Matrix metalloproteinase 10 and the slow demise of the peritoneal membrane.
Matrix metalloproteinases (MMPs) cleave matrix components along with multiple other effects. They are integral to virtually all biological processes, including inflammation and wound healing. As such, MMPs have been studied in the context of peritoneal membrane injury. MMP10 is a stromelysin and is involved in the degradation of matrix proteoglycans. Ishimura et al. demonstrate that MMP10 is involved in peritoneal membrane fibrosis. The clinical implications of these observations are presently unknown.


The Impact of Clostridium difficile Infection on Future Outcomes of Solid Organ Transplant Recipients.
OBJECTIVEClostridium difficile infection (CDI) is common in solid organ transplant (SOT) recipients, but few studies have examined long-term outcomes. We studied the impact of CDI after SOT on mortality and transplant organ complication-related hospitalizations (TOH).METHODSSOT recipients ≥18 years of age with at least 1 year of posttransplant data were analyzed using the MarketScan database for 2007-2014. Patients who died within one year of transplant were followed until death. Patients were grouped as early CDI (ie, first occurrence ≤90 days posttransplant), late CDI (ie, first occurrence >90 days posttransplant) and controls (ie, no CDI occurrence during follow-up). The risk of mortality or TOH after CDI was evaluated using Cox and logistic regressions, respectively.RESULTSOverall, 96 patients had early CDI, 97 patients had late CDI, and 5,913 patients were used as controls. The risk for death was significantly higher in the early CDI group than the control group (hazard ratio [HR],1.92; 95% confidence interval [CI], 1.12-3.29; P=.018); there was no significant difference between the late CDI group and the control group (HR, 0.86; 95% CI, 0.38-1.94; P=.717). Both the early CDI group (odds ratio [OR], 2.19; 95% CI, 1.45-3.31; P90 days posttransplant, both the early CDI group (n=89) and the late CDI group (n=97) had increased risk for death or TOH during follow-up than the control group (n=5,734).CONCLUSIONThough our study could not prove causality, both early and late CDI occurrence in SOT recipients were associated with worse future outcomes than for SOT recipients without CDI.Infect Control Hosp Epidemiol 2018;39:563-570.


Dyslexia and learning disabilities in Canada and the UK: the impact of its disability employment laws.
The impact of employment laws pertaining to individuals with learning disabilities in Canada and dyslexia in the UK were investigated via the extant research literature. Currently, there is very little research in this area despite Canada and the UK having laws in effect for decades. Surprisingly, their laws have been revamped despite an absence of data that measures impact and effectiveness. This finding is not unlike the Americans with Disabilities Act, reauthorized as the Americans with Disabilities Act Amendments in 2008, without substantive research to guide legal policies and practices going forward. Investigation in this area is needed to seek the positive and negative effects of legislation on those with learning disabilities in Canada and dyslexia in the UK, a high incidence population that finds most employment opportunities in competitive employment.


Drivers Motivating Community Health Improvement Plan Completion by Local Public Health Agencies and Community Partners in the Rocky Mountain Region and Western Plains.
There are numerous drivers that motivate completion of community health improvement plans (CHIPs). Some are more obvious and include voluntary public health accreditation, state requirements, federal and state funding, and nonprofit hospital requirements through IRS regulations. Less is known about other drivers, including involvement of diverse partners and belief in best practices, that may motivate CHIP completion. This research investigated the drivers that motivated CHIP completion based on experiences of 51 local public health agencies (LPHAs). An explanatory mixed-methods design, including closed- and open-ended survey questions and key informant interviews, was used to understand the drivers that motivated CHIP completion. Analysis of survey data involved descriptive statistics. Classical content analysis was used for qualitative data to clarify survey findings. The surveys and key informant interviews were conducted in the Rocky Mountain Region and Western Plains among 51 medium and large LPHAs in Colorado, Kansas, Montana, Nebraska, North Dakota, South Dakota, Utah, and Wyoming. More than 50% of respondents were public health directors; the balance of the respondents were division/program directors, accreditation coordinators, and public health planners. CHIP completion. Most LPHAs in the Rocky Mountains and Western Plains have embraced developing and publishing a CHIP, with 80% having completed their plan and another 13% working on it. CHIP completion is motivated by a belief in best practices, with LPHAs and partners seeing the benefit of quality improvement activities linked to the CHIP and the investment of nonprofit hospitals in the process. Completing a CHIP is strengthened through engagement of diverse partners and a well-functioning partnership. The future of CHIP creation depends on LPHAs and partners investing in the CHIP as a best practice, dedicating personnel to CHIP activities, and enhancing leadership skills to contribute to a synergistic partnership by effectively working and communicating with diverse partners and developing and achieving common goals.


Radiological differentiation of phaeochromocytoma from other malignant adrenal masses: importance of wash-in characteristics on multiphase CECT.
To evaluate the computerised tomography (CT) characteristics of phaeochromocytoma (PCC) that differentiate them from other non-benign adrenal masses such as adrenocortical carcinoma (ACC), primary adrenal lymphoma (PAL) and adrenal metastases (AM). This retrospective study was conducted at a tertiary health care institute from Western India. Patients presented between January 2013 and August 2016 with histological diagnosis of PCC or other non-benign adrenal mass having adequate reviewable imaging data comprising all four CECT phases were included. The study cohort consisted of 72 adrenal masses from 66 patients (33 PCC, 22 ACC, 4 PAL, 13 AM). Unlike other masses, majority of PCC (25/33) showed peak enhancement in early arterial phase (EAP). PCC had significantly higher attenuation in EAP and early venous phase (EVP), and higher calculated percentage arterial enhancement (PAE) and percentage venous enhancement (PVE) than other adrenal masses (P < 0.001). For diagnosis of PCC with 100% specificity, PAE value ≥100% and EAP attenuation ≥100 HU had 78.8 and 63.6% sensitivity respectively. ACC were significantly larger in size as compared to PCC and metastasis. The adreniform shape was exclusively found in PAL (two out of four) and AM (4 out of 13). None of the enhancement, wash-in or washout characteristics were discriminatory among ACC, PAL and AM. Peak enhancement in EAP, PAE value ≥100% and EAP attenuation ≥100 HU differentiate PCC from other malignant adrenal masses with high specificity.


Regulation of Triglyceride Metabolism. III. Emerging role of lipid droplet protein ADFP in health and disease.
ADFP is the major lipid droplet protein present in all cells that accumulate lipids either normally or abnormally. Although discovered about 15 years ago, it was only in the last few years that we began to have a working knowledge of its possible role in lipid droplet homeostasis at the whole organism level. In this perspective, we concentrate on the potential function of ADFP in various tissues. Space limitation has precluded a complete cataloging of all publications on the topic. We instead highlight some of the salient developments in the last few years.


[Laser thermokeratoplasty: clinico-functional aspects of postoperative eye condition].
Laser thermokeratoplasty (LTK) induces postoperative inflammation of the cornea. Its clinical manifestation as well as the degree of endothelial cell loss depend on laser irradiation energy and the number of coagulates. The refractive effect of LTK is most stable in a hyperopia of up to 3.0 D and a laser energy value of up to 170 mJ; in this case, endothelial cell loss dose not exceed 2.2%. According to biomicroscopy, ultrasound pachimetry, and optical coherent tomography of the anterior segment of the eye, LTK results in corneal thickening, after which the volume of the coagulant gradually decreases and stabilizes by the end of the first year after LTK. Two types of scar, biomicroscopically different in size and optical density, form after LTK. The authors distinguish four clinical periods of healing after LTK, which makes it possible to evaluate and systematize physiological and biomechanical processes taking place in the cornea during refraction formation.


Patterns of hippocampal neuronal loss and axon reorganization of the dentate gyrus in the mouse pilocarpine model of temporal lobe epilepsy.
The patterns of hippocampal neuronal loss and rewiring of the dentate gyrus (DG) were studied in the mouse model of temporal lobe epilepsy at 2 months after pilocarpine-induced status epilepticus (PISE). NeuN immunocytochemistry showed two patterns of neuronal damage, i.e., type 1 with partial loss of pyramidal neurons in CA3 area and type 2 with almost compete loss of CA3 pyramidal neurons. Anterograde tracing with Phaseolus vulgaris leucoagglutinin (PHA-L) demonstrated that, at different rostrocaudal segments of the hippocampus, associational and commissural connections in the DG changed differently between mice with type 1 vs. type 2 neuronal loss. Calretinin (CR)-immunopositive mossy cells in ventral hilus and its fibers in inner molecular layer of bilateral DG remained in mice with type 1 but almost disappeared in mice with type 2 neuronal loss, which was further supported by retrograde labeling with cholera toxin subunit B (CTB) showing colocalization of CTB with CR in the ventral hilus of bilateral DG in mice with type 1 neuronal loss, which was lost in those with type 2 neuronal loss. Furthermore, the sprouted PHA-L-immunopositive en passant and terminal boutons from the DG were found in CA1 area to contact with surviving calbindin-, CR-, and parvalbumin-immunopositive neurons. The present study therefore suggests that different patterns of neuronal loss in CA3 area may be linked to different axon reorganizations in the DG.


