healthcare systems. Yet, there has been little research on the process by which PBF was put on the national policy agenda in Africa. This study examines the policy process behind the introduction of PBF program in Cameroon. The research is an explanatory case study using the Kingdon multiple streams framework. We conducted a document review and 25 interviews with various types of actors involved in the policy process. We conducted thematic analysis using a hybrid deductive-inductive approach for data analysis. By 2004, several reports and events had provided evidence on the state of the poor health outcomes and health financing in the country, thereby raising awareness of the situation. As a result, decision-makers identified the lack of a suitable health financing policy as an important issue that needed to be addressed. The change in the political discourse toward more accountability made room to test new mechanisms. A group of policy entrepreneurs from the World Bank, through numerous forms of influence (financial, ideational, network and knowledge-based) and building on several ongoing reforms, collaborated with senior government officials to place the PBF program on the agenda. The policy changes occurred as the result of two open policy windows (i.e. national and international), and in both instances, policy entrepreneurs were able to couple the policy streams to effect change. The policy agenda of PBF in Cameroon underlined the importance of a perceived crisis in the policy reform process and the advantage of building a team to carry forward the policy process. It also highlighted the role of other sources of information alongside scientific evidence (eg.: workshop and study tour), as well as the role of previous policies and experiences, in shaping or influencing respectively the way issues are framed and reformers' actions and choices.


Dopamine D4 receptor stimulation contributes to novel object recognition: Relevance to cognitive impairment in schizophrenia.
Several atypical antipsychotic drugs (APDs) have high affinity for the dopamine (DA) D4 receptor, but the relevance to the efficacy for the treatment of cognitive impairment associated with schizophrenia (CIAS) is poorly understood. The aim of this study was to investigate the effects of D4 receptor stimulation or blockade on novel object recognition (NOR) in normal rats and on the sub-chronic phencyclidine (PCP)-induced novel object recognition deficit. The effect of the D4 agonist, PD168077, and the D4 antagonist, L-745,870, were studied alone, and in combination with clozapine and lurasidone. In normal rats, L-745,870 impaired novel object recognition, whereas PD168077 had no effect. PD168077 acutely reversed the sub-chronic phencyclidine-induced novel object recognition deficit. Co-administration of a sub-effective dose (SED) of PD168077 with a sub-effective dose of lurasidone also reversed this deficit, but a sub-effective dose of PD168077 with a sub-effective dose of clozapine, a more potent D4 antagonist than lurasidone, did not reverse the sub-chronic phencyclidine-induced novel object recognition deficit. At a dose that did not induce a novel object recognition deficit, L-745,870 blocked the ability of clozapine, but not lurasidone, to reverse the novel object recognition deficit. D4 receptor agonism has a beneficial effect on novel object recognition in sub-chronic PCP-treated rats and augments the cognitive enhancing efficacy of an atypical antipsychotic drug that lacks affinity for the D4 receptor, lurasidone.


Dose calculation and treatment plan optimization including imaging dose from kilovoltage cone beam computed tomography.
With the increasing use of cone beam computed tomography (CBCT) for patient position verification and radiotherapy treatment adaptation, there is an increasing need to develop techniques that can take into account concomitant dose using a personalized approach. A total of 20 patients (10 pelvis and 10 head and neck) who had undergone radiation therapy using intensity modulated radiation therapy (IMRT) were selected and the dose from kV CBCT was retrospectively calculated using a treatment planning system previously commissioned for this purpose. The imaging dose was added to the CT images used for treatment planning and the difference in its addition prior to and after the planning was assessed. The additional isocenter dose as a result of daily CBCT is in the order of 3-4 cGy for 35-fraction head and neck and 23-47 cGy for 25-fraction pelvis cases using the standard head and neck and pelvis image acquisition protocols. The pelvic dose is especially dependent on patient size and body mass index (BMI), being higher for patients with lower BMI. Due to the low energy of the kV CBCT beam, the maximum energy deposition is at or near the surface with the highest dose being on the patient's left side for the head and neck (∼7 cGy) and on the posterior for the pelvic cases (∼80 cGy). Addition of imaging dose prior to plan optimization resulted in an average reduction of 4% in the plan monitor units and 5% in the number of control points. Dose from daily kV CBCT has been added to patient treatment plans using previously commissioned kV CBCT beams in a treatment planning system. Addition of imaging dose can be included in IMRT treatment plan optimization and would facilitate customization of imaging protocol based on patient anatomy and location of isocenter.


Treatment of RO brine-towards sustainable water reclamation practice.
Treatment and disposal of RO brine is an important part in sustaining the water reclamation practice. RO brine generated from water reclamation contains high concentration of organic and inorganic compounds. Cost-effective technologies for treatment of RO brine are still relatively unexplored. Thus, this study aim to determine a feasible treatment process for removal of both organic and inorganic compounds in RO brine generated from NEWater production. The proposed treatment consists of biological activated carbon (BAC) column followed by capacitive deionization (CDI) process for organic and inorganic removals, respectively. Preliminary bench-scale study demonstrated about 20% TOC removal efficiency was achieved using BAC at 40 mins empty bed contact time (EBCT) while the CDI process was able to remove more than 90% conductivity reducing it from 2.19 mS/cm to only about 164 microS/cm. More than 90% cations and anions in the BAC effluent were removed using CDI process. In addition, TOC and TN removals of 78% and 91%, respectively were also attained through this process. About 90% water recovery was achieved. This process shows the potential of increased water recovery in the reclamation process while volume for disposal can be further minimized. Further studies on the sustainable operation and process optimization are ongoing.


The effect of push factors in the leisure sports participation of the retired elderly on re-socialization recovery resilience.
This study aimed to provide useful materials for the realization of healthy and happy welfare society through the re-socialization of the retired elderly by identifying the effect of the push factors in the leisure sports participation of the retired elderly on re-socialization and recovery resilience. To achieve the study purpose, 304 subjects over the age of 55 residing in Seoul and Gyeonggin among the retired elderly were selected by using the method of systematic stratified cluster random sampling. As research methods, questionnaire papers were used. The data were collected and data which were judged to be incomplete or unreliable in responses were excluded from the analysis. After inputting data which are available to analysis and SPSS 18.0 program was used for statistical techniques. In this, data were processed by factor analysis, correlation analysis, and multiple regression analysis. The study results that were obtained from this analysis are as follows: First, the psychological stability among the push factors in the leisure sports participation of the elderly had a significant effect on re-socialization, while health pursuit had a significant effect on personal exchange and economic activity among the sub-factors of re-socialization. Second, psychological stability among the push factors in the leisure sports participation of the retired elderly had a significant effect on recovery resilience; personal relationships had an effect on empathy skills, impulse control, and self-efficacy; and health pursuit had a significant effect on impulse control, optimism, and self-efficacy.


Human keratin 1/10-1B tetramer structures reveal a knob-pocket mechanism in intermediate filament assembly.
To characterize keratin intermediate filament assembly mechanisms at atomic resolution, we determined the crystal structure of wild-type human keratin-1/keratin-10 helix 1B heterotetramer at 3.0 Å resolution. It revealed biochemical determinants for the A11 mode of axial alignment in keratin filaments. Four regions on a hydrophobic face of the K1/K10-1B heterodimer dictated tetramer assembly: the N-terminal hydrophobic pocket (defined by L227K1, Y230K1, F231K1, and F234K1), the K10 hydrophobic stripe, K1 interaction residues, and the C-terminal anchoring knob (formed by F314K1 and L318K1). Mutation of both knob residues to alanine disrupted keratin 1B tetramer and full-length filament assembly. Individual knob residue mutant F314AK1, but not L318AK1, abolished 1B tetramer formation. The K1-1B knob/pocket mechanism is conserved across keratins and many non-keratin intermediate filaments. To demonstrate how pathogenic mutations cause skin disease by altering filament assembly, we additionally determined the 2.39 Å structure of K1/10-1B containing a S233LK1 mutation linked to epidermolytic palmoplantar keratoderma. Light scattering and circular dichroism measurements demonstrated enhanced aggregation of K1S233L/K10-1B in solution without affecting secondary structure. The K1S233L/K10-1B octamer structure revealed S233LK1 causes aberrant hydrophobic interactions between 1B tetramers.


Parkin directly modulates 26S proteasome activity.
Parkinson's disease (PD) is a common neurodegenerative disease that involves the deterioration of dopaminergic neurons in the substantia nigra pars compacta. Although the etiology of PD remains poorly understood, recent genetic, postmortem, and experimental evidence shows that abnormal protein accumulation and subsequent aggregate formation are prominent features of both sporadic and familial PD. While proteasome dysfunction is observed in PD, diverse mutations in the parkin gene are linked to early-onset autosomal-recessive forms of familial PD. We demonstrate that parkin, an E3 ubiquitin ligase, activates the 26S proteasome in an E3 ligase activity-independent manner. Furthermore, an N-terminal ubiquitin-like domain within parkin is critical for the activation of the 26S proteasome through enhancing the interaction between 19S proteasomal subunits, whereas the PD-linked R42P mutant abolishes this action. The current findings point to a novel role for parkin for 26S proteasome assembly and suggest that parkin mutations contribute to the proteasomal dysfunction in PD.


Should patient age thresholds dictate fixation strategy in total hip arthroplasty?
Total hip arthroplasty (THA) is a very successful and cost-effective operation, yet debate continues about the optimum fixation philosophy in different age groups. The concept of the 'cementless paradox' and the UK 'Getting it Right First Time' initiative encourage increased use of cemented fixation due to purported lower revision rates, especially in elderly patients, and decreased cost. In a high-volume, tertiary referral centre, we identified 10,112 THAs from a prospectively collected database, including 1,699 cemented THAs, 5,782 hybrid THAs, and 2,631 cementless THAs. The endpoint was revision for any reason. Secondary analysis included examination of implant survivorship in patients aged over 70 years, over 75 years, and over 80 years at primary THA. Cemented fixation had the lowest implant survival in all age groups, with a total ten-year survivorship of 97.0% (95% confidence interval (CI) 95.8 to 97.8) in the cemented group, 97.6% (95% CI 96.9 to 98.1) in the hybrid group, and 97.9% (95% CI 96.9 to 98.6) in the cementless group. This was not statistically significant (p = 0.092). There was no age group where cemented fixation outperformed hybrid or cementless fixation. While all fixation techniques performed well at long-term follow-up, cemented fixation was associated with the lowest implant survival in all age groups, including in more elderly patients. We recommend that surgeons should carefully monitor their own outcomes and use fixation techniques that they are familiar with, and deliver the best outcomes in their own hands. Cite this article: Bone Joint J 2022;104-B(2):206-211.