Heterogeneous Mechanisms of Secondary Resistance and Clonal Selection in Sarcoma during Treatment with Nutlin.
Nutlin inhibits TP53-MDM2 interaction and is under investigation in soft-tissue sarcomas (STS) and other malignancies. Molecular mechanisms of secondary resistance to nutlin in STS are unknown. We performed whole-transcriptome sequencing (RNA-seq) on three pretreatment and secondary resistant STS cell lines selected based on their high primary sensitivity to nutlin. Our data identified a subset of cancer gene mutations and ploidy variations that were positively selected following treatment, including TP53 mutations in 2 out of 3 resistant cell lines. Further, secondary resistance to nutlin was associated with deregulation of apoptosis-related genes and marked productive autophagy, the inhibition of which resulted in significant restoration of nutlin-induced cell death. Collectively, our findings argue that secondary resistance to nutlin in STS involved heterogeneous mechanisms resulting from clonal evolution and several biological pathways. Alternative dosing regimens and combination with other targeted agents are needed to achieve successful development of nutlin in the clinical setting.


The human tumor-bearing limb: an ex vivo model.
The present report describes a viable, isolated, perfused, human, tumor-bearing limb model suitable for the study of human host-tumor metabolism. The model is hemodynamically stable with high flow rates (50 cc/kg/min) and low perfusion pressures (mean, 77.2 mm Hg) which are stable over time. Metabolically, the preparation is viable with initial oxygen and glucose uptake 0.88 cc/kg/min and 0.029 mmole/kg/min, respectively. These parameters and lactate concentrations do not change significantly with time.


Frozen shoulder syndrome: diagnostic and treatment strategies in the primary care setting.
The term "frozen shoulder" has been used to describe an array of clinical conditions. The authors consider a patient as meeting the criteria of primary or secondary frozen shoulder syndrome if he/she has a clinical history of worsening painful shoulder motion loss of at least 1 month duration and a physical examination documenting painful restricted shoulder motion. In the evaluation of the patient with suspected FSS, initial screening shoulder radiographs are required to exclude other conditions. The physical examination of the frozen shoulder patient should include observation, cervical examination, assessment of range of motion, and the use of provocative testing. The treatment of the patient with FSS should include preventative education, various medications including NSAIDS and oral corticosteroids, physical therapy, and finally, for the patient with refractory symptoms, surgical intervention. For those patients necessitating surgical intervention, the authors recommend a selective arthroscopic capsular release.


Low-dose photodynamic therapy promotes a cytotoxic immunological response in a murine model of pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a deadly disease with limited treatment options. Approaches to enhance patient immunity against MPM have been tested but shown variable results. Previously, we have demonstrated interesting vascular modulating properties of low-dose photodynamic therapy (L-PDT) on MPM. Here, we hypothesized that L-PDT vascular modulation could favour immune cell extravasation in MPM and improve tumour control in combination with immune checkpoint inhibitors. First, we assessed the impact of L-PDT on vascular endothelial E-selectin expression, a key molecule for immune cell extravasation, in vitro and in a syngeneic murine model of MPM. Second, we characterized the tumour immune cell infiltrate by 15-colour flow cytometry analysis 2 and 7 days after L-PDT treatment of the murine MPM model. Third, we determined how L-PDT combined with immune checkpoint inhibitor anti-CTLA4 affected tumour growth in a murine MPM model. L-PDT significantly enhanced E-selectin expression by endothelial cells in vitro and in vivo. This correlated with increased CD8+ T cells and activated antigen-presenting cells (CD11b+ dendritic cells and macrophages) infiltration in MPM. Also, compared to anti-CTLA4 that only affects tumour growth, the combination of L-PDT with anti-CTLA4 caused complete MPM regression in 37.5% of animals. L-PDT enhances E-selectin expression in the MPM endothelium, which favours immune infiltration of tumours. The combination of L-PDT with immune checkpoint inhibitor anti-CTLA4 allows best tumour control and regression.


Assessing the spatial and temporal variability of bacterial communities in two Bardenpho wastewater treatment systems via Illumina MiSeq sequencing.
Next generation sequencing provides new insights into the diversity and ecophysiology of bacteria communities throughout wastewater treatment plants (WWTP), as well as the fate of pathogens in wastewater treatment system. In the present study, we investigated the bacterial communities and human-associated Bacteroidales (HF183) marker in two WWTPs in North America that utilize Bardenpho treatment processes. Although, most pathogens were eliminated during wastewater treatment, some pathogenic bacteria were still observed in final effluents. The HF183 genetic marker demonstrated significant reductions between influent and post-Bardenpho treated samples in each WWTP, which coincided with changes in bacteria relative abundances and community compositions. Consistent with previous studies, the major phyla in wastewater samples were predominantly comprised by Proteobacteria (with Gammaproteobacteria and Alphaproteobacteria among the top two classes), Actinobacteria, Bacteroidetes, and Firmicutes. Dominant genera were often members of Proteobacteria and Firmicutes, including several pathogens of public health concern, such as Pseudomonas, Serratia, Streptococcus, Mycobacterium and Arcobacter. Pearson correlations were calculated to observe the seasonal variation of relative abundances of gene sequences at different levels based on the monthly average temperature. These findings profile how changes in bacterial communities can function as a robust method for monitoring wastewater treatment quality and performance for public and environmental health purposes.


[Effectiveness of vestibular rehabilitation in patients with vestibular dysfunction].
Vertigo and instability due to vestibular dysfunction have been a frequent cause of work absence, with a clearly upward tendency observed in recent years. Uncompensated vestibular hypofunction requires vestibular rehabilitation, but access to this form of treatment remains limited. Therefore, innovative methods of rehabilitation utilizing new technologies, which could promote this therapy, are searched for. Virtual reality (VR) is becoming a popular method of rehabilitation used, for example, in the treatment of stroke or schizophrenia. The aim of this study was to compare and evaluate 2 methods of vestibular rehabilitation in patients with unilateral vestibular disorders. Forty-three patients with unilateral vestibular disorders diagnosed at the Balance Disorders Unit, 1st Otolaryngology Department of the Medical University of Lodz, were included in this study. The patients, divided into 2 groups, received 10 sessions of rehabilitation. Group 1 (N = 22) was rehabilitated using a VR unit consisting of a forceplate and a motion sensor, while Group 2 (N = 21) performed training on a static posturography platform under physiotherapist supervision. The patients were examined at the baseline, 1 month and 3 months after rehabilitation. During each assessment, posturography was performed which recorded the center of pressure (CoP) displacement. The patients also filled out a questionnaire to quantify vertigo symptoms. The CoP parameters decreased in both groups, with no superiority of either form of training. Analysis of the subjective symptoms reduction revealed a decrease in the Vertigo Syndrome Scale - short form (VSS-sf) score in the second evaluation in both groups, which was slightly greater in the VR group. The improvement remained stable 3 months after rehabilitation. Both forms of rehabilitation are effective in increasing postural stability and reducing subjective symptoms. Virtual reality training achieves a slightly greater subjective improvement. Med Pr. 2019;70(5):545-53.


Psoriasis triggered by mefloquine.
A 46-year-old Caucasian man living on the central Mediterranean island of Gozo (Malta) was started on mefloquine 250 mg once weekly before a trip to lower Egypt. He took his medication 1 week before starting his holiday and was advised to continue it for 4 weeks after returning. He did not take any other medication and enjoyed the holiday, which he initially intended to repeat in the near future. His medical history revealed a number of episodes of psoriasis for which he sought dermatologic advice. He had been given systemic therapy on at least one occasion, but the condition had been fairly quiescent for some time and he had not needed to consult a dermatologist for more than 4 years. Soon after the third tablet of mefloquine and effectively just after his return home to Gozo, the patient noticed that the psoriasis was "creeping back." He noted progressive deterioration in his skin problem but nevertheless finished the recommended course of therapy considering that "being sure about not developing malaria was far more important than a touch of psoriasis." The psoriasis worsened to the extent that he had taken off work for 2 weeks from his job as a self-employed carpenter at the time of referral. On examination, clearly there was a significant flare up of his psoriasis with severe involvement of the hands (Figure 1) and feet and less so over the rest of his body. He had been off work and matters were steadily getting worse in spite of topical treatment with a combination of calcipotriol-betamethasone ointment. Oral methotrexate 15 mg once weekly was commenced together with topical therapy with good results (Figure 2).


Development of a peer-led, network mapping intervention to improve the health of individuals with severe mental illnesses: protocol for a pilot study.
Adults with severe mental illness (SMI) have reduced life expectancy and many have comorbid physical health conditions. Primary care providers are experiencing increased demands for care for people with SMI. Barriers to accessing physical healthcare have been identified which negatively affect quality of care. We propose that peer support workers (PSWs) could deliver an intervention to service users to promote their physical health by drawing on existing social support. The aim of this research was to pilot a novel PSW-led intervention, including personal well-being network mapping, to improve access to primary care for physical health needs. Twenty-four participants will be recruited from community-based mental health teams in two boroughs of London. Each participant will be offered a six-session intervention. Quantitative data will be collected before and after intervention (at 4-month follow-up). Qualitative interviews will be conducted with PSWs after completion of the intervention and with participants at a 4-month follow-up. Some intervention sessions will be observed by a member of the research team. This is a pilot study with a small sample aiming to assess acceptability and feasibility of an intervention. We aim to use the results to refine the existing theory of change and to optimise the intervention and its evaluation in a future randomised controlled trial. This study is strengthened by its potential clinical importance and origin in previous research where service users engaged with well-being network mapping. This study has been approved by the London-Chelsea Regional Ethics Committee (ref: 17/LO/0585). The findings will be disseminated to participants, the National Health Service trusts that we recruited from, primary care mental health leads, commissioners and in peer-reviewed journals and academic conferences.


Regulation of ribosomal RNA synthesis and processing during inhibition of protein synthesis by 1,3-bis(2-chloroethyl)-1-nitrosourea.
The antineoplastic agent BCNU (1,3-bis(2-chloroethyl)-1nitrosourea) at a concentration of 25 mug/ml inhibits initiation of protein synthesis in HeLa cells. At this low concentration of the drug, the rate of synthesis of 45S ribosomal precursor RNA (pre-rRNA) is selectively inhibited without a marked inhibition of nucleoplasmic RNA. The inhibitory effects of the drug are readily reversible upon removal of BCNU from the growth medium. Pulse-chase analysis of the labeled nucleolar RNA in sucrose-gradients and acrylamide gels indicated that the 45S pre-rRNA synthesized before the addition of BCNU matures normally in the presence of the inhibitor. However, the processing of precursor RNA molecules synthesized following the addition of the drug is inhibited when incubation is continued on in the presence of 25 mug/ml BCNU. Since the formation of mature ribosomes is blocked by BCNU, the data would suggest that the effectiveness of the drug as a potent cell growth inhibitor may result from its inhibition of ribosome formation induced by inhibition of protein synthesis.


Duration of Effectiveness Evaluation of Additional Risk Minimisation Measures for Centrally Authorised Medicinal Products in the EU Between 2012 and 2021.
In studies evaluating the effectiveness of additional risk minimisation measures (aRMMs), the need for speed must be properly balanced with the quality of the study. We assessed the duration of aRMM effectiveness evaluations, using additional pharmacovigilance activities, for centrally authorised medicinal products in the European Union. We established a cohort of medicinal products with aRMMs at marketing authorisation (MA) that were centrally authorised from July 2012-December 2021 using the European Public Assessment Reports. Evaluation studies were identified from the Risk Management Plans at the time of MA. Subsequently, we retrieved protocols, final study reports, Pharmacovigilance Risk Assessment Committee (PRAC) assessment reports, and PRAC minutes. We calculated the probability of completing an effectiveness evaluation within 60 months after MA using time-to-event analyses. Besides, we compared the planned final report with the actual final report date. We identified 134 medicinal products authorised with aRMMs, of which almost half (n = 63, 47.0%) had an effectiveness evaluation study. The probability of an evaluation for a medicinal product being completed within 60 months after MA was 20.7% (95% CI 6.8-32.6). Regarding study design, the probability of completing a study was higher for cross-sectional studies when compared to cohort studies (p = 0.002). Moreover, 81.0% of studies were delayed when compared to their planned final report date. The probability of completing an aRMM effectiveness evaluation at time for renewal of the MA was only one in five. Furthermore, estimates of the duration of studies around MA are too optimistic, with the majority being delayed.


The Role of Ferroelectric Polarization in Resistive Memory Properties of Metal/Insulator/Semiconductor Tunnel Junctions: A Comparative Study.
Recently, tunnel junction devices adopting semiconducting Nb:SrTiO3 electrodes have attracted considerable attention for their potential applications in resistive data storage and neuromorphic computing. In this work, we report on a comparative study of Pt/insulator/Nb:SrTiO3 tunnel junctions between ferroelectric BaTiO3 and nonferroelectric SrTiO3 and LaAlO3 barriers to reveal the role of polarization in resistance switching properties. Although hysteretic behaviors appear in current-voltage measurements of all devices regardless of the barrier character, significantly improved current ratios by more than three orders of magnitude are observed in the Pt/BaTiO3/Nb:SrTiO3 tunnel junctions due to the dominance of polarization in modulation of junction barrier profiles between the low and high resistance states. The switchable polarization also gives rise to enhanced resistance retention since the electron diffusion that smears the barrier contrast of the bistable resistance states is suppressed by the polar BaTiO3/Nb:SrTiO3 interface associated with the ferroelectric bound charges. These polarization-induced effects are absent in the nonferroelectric Pt/SrTiO3/Nb:SrTiO3 and Pt/LaAlO3/Nb:SrTiO3 devices in which serious resistance state decay, described by Fick's second law, is observed since there are no switchable interface charges on SrTiO3/Nb:SrTiO3 and LaAlO3/Nb:SrTiO3 to block the electron diffusion. In addition, the Pt/BaTiO3/Nb:SrTiO3 device also exhibits an excellent switching endurance up to ∼4.0 × 106 bipolar cycles. These enhancements indicate the importance of ferroelectric polarization for achieving high-performance resistance switching and suggest that metal/ferroelectric/Nb:SrTiO3 tunnel junctions are promising candidates for nonvolatile memory applications.


Can carcinoembryonic antigen replace computed tomography in response evaluation of metastatic colorectal cancer?
Response Evaluation Criteria in Solid Tumours (RECISTs 1.1) define computed tomography (CT) as the gold standard in response evaluation of patients with metastatic colorectal cancer (mCRC) who are undergoing chemotherapy. The aim of this study was to evaluate whether carcinoembryonic antigen (CEA), which is cheaper and easier to perform, can replace repeated CT. The study included 66 patients with non-resectable mCRC participating in a phase I-II study. CEA values were determined, and CT images were taken every 2 months. CT images were externally and retrospectively reviewed according to the RECIST 1.1 criteria. Different cut-off values for CEA change in percent (DeltaCEA%) compared with baseline or nadir value underwent testing to find patients with disease control (that is stable disease, partial or complete response) at 2, 4, 6 and 8 months, in order to identify those who could have continued with chemotherapy based on CEA values alone. CT verification is needed in progressive disease (PD), and therefore identifying PD patients was our secondary endpoint. The results showed that by using a cut-off value of 0 for DeltaCEA%, disease control was seen in all patients at all measuring points (negative predictive value (NPV) = 1.0). Secondarily, increasing CEA was able to identify all PD patients (sensitivity (Se) = 1.0) and in 50-74% of the patients increasing CEA provided a lead time to PD on upcoming CT. It was possible to replace CT with CEA in all patients with decreasing CEA, meaning that 23-47% of CT scans could have been avoided at any given time point. When the CEA level at a certain measuring point is the same or lower than CEA at baseline or at nadir (the measuring point with the lowest CEA value) during treatment, CEA can replace CT.