Importance of postprocedural Wound, Ischemia, and foot Infection (WIfI) restaging in predicting limb salvage.
The Wound, Ischemia, and foot Infection (WIfI) classification system was created to encompass demographic changes and expanding techniques of revascularization to perform meaningful analyses of outcomes in the treatment of the threatened limb. The WIfI index is intended to be analogous to the TNM staging system for cancer, with restaging to be done after control of infection and after revascularization. Our goal was to evaluate the effectiveness of WIfI restaging after therapy in the prediction of limb outcomes. Preoperative WIfI scoring was performed prospectively for all critical limb ischemia patients who underwent revascularization from January 2014 to June 2015. WIfI restaging and assessment of outcomes were performed retrospectively through August 2016. WIfI classification was determined at the following intervals: preoperatively, immediately postoperatively, and 1 month and 6 months after intervention. Amputation-free survival (AFS) was the primary end point. Kaplan-Meier plot analysis and comparisons of preoperative grades with respective postoperative grades were performed using paired t-test, χ2 test, and correlation analyses. A total of 180 limbs and 172 critical limb ischemia patients underwent revascularization, of which 29 limbs had major amputations (16%). Wound grades generally improved after surgery across the entire cohort. Major amputation was associated with preoperative wound grade and remained associated with wound grade at postoperative restaging at 1 month and beyond on the basis of amputation frequency analysis (preoperatively, 1 month, and 6 months, P = .03, < .001, and < .001, respectively). Wound grade was significantly associated with AFS at 1 month and 6 months after intervention (log-rank, P < .001 for restaging intervals). Ischemia grades improved initially with a slight decline across the cohort at 6 months. Ischemia grade at 1 month postoperatively was associated with AFS (log-rank, P = .03). Foot infection grades also improved at each time interval. Foot infection grade was associated with AFS at 1 month postoperatively (log-rank, P < .001) and at 6 months (log-rank, P = .017). WIfI restaging is an important tool for predicting limb loss and assessing adequacy of intervention, more so than baseline WIfI alone. The 1- and 6-month postoperative ischemia grade correlated with AFS, whereas preoperative grade did not. The 1- and 6-month postoperative wound and foot infection grades additionally correlated with AFS. WIfI restaging at 1 month and 6 months postoperatively may help identify a cohort that remains at higher risk for limb loss and may merit more expeditious reintervention.


Challenging the challenge hypothesis on testosterone in fathers: Limited meta-analytic support.
In fathers testosterone levels are suggested to decrease in the context of caregiving, but results seem inconsistent. In a meta-analysis including 50 study outcomes with N = 7,080 male participants we distinguished three domains of research, relating testosterone levels to parental status (Hedges' g = 0.22, 95% CI: 0.09 to 0.35; N = 4,150), parenting quality (Hedges' g = 0.14, 95% CI: 0.03 to 0.24; N = 2,164), and reactivity after exposure to child stimuli (Hedges' g = 0.19, 95% CI: -0.03 to 0.42; N = 766). The sets of study outcomes on reactivity and on parenting quality were both homogeneous. Parental status and (higher) parenting quality were related to lower levels of testosterone, but according to conventional criteria combined effect sizes were small. Moderators did not significantly modify combined effect sizes. Results suggest that publication bias might have inflated the meta-analytic results, and the large effects of pioneering but small and underpowered studies in the domains of males' parental status and parenting quality have not been consistently replicated. Large studies with sufficient statistical power to detect small testosterone effects and, in particular, the moderating effects of the interplay with other endocrine systems and with contextual determinants are required.


Beyond Binary: Influence of Sex and Gender on Outcome after Traumatic Brain Injury.
Traumatic brain injury (TBI) affects millions of individuals each year and is a leading cause of death and disability worldwide. TBI is heterogeneous and outcome is influenced by a combination of factors that include injury location, severity, genetics, and environmental factors. More recently, sex as a biological variable has been incorporated into TBI research, although there is conflicting literature regarding clinical outcomes in males versus females after TBI. We review the current clinical literature investigating sex differences after TBI. We focus our discussion on differences within contemporary gender categories to suggest that binary categories of male and female are not sufficient to guide clinical decisions for neurotrauma. Some studies have considered physiological variables that influence sex such as hormone cycles and stages in males and females pre- and post-TBI. These data suggest that there are phasic differences within male populations and within female populations that influence an individual's outcome after TBI. Finally, we discuss the impact of gender identity and expression on outcome after TBI and highlight the lack of neurotrauma research that includes non-binary individuals. Social constructs regarding gender impact an individual's vulnerability to violence and consequent TBI, including the successful reintegration to society after TBI. We call for incorporation of gender beyond the binary in TBI education, research, and clinical care. Precision medicine necessarily must progress beyond the binary to treat individuals after TBI.


Gametocyte dynamics and the role of drugs in reducing the transmission potential of Plasmodium vivax.
Designing interventions that will reduce transmission of vivax malaria requires knowledge of Plasmodium vivax gametocyte dynamics. We analyzed data from a randomized controlled trial in northwestern Thailand and 2 trials in Papua, Indonesia, to identify and compare risk factors for vivax gametocytemia at enrollment and following treatment. A total of 492 patients with P. vivax infections from Thailand and 476 patients (162 with concurrent falciparum parasitemia) from Indonesia were evaluable. Also, 84.3% (415/492) and 66.6% (209/314) of patients with monoinfection were gametocytemic at enrollment, respectively. The ratio of gametocytemia to asexual parasitemia did not differ between acute and recurrent infections (P = .48 in Thailand, P = .08 in Indonesia). High asexual parasitemia was associated with an increased risk of gametocytemia during follow-up in both locations. In Thailand, the cumulative incidence of gametocytemia between day 7 and day 42 following dihydroartemisinin + piperaquine (DHA + PIP) was 6.92% vs 29.1% following chloroquine (P < .001). In Indonesia, the incidence of gametocytemia was 33.6% following artesunate + amodiaquine (AS + AQ), 7.42% following artemether + lumefantrine, and 6.80% following DHA + PIP (P < .001 for DHA + PIP vs AS + AQ). P. vivax gametocyte carriage mirrors asexual-stage infection. Prevention of relapses, particularly in those with high asexual parasitemia, is likely the most important strategy for interrupting P. vivax transmission.


Long-term mortality after acute myocardial infarction in relation to prescribed dosages of a beta-blocker at hospital discharge.
This study was designed to describe the 5-year mortality rate in relation to the dose of metoprolol prescribed at hospital discharge after hospitalisation for acute myocardial infarction (AMI). All patients discharged alive after being hospitalized for AMI at Sahlgrenska Hospital (covering half of the community of Göteborg, with 500,000 inhabitants) during 1986-1987 (period I) and all patients discharged alive after hospitalization for AMI at Sahlgrenska Hospital and Ostra Hospital (covering the whole area of the community of Göteborg) in 1990-1991 (period II) were included. Overall mortality was retrospectively evaluated over 5 years of follow-up. In all there were 2161 patients who were discharged after AMI. Seventy-three percent of these patients were prescribed a beta-blocker and 59% were prescribed metoprolol. Of the patients prescribed metoprolol, 34% were on 200 mg, 46% on 100 mg, and 20% on 50 mg or less. Information on 5-year mortality was available for 2142 of the 2161 patients (99.1%). The 5-year mortality was 24% among patients prescribed 200 mg, 33% among patients prescribed 100 mg, and 43% among patients prescribed 50 mg (P < 0.0001). Patients prescribed another beta-blocker had a 5-year mortality of 39%, and patients prescribed no beta-blocker at all had a 5-year mortality of 61%. When correcting for dissimilarities at baseline, patients who were prescribed < or =100 mg had an adjusted risk ratio for death of 0.79 (95% confidence limit 0.64-0.96; P = 0.021) as compared with patients not prescribed a beta blocker. The corresponding figure for patients prescribed >100 mg was 0.63 (95% confidence limit 0.48-0.84; P = 0.001). Both patients prescribed high and low doses of metoprolol after AMI appeared to benefit from treatment. There was a trend indicating more benefit when larger doses were prescribed.


Comparative safety of vascular closure devices and manual closure among patients having percutaneous coronary intervention.
The role of vascular closure devices (VCDs) in patients having percutaneous coronary intervention (PCI) is controversial, and recommendations for use vary. To examine the use of and outcomes associated with VCDs in real-world practice. Observational cohort study. 32 hospitals in Michigan that participate in a large multicenter quality improvement collaborative. Consecutive patients having emergent and nonemergent PCI from 2007 to 2009. Vascular complications and the need for transfusion. Of the 85 048 PCIs performed during the study that met the inclusion criteria, 28 528 (37%) procedures used VCDs. In propensity score-matched analysis, VCDs were associated with reductions in vascular complications (odds ratio [OR], 0.78 [95% CI, 0.67 to 0.90]; P = 0.001) and postprocedure transfusions (OR, 0.85 [CI, 0.74 to 0.96]; P = 0.011). These findings were consistent across many prespecified subgroups except for patients with a body mass index (BMI) less than 25 kg/m2 and those treated with platelet glycoprotein (GP) IIb/IIIa inhibitors, in whom the benefit of VCDs over manual closure was attenuated. When the specific subtypes of vascular complications were evaluated, VCDs were associated with fewer hematomas (OR, 0.69 [CI, 0.58 to 0.83]; P < 0.001) or pseudoaneurysms (OR, 0.54 [CI, 0.38 to 0.76]; P < 0.001) but an increase in the odds of retroperitoneal bleeding (OR, 1.57 [CI, 1.12 to 2.20]; P = 0.009). Unmeasured confounding cannot be excluded despite the study having measured and balanced many confounders. Vascular closure devices were associated with a significant reduction in vascular complications and need for transfusion in this large cohort of patients having transfemoral PCI. This benefit was lost in patients receiving GP IIb/IIIa inhibitors and those with normal or lean BMI and was counterbalanced by a small increase in the more serious risk for retroperitoneal bleeding.