Effect of ingestion of unsaturated fat on lipolytic activity of rat tissues.
Homogenates of some rat tissues, incubated in Tris-maleate buffer containing bovine serum albumin, olive oil emulsion, heparin, and serum, liberated free fatty acids. The total lipolytic activity in tissues of rats fed a low fat, 20% lard, or 20% corn oil diet for 6 wk was measured. Similar activities were found in all the livers, but there was a significant increase in the total lipolytic activity of the mucosa, epididymal fat, and mesenteric tissues after ingestion of an unsaturated fat diet as compared with that containing a more saturated fat. From measurements of the lipolytic activity in the presence of 1 M NaCl or 0.2 M NaF and in the absence and presence of heparin and serum, the conclusion is drawn that more lipoprotein lipase was present in adipose tissue of rats on unsaturated fat diets. An increase in available lipoprotein lipase after unsaturated fat diets may aid in clearing lipids from the blood of these rats and thus in producing the lower blood lipid levels obtained.


Reconstitution in vitro of MSP-based filopodium extension in nematode sperm.
The major sperm protein (MSP) motility system in nematode sperm is best known for propelling the movement of mature sperm, where it has taken over the role usually played by actin in amoeboid cell motility. However, MSP filaments also drive the extension of filopodia, transient organelles composed of a core bundle of MSP filaments, that form in the late in sperm development but are not found on crawling cells. We have reconstituted filopodial extension in vitro whereby thin bundles of MSP filaments, each enveloped by a membrane sheath at their growing end, elongated at rates up to 17 microm/min. These bundles often exceeded 500 microm in length but were comprised of filaments only 1 microm long. The reconstituted filopodia assembled in the same cell-free sperm extracts that produced MSP fibers, robust meshworks of filaments that exhibit the same organization and dynamics as the lamellipodial filament system that propels sperm movement. The filopodia and fibers that assembled in vitro both had a membranous structure at their growing end, shared four MSP accessory proteins, and responded identically to agents that alter MSP-based motility by modulating protein phosphorylation. However, filopodia grew three- to four-fold faster than fibers. The reconstitution of filopodial extension shows that, like the actin cytoskeleton, MSP filaments can adopt two architectures, bundles and meshworks, each capable of pushing against membranes to generate protrusion. The reconstitution of both forms of motility in the same in vitro system provides a promising avenue for understanding how the forces for membrane protrusion are produced.


Zinc metabolism and homeostasis in rats fed a wide range of high dietary zinc levels.
Zinc metabolism and homeostasis were studied in young growing rats fed a 38 ppm zinc diet with added zinc levels ranging from 0 to 8400 ppm for 21 days. High dietary zinc did not cause toxicity symptoms. Stable zinc in feces increased linearly with dietary zinc intake but fecal 65Zn, from a single oral dose, did not increase above the 1200 ppm dietary level. Stable zinc in liver, kidney, and tibia increased two to three times with 2400 ppm added zinc, but was not further elevated until 8400 ppm was fed. Stable zinc in muscle and heart was not affected appreciably by dietary zinc level. In all tissues, 65Zn retention was drastically reduced with 1200 ppm added dietary zinc. Additional dietary zinc reduced 65Zn in muscle and heart but had little effect on liver and kidney 65Zn. The data indicate that rats have fairly effective homeostatic control mechanisms for tissue zinc below about 7200 ppm dietary zinc. Whereas, with dietary zinc up to about 1200 ppm, decreasing absorption is the main route of homeostatic control, above this level, more rapid zinc turnover rates and increasing endogenous zinc excretion appear to have major importance.


Comparison of release-controlling efficiency of polymeric coating materials using matrix-type casted films and diffusion-controlled coated tablet.
Polymeric coating materials have been widely used to modify release rate of drug. We compared physical properties and release-controlling efficiency of polymeric coating materials using matrix-type casted film and diffusion-controlled coated tablet. Hydroxypropylmethyl cellulose (HPMC) with low or high viscosity grade, ethylcellulose (EC) and Eudragit(R) RS100 as pH-independent polymers and Eudragit S100 for enteric coatings were chosen to prepare the casted film and coated tablet. Tensile strength and contact angle of matrix-type casted film were invariably in the decreasing order: EC> Eudragit S100> HPMC 100000> Eudragit RS100>HPMC 4000. There was a strong linear correlation between tensile strength and contact angle of the casted films. In contrast, weight loss (film solubility) of the matrix-type casted films in three release media (gastric, intestinal fluid and water) was invariably in the increasing order: EC < HPMC 100000 < Eudragit RS100 < HPMC 4000 with an exception of Eudragit S100. The order of release rate of matrix-type casted films was EC > HPMC 100000 > Eudragit RS100 > HPMC 4000 > Eudragit S100. Interestingly, diffusion-controlled coated tablet also followed this rank order except Eudragit S100 although release profiles and lag time were highly dependent on the coating levels and type of polymeric coating materials. EC and Eudragit RS100 produced sustained release while HPMC and Eudragit S100 produced pulsed release. No molecular interactions occurred between drug and coating materials using (1)H-NMR analysis. The current information on release-controlling power of five different coating materials as matrix carrier or diffusion-controlled film could be applicable in designing oral sustained drug delivery.


Etiology and impact of cytomegalovirus disease on solid organ transplant recipients.
The characteristics, etiology, natural history, and direct and indirect effects of CMV disease in solid organ transplant recipients are described. CMV is a common herpesvirus that may be present in the donor or recipient of a solid organ transplant. Even though it is rarely pathogenic in healthy patients, transplant recipients are at risk for CMV viremia and symptomatic disease due to their immune-suppressed status. In addition to symptoms directly attributed to active disease, CMV can have a variety of indirect effects. Indirect effects may include additional infectious complications, posttransplant lymphoproliferative disease, allograft rejection, allograft loss, or death. The three most prevalent risk factors for CMV infection are CMV seronegativity in a recipient of an organ from a CMV-seropositive donor, the type of organ transplanted, and the degree of immune suppression. CMV prophylaxis is effective at preventing disease, but may result in a delayed onset where CMV disease occurs once the prophylaxis is stopped. Knowledge of risk factors for CMV infection and disease, the natural history in transplant recipients, and its direct and indirect effects will help clinicians make appropriate decisions regarding the use of preventive strategies.


Color and structural modifications of alkaline extracted sunflower protein concentrates and isolates using L-cysteine and glutathione.
Alkaline sunflower protein extraction can be performed along with de-phenolization of sunflower seed proteins if greening is unwanted. This greening is promoted at alkaline pH when chlorogenic acid (CGA) oxidizes and reacts with amino acids such as lysine. Thiol-containing dough conditioners: L-cysteine hydrochloride and glutathione (GSH) were investigated as an alternative de-greening strategy to acidification and de-phenolization. Greening and browning inhibition of thiols (GSH and Cysteine) were modeled by a combination of additive and interaction effects of extraction pH (7.0 to 11.0) and thiol concentration (0.00 to 5.60 mM) randomly assigned by Response Surface Methodology (RSM). The powders with the highest greening were the controls (pH 8.9-9.3 and no added thiols) and powders at pH 10.41 with 0.82 mM thiols. From RSM, the maximum greening inhibition was achieved at pH 8.71 and 4.23 mM cysteine, and pH 8.51 and 3.78 mM GSH. However, cysteine caused more browning at alkaline pH than GSH. Furthermore, fluorescence spectroscopy showed that cysteine had a protective effect against alkaline unfolding, whereas GSH quenched fluorescence in a concentration-dependent manner. Overall, de-greening of alkaline extracted sunflower protein was achieved by adding cysteine or glutathione, but the thiols differed in their contribution to the browning and unfolding effect.


Dual specificity of Src homology 2 domains for phosphotyrosine peptide ligands.
SH2 domains mediate protein-protein interactions and are involved in a wide range of intracellular signaling events. SH2 domains are 100-amino acid stretches of protein that bind to other proteins containing phosphotyrosine residues. A current major research goal is formulation of the structural principles which govern peptide-binding specificity in SH2 domains. Several structures (both X-ray and NMR) of SH2 domains have now been determined. Short peptide fragments on the carboxyl-terminal side of the phosphotyrosine residue carry the sequence specific information for SH2 recognition. The bound peptides are held in an extended conformation. However, for the GRB2 SH2 domain, the peptide adopts a beta-turn as the motif for recognition [Rahuel, J., et al. (1996) Nat. Struct. Biol. 3, 586-589]. Our SAR data and molecular modeling studies suggest that many SH2 domains, such as the SH2 domains of Lck, Src, and p85, can interact with high affinity with short peptide sequences at least in two ways which are sequence-dependent. The peptide forms either an extended chain across the D-strand of SH2 domains with anchors at pY and pY+3 or, as in the case of GRB2 SH2, a beta-turn with anchors at pY and pY+2. Due to a bulky tryptophan in its EF1 loop, GRB2 SH2 cannot bind peptide conformations such as the extended chain and thus has a unique specificity.


Studying fine-grained elements of psychopathology to advance mental health science.
Given the now well-recognized limitations of traditional classification systems for research, this editorial proposes to advance mental health science by focusing research efforts on studying fine-grained elements of mental health and illness such as symptoms, mechanisms, and processes. Our own perspectives are informed by three approaches in particular that have gained traction over the last decade: the Hierarchical Taxonomy of Psychopathology, the network or systems approach, and the National Institute of Mental Health Research Domain Criteria. Drawing on these and other perspectives as well as the diverse views of the author teams that contributed to this Special Section, we summarize the state of the field and propose an ambitious plan for the way ahead. Specifically, we propose that embracing pluralistic, multimethod, and multisystem approaches offers a way forward. This will require strategies to reduce research waste and much stronger channels for communication to identify confluence, discoveries, and dead ends within and between disciplines. We are optimistic this will lead to a better understanding of the mechanisms underpinning psychopathology and ultimately to more effective interventions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Pretreatment with empty liposomes attenuates the immunopathology of invasive pulmonary aspergillosis in corticosteroid-immunosuppressed mice.
In a nonneutropenic murine model of invasive pulmonary aspergillosis, pretreatment with empty liposomes (E-lipo) was nearly as effective as 10 mg/kg of body weight liposomal amphotericin B and superior to 1 mg/kg amphotericin B deoxycholate. The beneficial immunomodulatory properties of E-lipo appear to compensate for their lack of direct antifungal activity.


Thyroid function and prevalence of anti-thyroperoxidase (TPO) and anti-thyroglobulin (Tg) antibodies in outpatients hospital setting in an area with sufficient iodine intake: influences of age and sex.
In order to examine the prevalence of thyroid disease in a hospital outpatient setting, in an area of sufficient iodine intake, serum levels of TSH, T4, T3, anti-Tg and anti-TPO antibodies were examined in 909 individuals with an age range of 12.4 to 88.5 years, participating in a checkup outpatient setting. The study was conducted in Henry Dynant Hospital located in the metropolitan area of Athens, Greece, during a 2 year period. Hormonal parameters were determined by chemiluminescence immunoassay. Overt thyrotoxicosis was found in 4.95% of the total population and subclinical thyrotoxicosis in 5.5%. Overt hypothyroidism was found in 1.43% and subclinical hypothyroidism in 4.51%. In male population, overt thyrotoxicosis was found in 4.4 % and subclinical thyrotoxicosis was also found in 4.4%. On the other hand, overt hypothyroidism was found in 1.4% and subclinical hypothyroidism was found in 3.7% in males. In female population, overt thyrotoxicosis was found in 5.2% whereas subclinical thyrotoxicosis was found in 6.0%. Overt hypothyroidism was found in 1.5% and subclinical hypothyroidism was found in 4,9% in females. Positive anti-TPO antibodies were detected more often (30.4%) than anti-Tg (15.4%) in the tested population. The positivity in both anti-TPO and anti-Tg antibodies was correlated with abnormally high TSH concentrations after the age of 50 years, especially in female population. In conclusion distinct profile of thyroid hormonal parameters was observed in inhabitants in the metropolitan area of Athens, with overt thyrotoxicosis strikingly overcome overt hypothyroidism while subclinical forms of each dysfunction also exhibit analogous results.


The Holden Psychological Screening Inventory and sexual efficacy in urological patients with erectile dysfunction.
This paper examined the relationship between psychological adjustment and sexual ability in a sample of 33 men with erectile dysfunction and their spouses. Indices of sexual efficacy converged and were negatively associated with self-reported depression. Data are interpreted as confirming the association between erectile dysfunction and psychological disturbance and as providing evidence of validity for the Holden Psychological Screening Inventory Depression Scale and the Sexual Self-efficacy Scale.


Effects of Self-Talk Training on Competitive Anxiety, Self-Efficacy, Volitional Skills, and Performance: An Intervention Study with Junior Sub-Elite Athletes.
(1) Background: Self-talk (ST) is used to influence athletes' thoughts, feelings, and behaviors. Samples of squad and competitive athletes are underrepresented, although research has proven the positive effects of ST in the context of sports. Thus, the present study focused on the impact of ST on psychological and performance outcomes of junior sub-elite athletes. (2) Methods: N = 117 athletes (55 females, 62 males; M = 16.0 years) were randomly assigned to either one of two experimental groups or to a control group (n = 30). The experimental groups received an ST intervention for either one week (n = 36) or eight weeks (n = 38), and the control group received no ST training. The dependent variables (competitive anxiety, volitional skills, self-efficacy, and coaches' performance ratings) were assessed three times before and after the intervention. It was expected that (a) an ST intervention would reduce the competitive anxiety and increase volitional skills, self-efficacy, and performance; and, (b) long-term training would lead to higher effects than short-term training. (3) Results: As expected, ST training led to (less) somatic state anxiety and (higher) state self-confidence, self-optimization, self-efficacy, and performance. Additionally, long-term training was more effective than short-term training. (4) Conclusions: Targeted ST interventions may help to improve junior athletes' psychological states and performance.


Venous Diversion Surgery Revisited: A Baffling Situation.
With the increasing number of survivors with congenital heart disease (CHD) reaching adulthood, it is important for the clinician to be familiar with the various surgical options performed in this growing patient population. We describe the case of a 65-year-old female who presented with hypoxia and right-to-left shunting following a surgical repair of an atrial septal defect (ASD) secundum and anomalous pulmonary veins with a partial atrial diversion procedure in childhood. The use of multimodality cardiovascular imaging using echocardiography, computed tomography, magnetic resonance imaging, and invasive cardiac catheterization was complementary in the preoperative diagnosis and management of this unique baffling situation.


Out-of-hospital cardiac arrests in the young population; a 6-year review of the Irish out-of-hospital cardiac arrest register.
Out-of-hospital cardiac arrests (OHCA) in the young population have only been examined in a limited number of regional studies. Hence, we sought to describe OHCA characteristics and predictors of survival to hospital discharge for the young Irish population. An observational analysis of the national Irish OHCA register for all OHCAs aged ≤35 years between January 2012 and December 2017 was performed. The young population was categorised into three age groups: ≤1 year, 1-15 years and 16-35 years. Multivariable logistic regression was used to determine the independent predictors of survival to hospital discharge. A total of 1295 OHCAs aged ≤35 years (26.9% female, median age 25 (IQR 17-31)) had resuscitation attempted. OHCAs in those aged ≥16 years (n=1005) were more likely to happen outside the home (38.5% vs 22.8%, p<0.001) and be of non-medical aetiology (59% vs 27.6%, p<0.001) compared with those aged <16 years (n=290). Asphyxiation, trauma and drug overdoses accounted for over 90% of the non-medical OHCAs for those 16-35 years. Overall survival to hospital discharge for the cohort was 5.1%; survival was non-significantly higher for those aged 16-35 years compared with those aged 1-15 years (6.0%, vs 2.8% p=0.93). Independent predictors of survival to hospital discharge included bystander witnessed OHCA, a shockable initial rhythm and a bystander defibrillation attempt. The high prevalence of non-medical OHCAs and the OHCA location need to be considered when developing OHCA care pathways and preventative strategies to reduce the burden of OHCAs in the young population.


Activation of N-ras induced by ultraviolet irradiation in vitro.
Ultraviolet (UV) light is an important environmental mutagen and one of the major factors in the etiology of skin cancer in man. In this study we have addressed the question whether UV light can activate in vitro the N-ras proto-oncogene into an active oncogene, and whether pyrimidine cyclobutane dimers or (6-4) photoproducts are the premutagenic lesion. To that end, the cloned human N-ras proto-oncogene (pN-ras) was irradiated with UV light (254 nm) which results in the formation of cyclobutane dimers and (6-4) photoproducts and the irradiated DNA was transfected into Rat-2 cells. Whereas untreated pN-ras never gave foci upon transfection into Rat-2 cells, UV-irradiated pN-ras (100-300 J.m-2) yielded 1-2 foci/micrograms DNA. The DNAs of 49 primary foci were subjected to a second round of transfection. 13 of these were positive. The DNAs that did not give rise to secondary foci invariably contained high copy numbers of pN-ras. The DNAs from the secondary foci had only a low copy number of pN-ras. Using synthetic oligonucleotide probes we have found that all N-ras genes that gave rise to secondary foci contained a mutation at positions in codon 12 or 61. Only one primary transformant, negative in the secondary transformation assay, was shown to harbor a mutated N-ras gene. From these results we conclude that UV light can activate N-ras genes. Mutations were preferentially found at the 61st codon (11), harboring a TT doublet, while only 3 mutations were found at the 12th codon and none at the 13th codon, both harboring CC doublets. Of the 14 point mutations analysed 6 represented transitions and 8 transversions. No specific base-substitution could be regarded as predominant. Furthermore, treatment of the irradiated N-ras plasmids with photoreactivating enzyme prior to transfection, which specifically monomerizes cyclobutane dimers but not other photoproducts, reduced the transformation frequency several fold. None of the 36 DNAs from the primary foci obtained after transfection of photoreactivating enzyme-treated N-ras gave rise to secondary foci. These DNAs all contained high copy numbers of unmutated pN-ras. From this result we conclude that cyclobutane dimers, and not (6-4) photoproducts, are the major premutagenic lesions, responsible for the activation of N-ras. The possible role of ras genes as targets for UV-induced carcinogenesis is discussed.