Systematic review of interventions for low bone mineral density in children with cerebral palsy.
To systematically review the efficacy of interventions to improve low bone mineral density (LBMD) in children and adolescents with cerebral palsy (CP). We performed a systematic search for published randomized, controlled trials (RCTs) and controlled clinical trials (CCTs) of children with CP (aged 0-20 years, all Gross Motor Function Classification System [GMFCS] levels) who received various medical and physical interventions for LBMD compared with no intervention or standard care. Study validity was evaluated by using the Physiotherapy Evidence Database (PEDro) scale. Standardized mean differences (SMDs) were calculated when data were sufficient. Eight of 2034 articles met the inclusion criteria (6 RCTs, 2 CCTs). There were 3 trials of bisphosphonates, one of which (Henderson RC, Lark RK, Kecskemethy HH, Miller F, Harcke HT, Bachrach SJ. J Pediatr. 2002;141[5]:644-651) revealed a large and significant effect on BMD in 1 of 3 sites in the distal femur (SMD: 1.88 [95% confidence interval (CI): 0.52-3.24]). There were 3 trials of weight-bearing through varying approaches, one of which (Caulton JM, Ward KA, Alsop CW, Dunn G, Adams JE, Mughal MZ. Arch Dis Child. 2004;89[2]:131-135) showed a large and significant effect on the lumbar spine when increasing static standing time (SMD: 1.03 [95% CI: 0.21-1.85]). The administration of vitamin D and calcium produced a large, nonsignificant effect on BMD in the lumbar spine (Jekovec-Vrhovsek M, Kocijancic A, Prezelj J. Dev Med Child Neurol. 2000;42[6]:403-405) (SMD: 0.88 [95% CI: -0.07 to 1.84). Growth hormone combined with vitamin D and/or calcium resulted in effects comparable with vitamin D and/or calcium on BMD in the lumbar spine (Ali O, Shim M, Fowler E, et al. J Clin Endocrinol Metab. 2007;92[3]:932-937) (SMD 0 [95% CI: -1.24 to 1.24]). Important effects on LBMD have been observed in small and diverse cohorts of children with CP. It is unclear whether small sample sizes or variable treatment responses account for nonsignificant findings. Additional large RCTs are needed of both physical and medical approaches.


Effect of stress on hippocampal nociceptin expression in the rat.
Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor are not only ubiquitously expressed in mammalian brain and spinal cord but are also abundant in limbic structures, particularly in the hippocampus. The widespread distribution of N/OFQ reflects the broad spectrum of its biological actions such as nociception, food intake, spontaneous locomotor activity, and learning and memory processes. Since the hippocampus is involved in the control of adrenocortical activity, its role in stress-related phenomena is well characterized. In male Wistar rats, we first examined the effects of acute restraint stress (120 min) on the brain immunohistochemical localization of N/OFQ. The analysis carried out on sections obtained at the onset of stress revealed enhanced expression of N/OFQ in CA1, CA3, and the dentate gyrus as well as increased plasma corticosterone concentrations. Next, we examined whether endogenous glucocorticoid hormone plays a role in the modulation of hippocampal N/OFQ expression in response to stress. To this end, rats were injected with corticosterone (1 mg/kg) or subjected to restraint stress 1 week after adrenalectomy. Two hours after corticosterone administration, plasma glucocorticoid concentrations were comparable to those observed after restraint stress, while N/OFQ expression had significantly increased in all the hippocampal subfields examined. By contrast, in adrenalectomized rats, stress did not modify protein expression. These results confirm that stress can affect N/OFQ expression and that glucocorticoids may constitute hormonal mediators of this complex interplay.


Safety and Efficacy of Smooth Surface Tissue Expander Breast Reconstruction.
Traditional 2-stage breast reconstruction involves placement of a textured-surface tissue expander (TTE). Recent studies have demonstrated textured surface devices have higher propensity for bacterial contamination and biofilm formation. The purpose of this study was to evaluate the safety and efficacy of smooth surface tissue expanders (STE) in immediate breast reconstruction. The authors retrospectively reviewed consecutive women who underwent STE breast reconstruction from 2016 to 2017 at 3 institutions. Indications and outcomes were evaluated. A total 112 patients underwent STE reconstruction (75 subpectoral, 37 prepectoral placement), receiving 173 devices and monitored for a mean follow-up of 14.1 months. Demographics of patients included average age of 53 years and average BMI of 27.2 kg/m2, and 18.6% received postmastectomy radiation therapy. Overall complication rates were 15.6% and included mastectomy skin flap necrosis (10.4%), seroma (5.2%), expander malposition (2.9%), and infection requiring intravenous antibiotic therapy (3.5%). Six (3.5%) unplanned reoperations with explantation were reported for 3 infections and 3 patients requesting change of plan with no reconstruction. STEs represent a safe and efficacious alternative to TTE breast reconstruction with at least equitable outcomes. Technique modification including tab fixation, strict pocket control, postoperative bra support, and suture choice may contribute to observed favorable outcomes and are reviewed. Early results for infection control and explantation rate are encouraging and warrant comparative evaluation for potential superiority over TTEs in a prospective randomized trial.


Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II.
Therapeutic use of cyclooxygenase-inhibiting (COX-inhibiting) nonsteroidal antiinflammatory drugs (NSAIDs) is often complicated by renal side effects including hypertension and edema. The present studies were undertaken to elucidate the roles of COX1 and COX2 in regulating blood pressure and renal function. COX2 inhibitors or gene knockout dramatically augment the pressor effect of angiotensin II (Ang II). Unexpectedly, after a brief increase, the pressor effect of Ang II was abolished by COX1 deficiency (either inhibitor or knockout). Ang II infusion also reduced medullary blood flow in COX2-deficient but not in control or COX1-deficient animals, suggesting synthesis of COX2-dependent vasodilators in the renal medulla. Consistent with this, Ang II failed to stimulate renal medullary prostaglandin E(2) and prostaglandin I(2) production in COX2-deficient animals. Ang II infusion normally promotes natriuresis and diuresis, but COX2 deficiency blocked this effect. Thus, COX1 and COX2 exert opposite effects on systemic blood pressure and renal function. COX2 inhibitors reduce renal medullary blood flow, decrease urine flow, and enhance the pressor effect of Ang II. In contrast, the pressor effect of Ang II is blunted by COX1 inhibition. These results suggest that, rather than having similar cardiovascular effects, the activities of COX1 and COX2 are functionally antagonistic.


Alterations of regional spontaneous neuronal activity and corresponding brain circuit changes during resting state in migraine without aura.
Although previous resting-state studies have reported abnormal functional cerebral changes in patients with migraine without aura (MwoA), few have focused on alterations in both regional spontaneous neuronal activity and corresponding brain circuits in MwoA patients during rest. Eighteen MwoA patients and 18 age- and gender-matched healthy controls (HC) were recruited in the current study. Baseline cerebral alterations were investigated using amplitude of low-frequency fluctuation (ALFF) and region of interest (ROI)-based functional connectivity (FC) analyses. Compared with HC, MwoA patients showed decreased ALFF values in the left rostral anterior cingulate cortex (rACC) and bilateral prefrontal cortex (PFC) as well as increased ALFF values in the right thalamus. FC analysis also revealed abnormal FCs associated with these ROIs. In addition, ALFF values of the left rACC correlated with duration of disease in MwoA. Our findings could lead to a better understanding of intrinsic functional architecture of baseline brain activity in MwoA, providing both regional and brain circuit spontaneous neuronal activity properties.


Population Based Testing for Primary Prevention: A Systematic Review.
The current clinical model for genetic testing is based on clinical-criteria/family-history (FH) and a pre-defined mutation probability threshold. It requires people to develop cancer before identifying unaffected individuals in the family to target prevention. This process is inefficient, resource intensive and misses >50% of individuals or mutation carriers at risk. Population genetic-testing can overcome these limitations. It is technically feasible to test populations on a large scale; genetic-testing costs are falling and acceptability and awareness are rising. MEDLINE, EMBASE, Pubmed, CINAHL and PsychINFO databases were searched using free-text and MeSH terms; retrieved reference lists of publications were screened; additionally, web-based platforms, Google, and clinical-trial registries were searched. Quality of studies was evaluated using appropriate check-lists. A number of studies have evaluated population-based BRCA-testing in the Jewish population. This has been found to be acceptable, feasible, clinically-effective, safe, associated with high satisfaction rates and extremely cost-effective. Data support change in guidelines for population-based BRCA-testing in the Jewish population. Population panel testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 gene mutations is the most cost-effective genetic-testing strategy in general-population women and can prevent thousands more breast and ovarian cancers than current clinical-criteria based approaches. A few ongoing studies are evaluating population-based genetic-testing for multiple cancer susceptibility genes in the general population but more implementation studies are needed. A future population-testing programme could also target other chronic diseases.


First-trimester ultrasonographic investigation of cardiovascular anatomy in thoracoabdominally conjoined twins.
Options for the treatment of thoracoabdominally conjoined twins are dependent on the anatomy of the cardiovascular system. It is important to increase the accuracy of diagnosis of conjoined twins with a fused heart. Color Doppler imaging performed in a 23-year-old nulliparous Japanese woman at 12 weeks of gestation revealed synchronized blood flow in 2 aortic arches arising from a single heart. The patient underwent a therapeutic abortion, and the diagnosis of conjoined twins with a fused heart was confirmed. Thus, color Doppler imaging is useful for investigating the cardiovascular anatomy in conjoined twins suspected of having a fused heart, even in an early gestational age.


Under-reporting bicycle accidents to police in the COST TU1101 international survey: Cross-country comparisons and associated factors.
Police crash reports are often the main source for official data in many countries. However, with the exception of fatal crashes, crashes are often underreported in a biased manner. Consequently, the countermeasures adopted according to them may be inefficient. In the case of bicycle crashes, this bias is most acute and it probably varies across countries, with some of them being more prone to reporting accidents to police than others. Assessing if this bias occurs and the size of it can be of great importance for evaluating the risks associated with bicycling. This study utilized data collected in the COST TU1101 action "Towards safer bicycling through optimization of bicycle helmets and usage". The data came from an online survey that included questions related to bicyclists' attitudes, behaviour, cycling habits, accidents, and patterns of use of helmets. The survey was filled by 8655 bicyclists from 30 different countries. After applying various exclusion factors, 7015 questionnaires filled by adult cyclists from 17 countries, each with at least 100 valid responses, remained in our sample. The results showed that across all countries, an average of only 10% of all crashes were reported to the police, with a wide range among countries: from a minimum of 0.0% (Israel) and 2.6% (Croatia) to a maximum of a 35.0% (Germany). Some factors associated with the reporting levels were type of crash, type of vehicle involved, and injury severity. No relation was found between the likelihood of reporting and the cyclist's gender, age, educational level, marital status, being a parent, use of helmet, and type of bicycle. The significant under-reporting - including injury crashes that do not lead to hospitalization - justifies the use of self-report survey data for assessment of bicycling crash patterns as they relate to (1) crash risk issues such as location, infrastructure, cyclists' characteristics, and use of helmet and (2) strategic approaches to bicycle crash prevention and injury reduction.