[Stroke centers and stroke networks].
Admission to a stroke unit represents an established and efficient treatment for acute stroke. However, stroke care is yet not enough developed in many countries. In France, the organisational model is based on stroke unit admission for acute stroke patients associated with a network of stroke units covering the majority of the territory. That model fulfils the commitment of equity of access to medical care for the whole population, and optimises use of resources. The task of the five-year organisational plan Schéma régional d'organisation sanitaire is aimed achieve that goal.


Abscisic acid is a key inducer of hydrogen peroxide production in leaves of maize plants exposed to water stress.
The histochemical and cytochemical localization of water stress-induced H(2)O(2) production in the leaves of ABA-deficient vp5 mutant and wild-type maize (Zea mays L.) plants were examined, using 3,3-diaminobenzidine and CeCl(3) staining, respectively, and the roles of endogenous ABA in the production of H(2)O(2) induced by water stress were assessed. Water stress induced by polyethylene glycol resulted in the accumulation of H(2)O(2) in mesophyll cells, bundle-sheath cells and vascular bundles of wild-type maize leaves, and the accumulation was substantially blocked in the mutant maize leaves exposed to water stress. Pre-treatments with several apoplastic H(2)O(2) manipulators abolished the majority of H(2)O(2) accumulation induced by water stress in the wild-type leaves. The subcellular localization of H(2)O(2) production was demonstrated in the cell walls, xylem vessels, chloroplasts, mitochondria and peroxisomes in the leaves of wild-type maize plants exposed to water stress, and the accumulation of H(2)O(2) induced by water stress in the cell walls and xylem vessels, but not in the chloroplasts, mitochondria and peroxisomes, was arrested in the leaves of the ABA mutant or the ABA biosynthesis inhibitor (tungstate)-pre-treated maize plants. Pre-treatments with the apoplastic H(2)O(2) manipulators also blocked the apoplastic but not the intracellular H(2)O(2) accumulation induced by water stress in the leaves of wild-type plants. These data indicate that under water stress, the apoplast is the major source of H(2)O(2) production and ABA is a key inducer of apoplastic H(2)O(2) production. These data also suggest that H(2)O(2) generated in the apoplast could not diffuse freely into subcellular compartments.


Thy-1+/- fibroblast subsets in the human peritoneum.
Fibrotic thickening of the peritoneum develops in patients receiving peritoneal dialysis (PD) for renal failure. For unknown reasons, however, in some patients it progresses to extensive fibrosis that compromises dialysis capacity of the peritoneum. It is increasingly clear that fibroblasts display large heterogeneity not only between but also within tissues. Differential surface expression of thymocyte differentiation antigen 1 (Thy-1) has been shown to identify functionally distinct fibroblast subsets in several organs. Here, we isolated Thy-1+/- subsets of human peritoneal fibroblasts (HPFB) and analyzed them in terms of profibrotic myofibroblast features. In healthy individuals, Thy-1+ cells constituted ~45% of the HPFB population found in the greater omentum but were not detected in the parietal peritoneum. When propagated in culture and compared with Thy-1- cells, omentum-derived Thy-1+ HPFB consistently displayed an increased expression of α-smooth muscle actin, collagen I, and transforming growth factor-β1. They also showed greater proliferation capacity and enhanced contractile properties. The number of Thy-1+ HPFB increased significantly in PD patients and made up more than 70 and 95% of all HPFB found in the omentum and parietal peritoneum, respectively. These data indicate that the expansion of Thy-1+ fibroblasts may contribute to fibrotic thickening of the peritoneal membrane during PD.


[Contribution of serologic technics to the analysis of the cerebrospinal fluid in Congolese patients with sleeping sickness].
Three serological tests: the Card Agglutination Test (Testryp CATT), the Indirect Immunofluorescence Antibody Test (IFAT) and the Cellognost Indirect Haemagglutination technique (CIHA) were used to analyse the cerebrospinal fluid (CSF) of 41 patients infected with Trypanosoma gambiense and 30 uninfected persons. The authors reported the following data: --IFAT and especially CIHA were more efficient than CATT to demonstrate the presence of specific antibodies in the CSF; --the intensity of the cell and protein alterations paralleled the IFAT fluorescence intensity and the CIHA dilution titers; --this study indicated that the immunological analysis applied to CSF may prove to be a useful procedure to diagnosis the early onset of the attack on the nervous system and the evolution of the disease measured by the intensity of the reactions.


The Mediated Amplification of a Crisis: Communicating the A/H1N1 Pandemic in Press Releases and Press Coverage in Europe.
In the aftermath of the A/H1N1 pandemic, health authorities were criticized for failures in crisis communication efforts, and the media were accused of amplifying the pandemic. Considering these criticisms, A/H1N1 provides a suitable case for examining risk amplification processes that may occur in the transfer of information from press releases to print news media during a health crisis. We integrated the social amplification of risk framework with theories of news decisions (news values, framing) in an attempt to contribute to existing research both theoretically and empirically. We conducted a quantitative content analysis of press releases disseminated by health and governmental authorities, as well as the quality and tabloid press in 10 European countries between March 2009 and March 2011. Altogether 243 press releases, 1,243 quality press articles, and 834 tabloid press articles were coded. Consistent with research on news values and framing the results suggest that quality and tabloid papers alike amplified A/H1N1 risks by emphasizing conflict and damage, presenting information in a more dramatized way, and using risk-amplifying frames to a greater extent and risk-attenuating frames to a lesser extent than press releases. To some extent, the quality and tabloid press differed in how risk information was presented. While tabloid press articles seemed to follow the leading quality press with regards to content and framing of health crisis coverage, they exhibited a stronger emphasis on drama and emotion in the way they presented information.


Active interfacial shear microrheology of aging protein films.
The magnetically driven rotation of 300 nm diameter rods shows the surface viscosity of albumin at an air-water interface increases from 10(-9) to 10(-5) N s/m over 2 h while the surface pressure saturates in minutes. The increase in surface viscosity is not accompanied by a corresponding increase in elasticity, suggesting that the protein film anneals with time, resulting in a more densely packed film leading to increased resistance to shear. The nanometer dimensions of the rods provide the same sensitivity as passive microrheology with an improved ability to measure more viscous films.


A theoretical exploration of the structural feature, mechanical, and optoelectronic properties of Au-based halide perovskites A2AuIAuIIIX6 (A = Rb, Cs; X = Cl, Br, I).
As a possible alternative to lead halide perovskites, inorganic mixed-valence Au-based halide perovskites have drawn much attention. In the current research, we have conducted comprehensive theoretical calculations to reveal the structural feature, thermodynamic and dynamic stability, mechanical behavior, optoelectronic properties, and photovoltaic performance of Au-based halide perovskites A2AuIAuIIIX6 (A = Rb, Cs; X = Cl, Br, I). The structural parameters of these compounds are carefully analyzed. Our calculations indicate that the thermodynamic, dynamic, and mechanical stability of monoclinic Rb2AuIAuIIIX6 and tetragonal Cs2AuIAuIIIX6 are ensured, and they are all ductile. The electronic band structure analysis shows that Rb2AuIAuIIII6 illustrates a direct-gap feature, while Rb2AuIAuIIIX6 (X = Cl, Br) and Cs2AuIAuIIIX6 (X = Cl, Br, I) are indirect-gap materials. The effect of A-site cation substitution on the optical band gaps of the Au-based halide perovskites is elucidated. Our results further suggest that Rb2AuIAuIIIX6 (X = Br, I) and Cs2AuIAuIIIX6 (X = Cl, Br, I) are more suitable for single-junction solar cells due to their suitable band gaps within 1.1-1.5 eV. Furthermore, four compounds A2AuIAuIIIX6 (A = Rb, Cs; X = Br, I) not only have high absorption coefficients in the visible region but also show excellent photovoltaic performance, especially for A2AuIAuIIII6 (A = Rb, Cs), whose efficiency can reach over 29% with a film thickness of 0.5 μm. Our study suggests that inorganic Au-based halide perovskites are potential alternatives for optoelectronic devices in solar cells.


Role of a cell-wall glucan-degrading enzyme in mating of Schizophyllum commune.
Mycelial enzyme extracts of Schizophyllum commune were prepared during vegetative growth matings leading to common-A and common-B heterokaryons and the dikaryon, and were examined for hydrolytic activity against an alkaliinsoluble cell-wall glucan (R-glucan) isolated from this mushroom. In extracts from several individual homokaryotic mycelia the R-glucanase activity was low and did not increase when the cultures exhausted glucose in the medium. In common-A matings, a 30-fold increase in specific activity of intracellular R-glucanase was found even in the presence of glucose in the broth. An increase of this magnitude was not observed in the common-B mating nor in the fully compatible cross leading to the dikaryon. Extracts of the dikaryon did show elevated R-glucanase activity after exogenous glucose disappearance and subsequent fruiting. In none of these situations was an enzyme activity detected towards an alkali-soluble cell-wall glucan (S-glucan) prepared from S. commune. Changes in R-glucanase were not parallelled by identical changes in laminarinase, pustulanase, cellobiase, and p-nitrophenyl-beta-d-glucosidase, but comparable increases in specific activities were found for hydrolysis of glycogen and maltose. After interaction of the various mycelia in mating combinations, the S-glucan/R-glucan ratio of the cell wall of the dikaryon was found to be similar to that of the homokaryons, but increased in the common-B interaction and was elevated almost threefold in the common-A heterokaryon.


Adaptation of an outbreaking insect defoliator to chronic nutritional stress.
During insect outbreaks, the high number of individuals feeding on its host plant causes a depletion of the food source. Reduced availability and decreased quality of nutrients negatively influence life-history traits of insects driving them to develop adaptive strategies to persist in the environment. In a laboratory experiment with three repetitions, we tested the effect of chronic nutritional stress on spruce budworm performance during three generations to determine the adaptive strategies employed by the insect to deal with a selection pressure produced by low-quality diet. Our results show that all tested life-history traits (mortality, developmental time, pupal mass, growth rate and female fecundity) but female fertility were negatively influenced by the low-quality diet simulating food depletion during outbreak conditions. However, especially females in the third generation under chronic nutritional stress show an adaptive response in life-history traits when compared to those reared only one generation on low-quality diet. Larval developmental time significantly decreased and pupal mass, growth rate and fecundity significantly increased. The study demonstrates the capacity of spruce budworm to react to chronic nutritional stress with adaptations that may be caused by epigenetic parental effects. This information can help to understand the course of an outbreak especially at peak densities and during the collapse.


Experimental Rat Model of Bony Defects in the Facet Joint Maintained with Bone Wax for the Study of Spinal Pain.
Studies using experimental rat models for low back pain due to facet-joint defects are scarce. This study used a novel experimental rat model to determine whether bony defects induced by facetectomy could be maintained by bone wax, thus mimicking spondylolysis, and to analyze the effect of the facetectomy on rat behavior. Twelve 10-week-old male Wistar rats weighing 300-350 g were divided into group A (n = 6) that underwent unilateral facetectomy of the right L5-6 facet joint and group B (n = 6) that additionally applied water-soluble bone wax at the facetectomy site. The difference in the left and right stride length, detected by the footprint test, and change in the left and right facet joint area were compared before and 4 weeks after the experiment. Even though the difference between the left and right stride lengths of groups A and B was not statistically significant, in contrast to group A, group B showed a shorter stride length on the right side (p = 0.22 and 0.46, in group A and group B, respectively). The right facet joint area, where the facetectomy was performed, was significantly smaller in group B 4 weeks after surgery, but not in group A (p = 0.50 and < 0.01, in group A and group B, respectively). Based on the results, we concluded that the bony defects, induced by facetectomy at the L5-6 facet joint, were maintained with bone wax. This study will provide an experimental model for bony defects in the facet joint.


[Combined sciatic/3-in-1 block. III. Prilocaine 1% versus mepivacaine 1%].
In a randomized, double-blind study, the efficacy of prilocaine 1% (group 1, 30 patients) was compared to mepivacaine 1% (group 2, 30 patients). All patients had a combined sciatic/femoral block for surgery of the lower extremities; a tourniquet was applied in each case. In each patient the block was done using 50 ml of a 1% solution of local anesthetic: 20 ml for the sciatic and 30 ml for the 3-in-1 block. The time to onset of sensory block was approx. 4 min in both groups; the onset of motor blockade averaged 6 min and after 10-12 and 15 min sensory and motor blockades, respectively, were complete. On the average, patients were pain-free for 254 min with prilocaine and 267 min with mepivacaine. Four of 30 patients (= 13%) in group 1 an 6 of 30 patients (= 20%) in group 2 had an unsatisfactory blockade and had to be supplemented by analgesics or general anesthesia. The finding of a significant correlation between the voltage necessary for stimulation and the efficacy of the blockade underlines the importance of correct stimulation when identifying the nerves.


Detection of apoptotic alterations in sperm in subfertile patients and their correlations with sperm quality.
The aim of the present study was to define the effect of apoptosis on sperm quality and function. The apoptotic features in sperm were assessed in 60 subfertile subjects, using Annexin-V staining for phosphatidylserine (PS) externalization and Tdt-mediated dUTP nick end labelling (TUNEL) assay for DNA fragmentation. On average, about 45% of the sperm were found to be apoptotic based on the results from Annexin-V staining, including both early (Annexin-V-positive, PI-negative) and late apoptosis (Annexin-V-positive, PI-positive). TUNEL-positive cells (median value 15%) significantly correlated to late apoptosis but not early apoptosis, indicating that DNA fragmentation only occurs at the later stage of sperm apoptosis. TUNEL-positive and late apoptotic cells (Annexin-V-positive, PI-positive) were found to be inversely correlated to sperm motility and vitality, and positively to abnormal sperm morphology. On the other hand, it is surprising to note that the apoptotic alterations in sperm positively correlated to sperm concentration or total sperm counts. Overall results from this study support the abortive apoptosis theory; apoptosis in mature sperm is initiated during spermatogenesis, after which some cells earmarked for elimination via apoptosis may escape the removal mechanism and contribute to poor sperm quality.


Evaluation of occlusal splint therapy in temporomandibular joint disorder patients using real-time ultrasonography.
The aim of the present study was to evaluate the effect of occlusal splint therapy by determining the cross-sectional dimension of masseter muscle using ultrasound in patients with temporomandibular joint disc displacement with reduction. Twenty-seven patients aged between 20 and 40 years were included in the study. A detailed history was obtained, and a comprehensive clinical examination was carried out. Subjective assessment with structured pro forma was performed pre-occlusal and post-occlusal splint therapy. The objective measurement of the bilateral masseter muscle thickness was recorded using real-time ultrasonography before and after splint therapy. The mean ultrasound thickness of the masseter muscle in the pre-clenching state before splint therapy was 9.45 mm (SD 1.39), and the post-clenching state was 13.15 mm (SD 2.23). After splint therapy, the mean thickness in the pre-clenching state was 9.14 mm (SD 1.31), and the post-clenching state was 12.78 mm (SD 2.23; P<0.001). Ultrasonographic measurements of the masseter muscle in patients with temporomandibular joint disc displacement with reduction can be a useful tool to assess the effectiveness of occlusal splint therapy. Such conservative measures can significantly reduce masticatory muscle tenderness, especially of the temporalis and masseter.


α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability.
Pathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson's disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson's disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson's disease progression with significant therapeutic implications.


Lipopolysaccharide: an endotoxin or an exogenous hormone?
Conventional models of the pathogenesis of sepsis assume that microorganisms or their products are necessarily injurious to the host. In contrast, an evolutionary perspective suggests that host-microbial interactions are a symbiotic model and that disease results from the disruption of a mutually beneficial homeostatic state. Lipopolysaccharide (LPS) from gram-negative bacteria is a prototypical trigger of sepsis and a target for the development of novel therapeutics. The biological mechanisms underlying the recognition of, and response to, LPS are more characteristic of a hormone than of a toxin. All mammals carry endogenous stores of LPS and express dedicated carrier proteins, a cellular receptor complex, and mechanisms that specifically antagonize the response to LPS. Disruption of any component of this complex recognition system jeopardizes host defenses against infection with exogenous microorganisms. Thus, LPS is not less an endotoxin than an exohormone, and its neutralization may potentially result in either benefit or harm.