Active Sites Intercalated Ultrathin Carbon Sheath on Nanowire Arrays as Integrated Core-Shell Architecture: Highly Efficient and Durable Electrocatalysts for Overall Water Splitting.
The development of active bifunctional electrocatalysts with low cost and earth-abundance toward oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) remains a great challenge for overall water splitting. Herein, metallic Ni4 Mo nanoalloys are firstly implanted on the surface of NiMoOx nanowires array (NiMo/NiMoOx ) as metal/metal oxides hybrid. Inspired by the superiority of carbon conductivity, an ultrathin nitrogen-doped carbon sheath intercalated NiMo/NiMoOx (NC/NiMo/NiMoOx ) nanowires as integrated core-shell architecture are constructed. The integrated NC/NiMo/NiMoOx array exhibits an overpotential of 29 mV at 10 mA cm-2 and a low Tafel slope of 46 mV dec-1 for HER due to the abundant active sites, fast electron transport, low charge-transfer resistance, unique architectural structure and synergistic effect of carbon sheath, nanoalloys, and oxides. Moreover, as OER catalysts, the NC/NiMo/NiMoOx hybrids require an overpotential of 284 mV at 10 mA cm-2 . More importantly, the NC/NiMo/NiMoOx array as a highly active and stable electrocatalyst approaches ≈10 mA cm-2 at a voltage of 1.57 V, opening an avenue to the rational design and fabrication of the promising electrode materials with architecture structures toward the electrochemical energy storage and conversion.


Recruitment of the host plant heat shock protein 70 by Tomato yellow leaf curl virus coat protein is required for virus infection.
A functional capsid protein (CP) is essential for host plant infection and insect transmission of Tomato yellow leaf curl virus (TYLCV) and other monopartite begomoviruses. We have previously shown that TYLCV CP specifically interacts with the heat shock protein 70 (HSP70) of the virus insect vector, Bemisia tabaci. Here we demonstrate that during the development of tomato plant infection with TYLCV, a significant amount of HSP70 shifts from a soluble form into insoluble aggregates. CP and HSP70 co-localize in these aggregates, first in the cytoplasm, then in the nucleus of cells associated with the vascular system. CP-HSP70 interaction was demonstrated by co-immunopreciptation in cytoplasmic - but not in nuclear extracts from leaf and stem. Inhibition of HSP70 expression by quercetin caused a decrease in the amount of nuclear CP aggregates and a re-localization of a GFP-CP fusion protein from the nucleus to the cytoplasm. HSP70 inactivation resulted in a decrease of TYLCV DNA levels, demonstrating the role of HSP70 in TYLCV multiplication in planta. The current study reveals for the first time the involvement of plant HSP70 in TYLCV CP intracellular movement. As described earlier, nuclear aggregates contained TYLCV DNA-CP complexes and infectious virions. Showing that HSP70 localizes in these large nuclear aggregates infers that these structures operate as nuclear virus factories.


EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis.
Aberrant activation of EGFR in human cancers promotes tumorigenesis through stimulation of AKT signaling. Here, we determined that the discoidina neuropilin-like membrane protein DCBLD2 is upregulated in clinical specimens of glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. In multiple cancer cell lines, EGFR activated phosphorylation of tyrosine 750 (Y750) of DCBLD2, which is located within a recently identified binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, phosphorylation of DCBLD2 Y750 recruited TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent activation of AKT, thereby enhancing EGFR-driven tumorigenesis. Moreover, evaluation of patient samples of gliomas and HNCs revealed an association among EGFR activation, DCBLD2 phosphorylation, and poor prognoses. Together, our findings uncover a pathway in which DCBLD2 functions as a signal relay for oncogenic EGFR signaling to promote tumorigenesis and suggest DCBLD2 and TRAF6 as potential therapeutic targets for human cancers that are associated with EGFR activation.


Biphasic water splitting by osmocene.
The photochemical reactivity of osmocene in a biphasic water-organic solvent system has been investigated to probe its water splitting properties. The photoreduction of aqueous protons to hydrogen under anaerobic conditions induced by osmocene dissolved in 1,2-dichloroethane and the subsequent water splitting by the osmocenium metal-metal dimer formed during H(2) production were studied by electrochemical methods, UV-visible spectrometry, gas chromatography, and nuclear magnetic resonance spectroscopy. Density functional theory computations were used to validate the reaction pathways.


[Gerontosocial work in the context of Russian culture and recommendations of Madrid International Plan of Action on Ageing].
The definition of gerontosocial work adopted in the majority of the European countries in the context of the Russian culture and priority trends of the Madrid International Plan of Action on Ageing has been discussed. In the article the interaction and differences between terms being used in social work with the elderly people in Russia have been showed; tasks and peculiarities of gerontosocial work have been defined. Peculiarities of interaction between personnel and elderly patients have been studied; the increasing requirements to the professionalism of gerontosocial workers have been proved.


The immune system's role in the biology of autism.
The following is a review of the most recent research concerning the potential role of immune system dysfunction in autism. This body of literature has expanded dramatically over the past few years as researchers continue to identify immune anomalies in individuals with autism. The most exciting of these recent findings is the discovery of autoantibodies targeting brain proteins in both children with autism and their mothers. In particular, circulating maternal autoantibodies directed toward fetal brain proteins are highly specific for autism. This finding has great potential as a biomarker for disease risk and may provide an avenue for future therapeutics and prevention. Additionally, data concerning the cellular immune system in children with autism suggest there may be a defect in signaling pathways that are shared by the immune and central nervous systems. Although studies to explore this hypothesis are ongoing, there is great interest in the commonalities between the neural and immune systems and their extensive interactions. In summary, the exciting research regarding the role of the immune system in autism spectrum disorders may have profound implications for diagnosis and treatment of this devastating disease.


[Spectrophotometric determination of lipid peroxidation end products].
Spectrophotometric assay of the final lipoperoxidation products based upon light absorption at 400 nm was developed. Relative content of these products in different phases of lipid extract was calculated as E400/E220 ratio. Data obtained by the technique developed were consistent with those of histochemical results. Appreciable correlation between the relative lipoperoxidation products content and age was demonstrated.


Peripheral blood mononuclear cells acquire myofibroblast characteristics in granulation tissue.
Bone marrow-derived cell populations possess progenitor cell capacities. Emerging evidence also suggests significant plasticity of differentiated mononuclear cell lineages. We therefore assessed the distribution of transplanted peripheral blood mononuclear cells (PBMCs) in granulation tissue formation, and evaluated their possible transdifferentiation into myofibroblasts. Silastic tubes were inserted into the peritoneal cavity of rats, followed by injection of PKH26-labelled PBMCs isolated from donor animals. At 3, 14 and 21 days, the distribution of PKH26(+) cells as well as their colocalization with myofibroblast/smooth muscle cell [alpha-smooth muscle (alpha-SM) actin] or macrophage markers (ED1/ED2) were determined. Round-shaped PKH26(+) cells accumulated around the implants at 3 days, while myofibroblasts were rare. Later, peritoneal granulation tissue constituted an inner, multilayered capsule primarily comprising alpha-SM actin(+) cells that was surrounded by more loosely organized inflammatory connective tissue. PKH26-labelled, spindle-shaped cells were abundantly found in tissue capsules. As a key finding, granulation tissue at 14 and 21 days contained cells with both PKH26 and alpha-SM actin labelling. Accordingly, a subpopulation of cells staining positive for macrophage markers showed a spindle-shaped morphology and alpha-SM actin expression. Transplanted PBMCs contribute to granulation tissue, and acquire myofibroblast characteristics during de novo tissue formation. Mononuclear cells may transdifferentiate into myofibroblast-like cells within an inflammatory environment.


Carbon and nitrogen metabolism in mycorrhizal networks and mycoheterotrophic plants of tropical forests: a stable isotope analysis.
Most achlorophyllous mycoheterotrophic (MH) plants obtain carbon (C) from mycorrhizal networks and indirectly exploit nearby autotrophic plants. We compared overlooked tropical rainforest MH plants associating with arbuscular mycorrhizal fungi (AMF) to well-reported temperate MH plants associating with ectomycorrhizal basidiomycetes. We investigated (13)C and (15)N abundances of MH plants, green plants, and AMF spores in Caribbean rainforests. Whereas temperate MH plants and fungi have higher δ(13)C than canopy trees, these organisms displayed similar δ(13)C values in rainforests, suggesting differences in C exchanges. Although temperate green and MH plants differ in δ(15)N, they display similar (15)N abundances, and likely nitrogen (N) sources, in rainforests. Contrasting with the high N concentrations shared by temperate MH plants and their fungi, rainforest MH plants had lower N concentrations than AMF, suggesting differences in C/N of exchanged nutrients. We provide a framework for isotopic studies on AMF networks and suggest that MH plants in tropical and temperate regions evolved different physiologies to adapt in diverging environments.


Enantioselective aminocatalytic synthesis of tetrahydropyrano[2,3-c]pyrazoles via a domino Michael-hemiacetalization reaction with alkylidene pyrazolones.
An enantioselective organocatalytic domino Michael-hemiacetalization reaction between alkylidene pyrazolones and cyclic ketones/pentanal has been revealed. The fused tetrahydropyranopyrazole products having three contiguous stereocentres were obtained with perfect diastereoselectivities and in moderate to good yields with good to high enantioselectivities. Also, few synthetic transformations of the product including the formation of a spiro derivative have been demonstrated.


Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice.
Aging intersects with reproductive senescence in women by promoting a systemic low-grade chronic inflammation that predisposes women to several diseases including ovarian cancer (OC). OC risk at menopause is significantly modified by parity records during prior fertile life. To date, the combined effects of age and parity on the systemic inflammation markers that are particularly relevant to OC initiation and progression at menopause remain largely unknown. Herein, we profiled a panel of circulating cytokines in multiparous versus virgin C57BL/6 female mice at peri-estropausal age and investigated how cytokine levels were modulated by intraperitoneal tumor induction in a syngeneic immunocompetent OC mouse model. Serum FSH, LH and TSH levels increased with age in both groups while prolactin (PRL) was lower in multiparous respect to virgin mice, a finding previously observed in parous women. Serum CCL2, IL-10, IL-5, IL-4, TNF-α, IL1-β and IL-12p70 levels increased with age irrespective of parity status, but were specifically reduced following OC tumor induction only in multiparous mice. Animals developed hemorrhagic ascites and tumor implants in the omental fat band and other intraperitoneal organs by 12 weeks after induction, with multiparous mice showing a significantly extended survival. We conclude that previous parity history counteracts aging-associated systemic inflammation possibly by reducing the immunosuppression that typically allows tumor spread. Results suggest a partial impairment of the M2 shift in tumor-associated macrophages as well as decreased stimulation of regulatory B-cells in aged mice. This long term, tumor-concurrent effect of parity on inflammation markers at menopause would be a contributing factor leading to decreased OC risk.


Detection methods of epitranscriptomic mark N6-methyladenosine.
Research on N6-methyladenosine (m6A) in recent years has revealed the complex but elegant regulatory role of this RNA modification in multiple physiological processes. The advent of m6A detection technologies is the basis for studying the function of this RNA modification. These technologies enable the detection of m6A sites across transcriptome or at specific gene, thereby revealing the alternation and dynamic of RNA modification. However, non-specific signals that arise from the antibody-based methods and the low-resolution landscape have become the major drawback of classic m6A detection methods. In this review, we summarize the current available methods and categorized them into three groups according to the utilization purpose, including measurement of total m6A levels, detection m6A locus in single gene, and m6A sequencing. We hope this review helps researchers in epitranscriptomic field find an appropriate m6A detection tool that suites their experimental design.


Quantitative analysis of snoRNA association with pre-ribosomes and release of snR30 by Rok1 helicase.
In yeast, three small nucleolar RNAs (snoRNAs) are essential for the processing of pre-ribosomal RNA--U3, U14 and snR30--whereas 72 non-essential snoRNAs direct site-specific modification of pre-rRNA. We applied a quantitative screen for alterations in the pre-ribosome association to all 75 yeast snoRNAs in strains depleted of eight putative helicases implicated in 40S subunit synthesis. For the modification-guide snoRNAs, we found no clear evidence for the involvement of these helicases in the association or dissociation of pre-ribosomes. However, the DEAD box helicase Rok1 was required specifically for the release of snR30. Point mutations in motif I, but not in motif III, of the helicase domain of Rok1 impaired the release of snR30, but this was less marked than in strains depleted of Rok1, and resulted in a dominant-negative growth phenotype. Dissociation of U3 and U14 from pre-ribosomes is also dependent on helicases, suggesting that release of the essential snoRNAs might differ mechanistically from release of the modification-guide snoRNAs.


Laboratory evaluation of selected disinfectants as virucidal agents against porcine parvovirus, pseudorabies virus, and transmissible gastroenteritis virus.
Of a variety of disinfectants evaluated, only sodium hypochlorite and sodium hydroxide inactivated porcine parvovirus (PPV) after a 5-minute incubation period. After the same incubation time, pseudorabies and transmissible gastroenteritis viruses were inactivated by all of the disinfectants tested. When the incubation time was increased to 20 minutes, 2% glutaraldehyde and a double-strength concentration of a commercial formaldehyde preparation also inactivated PPV. Formaldehyde vapor and ultraviolet radiations inactivated PPV also, but relatively long exposure times were required.


Anxiety in fathers in the perinatal period: A systematic review.
fatherhood in the perinatal period can be a time of great excitement, happiness and joy. However, a growing body of literature indicates that fathers are at risk for elevated levels of anxiety symptoms during the perinatal period. the purpose of this systematic review is to determine the prevalence and levels of anxiety in fathers during the perinatal period, identify the risk factors and impact of anxiety, and establish if there are effective interventions that reduce father's anxiety. Systematic review. A systematic review protocol was developed and registered with PROSPERO (reference number: CRD42017073760). The review was guided by the PRISMA reporting process. Electronic databases Medline, CINAHL, Embase, the Cochrane Library, PsycARTICLES, PsycINFO, and Psychology were searched to identify eligible studies. Studies that researched fathers during the perinatal period were included if anxiety was the primary focus of the research or was an outcome or dependent variable. Data were extracted and presented in narrative form including tables and figures. Thirty-four studies met the inclusion criteria. Findings from these studies indicate that fathers experience anxiety in the perinatal period, particularly at the time of birth. Anxiety increased from the antenatal period to the time of birth, with a decrease in anxiety from the time of birth to the later postnatal period. The prevalence of anxiety ranged between 3.4% and 25.0% during the antenatal period and 2.4% and 51.0% during the postnatal period. Factors contributing to anxiety included lower education levels, lower income levels, lower co-parenting support, lower social support, work-family conflict, a partner' anxiety and depression, and being present during a previous birth. Anxiety had a negative impact on fathers' mental health, physical health, social relationships and parenting skills. Anxiety contributed to stress, depression, fatigue and lower paternal self-efficacy. Five studies reported on interventions to reduce anxiety and all the studies found that anxiety significantly decreased following the intervention. Fathers experience increased anxiety from the antenatal period to the time of birth, with a decrease in anxiety from the time of birth to the later postnatal period. Anxiety during the perinatal period that can impact negatively on fathers physical and mental health, and social relationships.


17-beta-estradiol affects brain protein synthesis rate in ovariectomized female rats.
The purpose of this study was to determine whether 17-ss-estradiol affects the rate of brain protein synthesis in ovariectomized female rats. Experiments were conducted on three groups of 12-wk-old female rats: group 1 were ovariectomized to reduce the level of plasma estradiol, group 2 were ovariectomized and treated with estradiol and group 3 were sham-operated controls. The fractional rates of protein synthesis in brain of ovariectomized rats treated with estradiol were significantly greater than that in ovariectomized rats without estradiol treatment. In the cerebral cortex and cerebellum, the RNA activity [g protein synthesized/(g RNA. d)] significantly correlated (r > 0.87, P < 0.001) with the fractional rate of protein synthesis. The RNA concentration (mg RNA/g protein) was not related to the fractional rate of protein synthesis in any organ. The results suggest that estrogen treatment of ovariectomized female rats is likely to increase the rate of protein synthesis in the brain and that RNA activity is at least in part related to the fractional rate of brain protein synthesis.


Oncologic resection for malignant tumors of the liver.
An evidence-based review to ascertain the operative strategy for oncologic resection of malignant tumors of the liver and an optimal postoperative outcome. Recommendations for resection of malignant tumors of the liver based on traditional considerations of locoregional control and survival benefit are modified by the functional reserve of the liver remnant. Recent publications including prospective randomized trials reporting outcomes with various surgical approaches were reviewed to establish the best current practices. The goal of hepatectomy for primary or metastatic tumors of the liver is complete resection with evidence that an anatomic resection in hepatocellular carcinoma and hilar cholangiocarcinoma improves survival. For nonanatomic resections the optimal width of the resection margin varies with the pathological type of tumor. Anterior approach to major hepatectomy is a "no-touch" technique that minimizes manipulation of the tumor-bearing liver. Vascular invasion is associated with dismal prognosis and limited major vascular resection is indicated to achieve an R0 (no residual disease) resection for prolongation of survival. Concomitant regional lymphadenectomy is of prognostic value, however it is not performed routinely because its therapeutic value remains unproven. Perioperative blood transfusion and postoperative morbidity are independent predictors of survival emphasizing the importance of measures such as portal vein embolization, hepatic pedicle clamping and preservation of venous drainage of the liver remnant. The operative strategy for resection of malignant tumors of the liver should address the key components of the extent of hepatectomy including anatomic resection and optimal pathologic margins, use of the anterior approach, necessity for vascular resection, regional lymphadenectomy and measures to minimize blood loss and postoperative morbidity for maximal survival benefit.


The acceptability of healthcare: from satisfaction to trust.
The assessment of healthcare quality increasingly emphasises lay acceptability, as evidenced by the emergence of patient satisfaction and patient-centred care in the literature and in policy. In this paper we aim to provide a conceptual overview of acceptability and propose ways to enhance its assessment. Firstly, we map how acceptability's importance in quality assessments has increased and how the term acceptability has been used as synonymous with patient satisfaction, despite it being a broader concept. We then critique the concept of patient satisfaction and its measurement and challenge its use as an indicator of acceptability and quality. By drawing on our research and those of others, the second half of the paper describes how trust in clinicians and health services has emerged as a related concept, including a theoretical discussion of trust in healthcare outlining how it can be built, undermined and abused. We propose trust as an alternative indicator of acceptability in healthcare quality and review its measurement. Finally, we consider how healthcare policy may impact on trust and make recommendations for future research.


Activation of the JAK-STAT3 pathway is associated with the growth of colorectal carcinoma cells.
Excessive activation of inflammatory signaling pathways facilitates colorectal carcinoma (CRC) malignancy. Continuous activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway plays a central role in the development and progression of CRC. With the intent to explore whether attenuation of the JAK-STAT3 signaling axis inhibits cancer cell proliferation or induces apoptosis, a sophisticated oncolytic adenoviral vector, AdCN305, carrying the SOCS3 gene was used to treat CRC cells. Our data revealed that i) in CRC cells, STAT3 was continuously activated by phosphorylation, and SOCS3 was at a relative low expression level; and ii) AdCN305-cppSOCS3 inhibited the continuous activation of the JAK/STAT3 pathway, suppressed CRC cell growth and induced apoptosis, in vitro and in vivo. We proved that SOCS3, a negative regulator of the JAK-STAT3 pathway, efficiently inhibited the activation of the pathway and decreased levels of downstream factors which regulate cell proliferation and the cell cycle.


[Epidemiological study of inflammatory periapical cysts].
We have realized an epidemiologic study of 467 inflammatory periapical cysts. We have valued: age, sex, radiographic size, localization, clinic, evolution time and morphologic aspects. Ware not agree with some authors about some morphologic description.


Discovery and biochemical characterization of two hexokinases from Crassostrea gigas.
Hexokinases (HKs) play a vital role in glucose metabolism, which controls the first committed step catalyzing the production of glucose-6-phosphate from glucose. Two HKs (CGIHK1 and CGIHK2) from the Pacific oyster Crassostrea giga were cloned and characterized. CGIHK1 and CGIHK2 were recombinantly expressed in Escherichia coli and successfully purified by the Ni-NTA column. The optimum pH of the two enzymes was pH 8.0 and 8.5, respectively. The optimum temperature of the two enzymes was 42 °C and 50 °C, respectively. Both enzymes showed a clear requirement for divalent magnesium and were strongly inhibited by SDS. CGIHK1 exhibited highly strict substrate specificity to glucose, while CGIHK2 could also catalyze other 11 monosaccharide substrates. This is the first report on the in vitro biosynthesis of glucose-6-phosphate by the hexokinases from Crassostrea gigas. The facile expression and purification procedures combined with different substrate specificities make CGIHK1 and CGIHK2 candidates for the biosynthesis of glucose-6-phosphate and other sugar-phosphates.


CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study.
Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.


A retrospective comparison of outcomes for open vs. laparoscopic surgical techniques in pediatric ulcerative colitis.
Ulcerative colitis (UC) is an aggressive disease in the pediatric population and a cause of significant, lifelong morbidity. The aim of this study is to compare surgical complications in pediatric patients undergoing laparoscopic vs. open surgical treatment for UC. We queried the Kids' Inpatient Database (KID) for all cases of UC undergoing surgical treatment in 2009 and 2012. We identified patients who received total colectomy without proctectomy (n=413) or total proctocolectomy (n=196) and performed univariate and multivariate analyses comparing laparoscopic vs. open procedures. In pediatric UC patients undergoing total colectomy without proctectomy, open procedures were associated with more complications than laparoscopic, including fluid and electrolyte disorders (40% vs. 28%), surgical wound dehiscence (6% vs. 2%), septicemia (18% vs. 2%), and gastrointestinal disorders (16% vs. 7%) among others, all P<0.05. Likewise, in patients with UC undergoing total proctocolectomy, there were more complications in open vs. laparoscopic technique, including increased transfusion requirements (25% vs. 7%, P=0.001) and significantly more gastrointestinal upset, including nausea, vomiting, and diarrhea (11% vs. 1%, P=0.003). In multivariate analysis, patients who underwent total colectomy with or without proctectomy had an increased risk of experiencing any complication when their procedure was performed in an open or non-elective fashion (all odds ratio >2.4; all P<0.001). The laparoscopic approach was associated with significantly lower rates of surgical complications in pediatric patients undergoing total colectomy with or without proctectomy for UC. These findings demonstrate that laparoscopic technique compares favorably, and may be preferable, to the open approach in selected pediatric patients with UC.


The intake of yam (Dioscorea bulbifera Linn) attenuated the hyperglycemia and the bone fragility in female diabetic rats.
Diabetic patients have a higher risk to osteoporotic fractures. Foods, such as yam, to oppose hyperglycemia, has been used to treatment of diabetes. The goal was assess the role of Brazilian yam (Dioscorea bulbifera) on glycemia and bone parameters of female diabetic rats. Female Wistar rats with 3 months age were allocated in three groups. Control group (C, n = 6), treated with normal fat diet. Diabetic rats treated with high-fat diet without (DM, n = 8) and with (DMY, n = 8) liofilized yam flour. After 5 weeks of the experiment, serum glucose and insulin, pancreas mass, number and area of pancreas islets were quantified. And femur parameters were analyzed by dual-energy X-ray absorptiometry (DXA) and computed tomography (CT). Differences were considered significant if P<0.05. Diabetic groups showed lower (P < 0.05): femur and pancreas mass, area of the pancreatic islets and insulin. However, DMY showed lower (-10%, P < 0.05) concentrations of glucose to DM group. Femur, by DXA, showed lower bone mineral density, content and area in the DM group. While the DMY group showed greater (+27%, P < 0.05) radiodensity of femoral head when compared to DM group. Brazilian yam flour supplement did not fix a defect, but alleviated the consequences of the experimental diabetic disease. It showed results to control the rise in blood glucose levels in diabetic rats, suggesting protection in oxidative agents and postpone harm in the bone. Considering all the findings of the present study, our results suggest that yam flour does act producing benefits in the experimental diabetes.


Identification of cdtB homologues and cytolethal distending toxin activity in enterohepatic Helicobacter spp.
A bacterial toxin that causes progressive distension and death of Chinese hamster ovary (CHO) cells and HeLa cells, termed cytolethal distending toxin (Cdt), has been identified in several diarrhoeagenic bacteria, including Campylobacter spp. (C. jejuni and Cq coli), some pathogenic strains of Escherichia coli and Shigella spp. Genes encoding this toxin were identified as a cluster of three adjacent genes cdtA, cdtB and cdtC. Homologues of cdtB from five species of enterohepatic helicobacters (Helicobacter hepaticus, H. bilis, H. canis and two novel Helicobacter spp. isolated from mice and woodchuck, respectively) were identified by means of degenerative PCR primers, cloned and sequenced. The similarities of these partial cdtB nucleotide sequences from these Helicobacter spp. to those of cdtB genes known to be present in other bacteria were: C. jejuni, 58.3-64.8%; E. coli, 52.3-57.8%, Haemophilus ducreyi, 53.4-58.4% and Actinobacillus actinomycetemcomitans, 52.7-58.1%. Bacterial lysates from four of these helicobacters caused characteristic cytolethal distension of HeLa cells. Cdt caused cell cycle arrest at G2/M phase as measured by flow cytometry. The results demonstrated the presence of a toxin in these Helicobacter spp. belonging to the family of Cdt.


Transcatheter and minimally invasive surgical left ventricular reconstruction for the treatment of ischaemic cardiomyopathy: preliminary results†.
Adverse remodelling of the left ventricle (LV) after myocardial infarction (MI) results in a pathological increase in LV volume and reduction in LV ejection fraction (EF). We describe the preliminary results of a novel, multicentre, combined transcatheter and minimally invasive technique to reconstruct the remodelled LV by plication and exclusion of the scar, and to reduce the excess volume, resulting in decreased wall stress and increased EF. A novel hybrid transcatheter technique that relies on microanchoring technology (Revivent TC™ System, BioVentrix Inc., San Ramon, CA, USA) was used. The LV is reconstructed without the use of extracorporeal circulation by plication of the fibrous scar. This is achieved by implantation of a series of internal and external microanchors brought together over a PEEK (poly-ether-ether-ketone) tether to form a longitudinal line of apposition between the LV free wall and the anterior septum. Internal anchors are deployed by a transcatheter technique on the right side of the ventricular septum through the right internal jugular vein. Paired external anchors are advanced through a left-sided minithoracotomy and deployed on the LV epicardium. A specialized force gauge is used to bring these 'right ventricle (RV)-LV' anchors together under measured compression forces. LV-LV' anchor pairs through the LV apex beyond the distal tip of the RV complete the reconstruction. Patients who were considered eligible for the procedure presented with symptomatic heart failure (New York Heart Association class ≥II) and ischaemic cardiomyopathy (EF <40%) after anteroseptal MI. All patients had a dilated LV with either an a- or dys-kinetic scar in the anteroseptal wall and apex of ≥50% transmurality. Between October 2016 and April 2017, 9 patients (8 men, 1 woman; mean age 60 ± 8 years) were operated on in 2 Dutch centres. Procedural success was 100%. On average, 2.6 anchor pairs were used to reconstruct the LV. Comparing echocardiographic data preoperatively and directly postoperatively, LV ejection fraction increased from 28 ± 8% to 40 ± 10% (change +43%, P < 0.001) and LV volumes decreased LV end-systolic volume index 53 ± 8 ml/m2 to 30 ± 11 ml/m2 (change -43%, P < 0.001) and LVEDVI 75 ± 23 ml/m2 to 45 ± 6 ml/m2 (change -40%, P = 0.001). In 1 patient, an RV perforation occurred which necessitated conversion to full sternotomy. One patient underwent a postoperative revision because of RV restriction. After the removal of 1 'RV-LV' anchor pair, the patient recovered completely. Hospital mortality was 0%. The median duration of intensive care unit stay was 2 days [interquartile range (IQR) 1-46 days], and the median length of hospital stay was 9 days (IQR 3-57 days). Hybrid transcatheter LV reconstruction is a promising novel treatment option for patients with symptomatic heart failure and ischaemic cardiomyopathy after anteroseptal MI. The early results demonstrate that the procedure is safe and results in a significant improvement in EF and reduction in LV volumes in the early postoperative period.


Corneal endothelium, retinal nerve fiber layer, ganglion cell complex, and perimetry measurements in normal eyes and those with primary open-angle glaucoma.
Corneal endothelial cell (CEC) loss in glaucoma can be attributed to the direct compressive effect of elevated intraocular pressure. Herein, we aimed to evaluate specular microscopic changes in CEC count and morphology in correlation to retinal nerve fiber layer (RNFL) changes detected by spectral-domain optical coherence tomography (SD-OCT) in early and advanced primary open-angle glaucoma (POAG). This descriptive-analytical study involved patients with medically controlled POAG versus non-glaucomatous patients of the same age group. Specular microscopy, visual field testing, and SD-OCT of the RNFL and macular ganglion cell complex (GCC) were performed. Eyes with POAG were further subcategorized into early and advanced stages. The study included 130 eyes of 130 participants; 70 were eyes with POAG (40 eyes with early-stage POAG, 30 eyes with advanced-stage POAG), and 60 were healthy eyes. The groups were comparable regarding mean age and sex. No significant difference was found in corneal parameters between healthy eyes, eyes with early POAG, and eyes with advanced POAG (all P > 0.05). In eyes with early-stage POAG, a significant negative correlation was found between the coefficient of variation (CV) and superior RNFL thickness (r = - 0.5; P = 0.018), and between the percentage of hexagonal cells (hexagonality) and vertical cup-to-disc ratio (r = - 0.43; P = 0.035). A significant positive correlation was found between hexagonality and superior as well as inferior RNFL thickness (r = + 0.53; P = 0.008 and r = + 0.50; P = 0.015, respectively). However, in the advanced glaucomatous eyes, no significant correlation was found between RNFL thickness and CEC parameters. CEC parameters were not affected in eyes with early or advanced POAG compared with healthy eyes, despite a significant thinning of RNFL and macular GCC. In eyes with early-stage POAG, a significant correlation was found between morphological characteristics of CECs, such as CV and hexagonality, with superior and inferior RNFL thickness in the optic nerve head on SD-OCT images. Future longitudinal studies with larger sample sizes are needed to verify our results.


Authentication of collagen VI antibodies.
Collagen VI is a ubiquitously-expressed macromolecule that forms unique microfibrillar assemblies in the extracellular matrix. Mutations in the COL6A1, COL6A2 and COL6A3 genes result in congenital muscular dystrophy, arguing that collagen is critical for skeletal muscle development and function. Antibodies against collagen VI are important clinical and diagnostic tools in muscular dystrophy. They are used to confirm genetic findings by detecting abnormalities in the distribution, organization and overall levels of collagen VI in cells and tissues isolated from patients. Many antibodies have been raised against tissue-purified collagen VI and individual collagen VI chains, however few have been properly validated for sensitivity and chain specificity. To address this deficiency, we compared the ability of 23 commercially-available antibodies to detect extracellular collagen VI by immunohistochemistry on frozen tissue sections. To determine chain specificity, immunoblot analyses were conducted on cell lysates isolated from cells transfected with cDNAs for each individual chain and cells expressing all three chains together. Our analyses identified 15 antibodies that recognized tissue collagen VI by immunohistochemistry at varying intensities and 20 that successfully detected collagen VI by immunoblotting. Three antibodies failed to recognize collagen VI by either method under the conditions tested. All chain-specific antibodies that worked by immunoblotting specifically recognized their correct chain, and no other chains. This series of side-by-side comparisons reveal at least two antibodies specific for each chain that work well for immunohistochemistry on frozen sections. This validation study expands the repertoire of antibodies available for muscular dystrophy studies caused by defects in collagen VI.


[Method of random selection of fields of view for pathological study of histological preparations].
A simple method for selection of fields of vision in microscopy of histological sections is suggested. The objective of the microscope is focused to any corner of the section, and values of integrator screws of the preparation driver are read. Two other diagonal corners of the section are placed under the objective and values of the integrator screws are read. Numbers of the natural series between the first and second readings of integrator screw values are taken as the numbers of fields of vision in the section examined. A random number of a field of vision is obtained from the table of random numbers in the interval of numbers obtained from values of the integrator screws.


Formula feeding can help illuminate long-term consequences of full ectogenesis.
Breastfeeding is analogous to pregnancy as an experience, in its exclusiveness to women, and in its cost and the effects it has on equitable share of labor. Therefore, the history of formula feeding provides useful insights into the future of full ectogenesis, which could evolve into a more severe version of what formula feeding is today: simplify life for some women and provide couples with a more equitable share of work at the cost of stigma, guilt and a daily diet of studies purporting to show the benefits of natural pregnancy. Making pregnancy an optional route to motherhood would make women's life trajectory more similar to men's and thus put pressure on women to compete with men on the ground shaped by men's preferences. Despite being a treasured experience of many women today, bearing children could become the luxury of the few, the province of the very poor and a choice working women will pay a high price for as women who choose pregnancy become stigmatized as self-indulgent or unprofessional and penalized for it in the workplace. At the same time, scarce societal resources that could be used to support pregnant women and working mothers would instead be directed toward proving to women or even forcing them to gestate children "the right way." While not necessarily threatening on its own, when added to formula feeding, IVF, stem-cell produced ova and sex robots, full ectogenesis could diminish men's stake in women's wellbeing and even existence.


Renal function and its association with blood pressure in Middle Eastern immigrants and native Swedes.
Iraqi-born immigrants residing in Sweden are at high risk for type 2 diabetes, obesity and hyperlipidemia compared with native Swedes. Paradoxically, hypertension is less prevalent in this immigrant population. The aim of this study was to investigate differences in renal function and further if differences in blood pressure (BP) levels were associated with differences across ethnicities in renal function as a possible explanation to the paradox. A population-based, cross-sectional study of men and women, born in Iraq or Sweden, aged 30-75 years was conducted in Malmö, Sweden, from 2010 to 2012. Blood samples were drawn, physical examinations performed and self-administrated questionnaires were assessed. Estimated glomerular filtration rate (eGFR) was calculated from the Caucasian Asian Pediatric Adult cohort formula based on cystatin C. Participants without history of cardiovascular disease born in Iraq (n = 1214), irrespective of age and sex, presented with higher eGFR than participants born in Sweden (n = 659), (96.5 ml/min per 1.73 m vs. 93.6, P = 0.009). Furthermore, eGFR showed weaker association with BP in Iraqis than in Swedes, especially for SBP. The relationship was confirmed by a significant interaction between eGFR and country of birth (Pinteraction country of birth × eGFRcystatinC = 0.004). The current study shows differences across ethnicities in renal function and its associations with BP. More studies are needed to understand mechanisms contributing to BP regulation and renal function in populations of different ethnic backgrounds.


Identification of a second endogenous Porphyromonas gingivalis insertion element.
In this study a second endogenous Porphyromonas gingivalis insertion element (IS element) that is capable of transposition within P. gingivalis was identified. Nucleotide sequence analysis of the Tn4351 insertion site in a P. gingivalis Tn4351-generated transconjugant showed that a complete copy of the previously unidentified IS element, designated PGIS2, had inserted into IS4351R in Tn4351. PGIS2 is 1,207 bp in length with 19-bp imperfect terminal inverted repeats, and insertion resulted in a duplicated 10-bp target sequence. Results of Southern hybridization of chromosomal DNA isolated from several P. gingivalis strains with a PGIS2-specific probe demonstrated that the number of copies of PGIS2 per genome varies among different P. gingivalis strains. Computer analysis of the putative polypeptide encoded by PGIS2 revealed strong homologies to the products encoded by IS1358 from Vibrio cholerae, ISAS1 from Aeromonas salmonicida, and H-rpt in Escherichia coli K-12.


Cellular organization of urinary acidification.
The turtle bladder contains transport systems for active sodium absorption, electrogenic proton secretion, and bicarbonate secretion (coupled to chloride absorption) that are functionally separate and occur in specialized epithelial cells. Maneuvers that alter the intracellular acid-base state, such as changes in PCO2, cause marked changes in the apical membrane area of alpha-type carbonic anhydrase (CA) cells by addition or retrieval of membrane vesicles but have no effect on the granular cells that transport sodium. The apical cell membrane of alpha-CA cells contains characteristic rod-shaped intramembrane particles (RSP) by freeze fracture and is coated on its cytoplasmic side with studs. A subpopulation of CA cells (beta-type), which is characterized by apical microvilli, fails to exhibit an apical response to CO2 stimulation and does not reveal RSPs or studs at its apical membranes; instead, these elements can be demonstrated at the basolateral membrane. The reversal in the polarity of these elements as well as physiological evidence suggest that beta-type cells are responsible for bicarbonate secretion. Structure-function studies of CO2 stimulation of H+ secretion by alpha-CA cells indicate that the secretion rate (JH) correlates with apical membrane area and numbers of RSPs. The view that RSPs represent arrays of transmembrane channels and that studs represent catalytic units of H+ pumps is supported by quantitative considerations but remains to be proven. Urinary acidification is regulated not only by changes in the number of H+ pumps but also by the intrinsic properties of the H+ pump itself. For a given pump population, JH is closely controlled by the delta microH across the active transport pathway.


Use of carnosine in the prevention of cardiometabolic risk factors in overweight and obese individuals: study protocol for a randomised, double-blind placebo-controlled trial.
Carnosine, an over the counter food supplement, has been shown to improve glucose metabolism as well as cardiovascular risk factors in animal and human studies through its anti-inflammatory, antioxidative, antiglycating and chelating properties. The aim of this study is to establish if carnosine supplementation improves obesity, insulin sensitivity, insulin secretion, cardiovascular risk factors including arterial stiffness and endothelial function, and other risk factors related to diabetes and cardiovascular disease in the overweight and obese population. Fifty participants will be recruited to be enrolled in a double-blind randomised controlled trial. Eligible participants with a body mass index (BMI) between 25 and 40 kg/m2 will be randomly assigned to the intervention or placebo group. Following a medical review and oral glucose tolerance test to check eligibility, participants will then undergo testing. At baseline, participants will have anthropometric measurements (BMI, dual X-ray absorptiometry and peripheral quantitative CT scan), measurements of glucose metabolism (oral glucose tolerance test, intravenous glucose tolerance test and euglycaemic hyperinsulinaemic clamp), cardiovascular measurements (central blood pressure, endothelial function and arterial stiffness), a muscle and fat biopsy, physical activity measurement, liver fibroscan, cognitive function and questionnaires to assess dietary habits, sleep quality, depression, and quality of life. Following baseline assessments, participants will be randomised to either 2 g carnosine or placebo for 15 weeks. In the 15th week, all assessments will be repeated. The preplanned outcome metric is the change between baseline and follow-up measures. This study is approved by the Human Research Ethics Committee of Monash Health and Monash University, Australia. NCT02686996.


Nintedanib: a novel therapeutic approach for idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease with no clear etiology and few therapeutic options. Growth factors that act as mediators in the development of this disease might be important therapeutic targets. Nintedanib is a triple-tyrosine kinase inhibitor and a potent antagonist of growth factors such as platelet-derived growth factor, vascular endothelial growth factor, and basic fibroblast growth factor, and it is currently evaluated in clinical trials as a potential IPF therapy. Treatment with nintedanib may slow decline in lung function, decrease the frequency of exacerbations, and improve quality of life in subjects with IPF. This observation, together with extensive safety and pharmacokinetic data from studies of nintedanib in malignancy, led the way for the clinical development of this drug in IPF. Observations from clinical trials, together with the preclinical data, suggest that nintedanib may become an important therapeutic option for individuals with IPF. High-dose nintedanib improved the quality of life, slowed the progression of lung fibrosis and the decline of lung function, and reduced the rate of exacerbations in individuals with mild and moderate IPF. This is a short review based on the available data (September 2013) on nintedanib.


Indices of membrane alterations in beta-thalassemic erythrocytes.
Analytical protocols for the study of thalassemic erythrocyte membrane alterations are described. Denatured hemoglobin derivatives and aggregated band 3 are separated from detergent membrane extracts by gel-filtration as high-molecular-weight aggregates and quantitated spectrophotometrically. Membrane-bound, low-molecular-weight iron is measured on SDS-solubilized ghosts by a ferrozine-based colorimetric test. We adapted these methods for microscale preparation and analysis of erythrocyte ghosts in order to have suitable tools to estimate oxidative membrane damage in human samples. Data from 11 beta-thalassemia intermedia patients and from 10 normal controls are reported as an example of the application of these methods.


Highly stereospecific epimerization of alpha-amino acids: conducted tour mechanism.
The highly stereospecific and regiospecific recognition of alpha-amino acids exhibited by a novel Co(III) metal complex embodied in the experimental work (Nature 1999, 401, 254) is rationalized from the energetics and structural characteristics with the use of density functional calculations. The steric repulsion between the chiral center of the receptor [Co(III) complex] and alanine has been a cause for the discrimination of complex stabilities. The energies evaluated for all possible alanine binding modes clearly reveal regiospecificity. Our main emphasis is laid on the base-catalyzed epimerization reaction that drives the stereospecific recognition to near completion. The conducted tour mechanism is found to be the most likely candidate. A similar role by the equivalent Zn(II) complex is found.


Current trends in cigarette advertising and marketing.
Because the nation's health is so greatly influenced by cigarette smoking, this report examines current trends in cigarette advertising and marketing. According to the Federal Trade Commission, total cigarette advertising and promotional expenditures reached $2.1 billion in 1984. From 1974 through 1984, total expenditures increased approximately sevenfold, or threefold after adjustment according to the consumer price index. In 1985, cigarette advertising expenditures accounted for 22.3 percent, 7.1 percent, and 0.8 percent of total advertising expenditures in outdoor media, magazines, and newspapers, respectively. When all products and services were ranked according to national advertising expenditures, cigarettes were first in the outdoor media, second in magazines, and third in newspapers. The proportion of total cigarette advertising and promotional expenditures devoted to promotional activities has increased steadily, from 25.5 percent in 1975 to 47.6 percent in 1984. The proportion of expenditures for cigarettes yielding 15 mg or less of "tar" has increased substantially and has consistently exceeded the domestic market share of these cigarettes. The fastest growing markets are discounted cigarettes and brands containing 25 cigarettes per pack. Several advertising campaigns have targeted women, minorities, and blue-collar workers. The study of these marketing trends should assist health officials in identifying and predicting patterns of cigarette use and in developing health promotion programs that counteract the influence of advertising by incorporating similar, effective techniques.


Anti-Endosialin Antibody-Drug Conjugate: Potential in Sarcoma and Other Malignancies.
Endosialin/TEM1/CD248 is a cell surface protein expressed at high levels by the malignant cells of about 50% of sarcomas and neuroblastomas. The antibody-drug conjugate (ADC) anti-endosialin-MC-VC-PABC-MMAE was selectively cytotoxic to endosialin-positive cells in vitro and achieved profound and durable antitumor efficacy in preclinical human tumor xenograft models of endosialin-positive disease. MC-VC-PABC-MMAE was conjugated with anti-endosialin with 3-4 MMAE molecules per ADC. The anti-endosialin-MC-VC-PABC-MMAE conjugate was tested for activity in four human cell lines with varied endosialin levels. The HT-1080 fibrosarcoma cells do not express endosialin, A-673 Ewing sarcoma cells and SK-N-AS neuroblastoma cells are moderate expressers of endosialin, and SJSA-1 osteosarcoma cells express very high levels of endosialin. To determine whether endosialin expression was maintained in vivo, A-673 Ewing sarcoma, SK-N-AS neuroblastoma, and SJSA-1 osteosarcoma cells were grown as xenograft tumors in nude mice. The SK-N-AS neuroblastoma and the A-673 Ewing sarcoma lines were selected for in vivo efficacy testing of the anti-endosialin-MC-VC-PABC-MMAE conjugate. The treatment groups included a vehicle control, unconjugated anti-endosialin, an admix control consisting of anti-endosialin and a dose of free MMAE equivalent to the dose administered as the ADC, and the anti-endosialin-MC-VC-PABC-MMAE conjugate. The unconjugated anti-endosialin had no antitumor activity and resulted in similar tumor growth as the vehicle control. The admix control produced a modest tumor growth delay. Administration of the anti-endosialin-MC-VC-PABC-MMAE conjugate resulted in a marked prolonged tumor response of both xenograts. These proof-of-concept results break new ground and open a promising drug discovery approach to these rare and neglected tumors.


Qac genes and biocide tolerance in clinical veterinary methicillin-resistant and methicillin-susceptible Staphylococcus aureus and Staphylococcus pseudintermedius.
Qac genes are associated with increased tolerance to quaternary ammonium compounds and other cationic biocides such as chlorhexidine. This study aimed to determine whether qac genes and increased biocide tolerance were present in 125 clinical methicillin-resistant and susceptible veterinary staphylococci. A total of 125 methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant and -susceptible Staphylococcus pseudintermedius (MRSP and MSSP) from three archived Australian veterinary staphylococci collections underwent whole genome sequencing, multilocus sequence typing and qac gene screening. Two MRSA isolates (12%) harboured qacA/B genes; both isolates were ST8 from horses. QacJ, qacG and smr genes were identified in 28/90 (31%) MRSP and 1/18 (6%) MSSP isolates. ST71 MRSP was significantly more likely to harbour qac genes than other MRSP clones (p < 0.05). A random subset of 31 isolates underwent minimum bactericidal concentration (MBC) testing against F10SCTM (benzalkonium chloride and biguanide), and HexaconTM (chlorhexidine gluconate), with and without the addition of bovine serum albumin (BSA) as an in vitro substitute for organic matter contamination. Qac genes were not associated with increased phenotypic biocide tolerance but biocide efficacy was significantly affected by the presence of BSA. In the absence of BSA, all MBC values were well below the recommended usage concentration. When BSA was present, regardless of qac gene presence, 50% of MRSA and 43% of MRSP had an F10SCTM MBC above the recommended concentration for general disinfection. Qac genes did not confer increased in vitro biocide tolerance to veterinary staphylococci. Organic matter contamination must be minimized to ensure the efficacy of biocides against MRSA and MRSP.


Nocturnal nasal obstruction is frequent and reduces sleep quality in patients with obstructive sleep apnea.
The prevalence and consequences of nasal obstruction in untreated obstructive sleep apnea patients are not known. The study objectives were to investigate the frequency of subjective and objective nasal obstruction in untreated sleep apnea patients and the associations with sleep and quality of life. Patients in the Icelandic Sleep Apnea Cohort were subjected to a type 3 sleep study, answered questionnaires and had their nasal dimensions measured by acoustic rhinometry. In total, 810 patients participated (including 153 females), aged 54.5 ± 10.6 years [mean ± standard deviation (SD)] with an apnea/hypopnea index 44.7 ± 20.7 h-1 . Nocturnal nasal obstruction (greater than or equal to three times per week) was reported by 35% of the patients. These patients had smaller nasal dimensions measured by the minimum cross-sectional area within the smaller nasal valve (0.42 ± 0.17 versus 0.45 ± 0.16 cm2 , P = 0.013), reported more daytime sleepiness (Epworth Sleepiness Scale score 12.5 ± 4.9 versus 10.8 ± 5.0; P < 0.001) and slightly lower mental quality of life than patients without nocturnal nasal obstruction. Nocturnal nasal obstruction is reported in one-third of the sleep apnea patients and they are more likely to suffer from daytime sleepiness and slightly reduced quality of life than other sleep apnea patients.


Acute increases in forebrain blood flow during altering responses in conscious rabbits.
We have previously shown that alerting responses (documented by appearance of theta rhythm in the hippocampal EEG) are associated with a characteristically timed acute vasoconstriction in the ear artery bed of the conscious rabbit. We have now determined what happens to forebrain blood flow (Doppler probe chronically implanted around the internal carotid artery) during similar alerting responses in conscious rabbits, comparing forebrain flow to simultaneously measured ear flow. During an alerting response, forebrain flow increased by 31 +/- 8% of baseline (n = 6, P < 0.01), with the increase commencing within 1 s of the stimulus, at approximately the same time as the decrease in ear flow. Arterial pressure increased from 77 +/- 3 to 81 +/- 3 mmHg (P < 0.01), so that internal carotid conductance increased from 0.17 +/- 0.02 to 0.20 +/- 0.02 kHz/mmHg (P < 0.01). During a 1 h continuous recording period in the laboratory there was a negative correlation between forebrain and skin flow, with the Pearson coefficient in individual rabbits ranging from -0.18 to -0.62 (n = 6, all correlations P < 0.01). During this period, forebrain blood flow was just as variable, from second to second, as distal aortic flow, but not as variable as ear blood flow. Our study thus demonstrates that alerting responses in rabbits are associated with rapid increases in cerebral vascular conductance. We believe that this is the first demonstration of this phenomenon in the conscious experimental animal.


Influence of recovery time on post-activation potentiation in professional rugby players.
Following a bout of heavy resistance training, the muscle is in both a fatigued and potentiated state with subsequent muscle performance depending on the balance between these two factors. To date, there is no uniform agreement about the optimal acute recovery required between the heavy resistance training and subsequent muscle performance to gain performance benefits. The aim of the present study was to determine the recovery time required to observe enhanced muscle performance following a bout of heavy resistance training. Twenty professional rugby players performed a countermovement jump at baseline and approximately 15 s, 4, 8, 12, 16, 20, and 24 min after a bout of heavy resistance training (three sets of three repetitions at 87% one-repetition maximum squat). Power output, jump height, and peak rate of force development were determined for all countermovement jumps. Despite an initial decrease in countermovement jump performance after the heavy resistance training (P<0.001), participants' performance increased significantly following 8 min recovery (P<0.001) (i.e. jump height increased by 4.9%, s=3.0). The findings suggest that muscle performance during a countermovement jump can be markedly enhanced following bouts of heavy resistance training provided that adequate recovery (approximately 8 min) is allowed between the heavy resistance training and the explosive activity.