Implementation of the systems approach to improve a pharmacist-managed vancomycin dosing service.
Quality improvements achieved by applying the systems approach to assess the clinical effectiveness, operational efficiency, and financial feasibility of a pharmacist-managed vancomycin dosing service are described. Faced with increased patient volumes and resource demands, the pharmacy department at Tufts Medical Center conducted an evaluation of its adult inpatient vancomycin dosing service using the systems approach, which emphasizes multidisciplinary assessment of system inputs, processes, and outcomes and consensus-building methods to identify needed changes and recommended action steps. A multidisciplinary committee composed of representatives of the medical center's pharmacy, internal medicine, infectious diseases, nursing, phlebotomy, and clinical laboratory services was assembled; in a series of three moderated monthly sessions, committee members deliberated and ultimately reached consensus on a list of action items. Relative to a concurrent intradepartmental assessment of the vancomycin dosing service based solely on pharmacist feedback, the systems approach identified a greater number and wider array of needed improvements in key program areas. Quality improvements implemented as a direct result of the systems-based analysis included a policy change authorizing pharmacists to order serum vancomycin determinations without physician cosignature and inclusion of a vancomycin dosing algorithm in the institutional antibiotic dosing guide. Future changes based on deliverable action items will result in a structured process to help direct program resources toward the patients most in need of pharmacist-managed vancomycin dosing services. The systems approach allowed for a comprehensive multidisciplinary evaluation of the service, as indicated by the identification of process improvements not identified by the department of pharmacy alone.


Evidence of differential control of renal and lumbar sympathetic nerve activity in conscious rabbits.
We have explored the possibility that renal sympathetic nerve activity (RSNA) and vasomotor sympathetic nerve activity are differentially regulated. We measured sympathetic nerve activity (SNA) to the kidney and the hind limb vasculature in seven conscious rabbits 6-8 days after the implantation of recording electrodes. Acute infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) (6 mg.kg(-1).min(-1) for 5 min) led to an increase in blood pressure (from 66 +/- 1 to 82 +/- 3 mmHg) and a decrease in heart rate (from 214 +/- 15 to 160 +/- 13 bpm). L-NAME administration caused a significantly greater decrease in RSNA than lumbar sympathetic nerve activity (LSNA) (to 68 +/- 14% vs. 84 +/- 4% of control values, respectively). Volume expansion (1.5 ml.kg(-1).min(-1)) resulted in a significant decrease in RSNA to 66 +/- 7% of control levels but no change in LSNA (127 +/- 20%). There was no difference in the gain of the baroreflex curves between the LSNA and RSNA [maximum gain of -7.6 +/- 0.4 normalized units (nu)/mmHg for LSNA vs. -7.9 +/- 0.75 nu/mmHg for RSNA]. A hypoxic stimulus (10% O2 and 3% CO2) led to identical increases in both RSNA and LSNA (195 +/- 40% and 158 +/- 21% of control values, respectively). Our results indicate tailored differential control of RSNA and LSNA in response to acute stimuli.


[Protein kinase C isoforms in corneal epithelium and endothelium].
Protein kinase C (PKC) plays a key role in cell metabolism. Three subgroups and 12 isoforms have been isolated so far, catalysing specific functions in cell metabolism. The demonstration of PKC subtypes in corneal tissue has been inconsistent. The aim of this study was to verify the expression of several PKC subgroups and isoforms in human and bovine corneal epithelial and endothelial cells. PKC subgroups and isoforms were studied using polyclonal antibodies. Antibodies to PKC-alpha, -delta, -epsilon and -zeta, representing all three PKC subgroups, bound in human and bovine corneal epithelium and endothelium. No binding was found for antibodies to PKC-beta2. For the first time the presence of all three PKC subgroups was demonstrated in human and bovine corneal epithelial and endothelial cells. Further studies are needed to show the role of these subgroups in cellular functions such as cell proliferation and differentiation.


Cytochemical localization of adenylate cyclase.
This study examined 1) the effect of lead and fixation on adenylate cyclase activity, 2) the effect of lead on App(NH)p, and 3) the specificity of App(NH)p as a substrate for adenylate cyclase under the conditions of the cytochemical assay. The results indicated that: 1) fixation that provides adequate structural preservation inhibits enzyme activity to varying degrees depending on the tissue, fixative, length and temperature of fixation; 2) millimolar concentrations of lead do not negatively affect the adenylate cyclase activity of several different tissues (especially if 10 mM NaF is present); 3) lead does not cause the nonenzymatic hydrolysis of App(NH)p; 4) the App(NH)p obtained from the supplier is contaminated and should be purified before use, since lead can interact with the contaminants and this may be a source of error in the assay; and 5) adenylate cyclase appears to be the major enzyme that cleaves App(NH)p under cytochemical conditions.


Resveratrol rescues cadmium-induced mitochondrial injury by enhancing transcriptional regulation of PGC-1α and SOD2 via the Sirt3/FoxO3a pathway in TCMK-1 cells.
Resveratrol has been reported to ameliorate Cd-induced nephrotoxicity. However, the beneficial effects of resveratrol on Cd-induced nephrotoxicity and the underlying mechanisms of this protection remain unclear. Here, we showed that mouse renal tubular epithelial (TCMK-1) cells exposed to Cd experienced significantly increased mitochondrial reactive oxygen species (mROS) production, as well as decreased mitochondrial biogenesis and function. Cd exposure dramatically decreased Sirt3 protein expression and activity and promoted the acetylation of forkhead box O3 (FoxO3a). Moreover, Cd exposure led to a decreased binding affinity of FoxO3a to the promoters of both peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α and superoxide dismutase 2 (SOD2), powerful and broad regulators of mitochondrial biogenesis and mROS metabolism. Meanwhile, resveratrol remarkably reduced mROS generation by promoting Sirt3 enrichment within the mitochondria and subsequent upregulation of FoxO3a-mediated mitochondria gene expression of PGC-1α and SOD2. Importantly, mechanistic study revealed that ERK1/2 activation was associated with increased apoptosis induced by Cd, resveratrol suppressed Cd-induced apoptosis in mice kidney. Taken together, our data suggest a novel mechanism of action for resveratrol-attenuated Cd-induced cellular damage, which, in part, was mediated through the activation of the Sirt3/FoxO3a signaling pathway.


[Cardiovascular risk in the kidney transplant patient].
Renal transplants have experienced a spectacular development in recent years, significantly improving the quality of life and life expectancy of patients. However, mortality due to cardiovascular disease in recent years has become the first cause of death in renal transplant patients, ahead of infections and neoplasic disorders. The causes of this increase are due to the following reasons: 1) Important changes in the characteristics of the donor and the renal receptor. 2) A significant decrease in the immediate post-transplant mortality rates, and 3) increase in the incidence of cardiovascular risk factors in transplant patients.


Rate-determining factors in nucleophilic aromatic substitution reactions.
Quantum chemical calculations (OPBE/6-311++G(d,p)) have been performed to uncover the electronic factors that govern reactivity in the prototypical S(N)Ar reaction. It was found that intrinsic nucleophilicity--expressed as the critical energy (the energy required for forming the Meisenheimer structure Ph(X)(2)(-)) in the identity substitution reaction X(-) + PhX --> X(-) + PhX (Ph = phenyl)--shows the following approximate trend: NH(2)(-) approximately OH(-) approximately F(-) >> PH(2)(-) approximately SH(-) approximately Cl(-) > AsH(2)(-) approximately SeH(-) approximately Br(-). The periodic trends are discussed in terms of molecular properties (proton affinity of X(-) expressing Lewis basicity of the nucleophile and C(1s) orbital energy expressing Lewis acidity of the substrate) based on a dative bonding model. Furthermore, the stepwise progress of the reactions and the critical structures are analyzed applying energy decomposition analysis. Increased stability, and thereby increased intrinsic nucleophilicity, correlates with decreasing aromatic character of the Meisenheimer structure. This apparent contradiction is explained in consistency with the other observations using the same model.


Hospital behavior under competition and cost-containment policies. The California experience, 1980 to 1985.
Previous studies of hospital competition have found that greater competition leads to higher hospital costs. We describe herein the change in behavior of California's hospitals since the introduction of competitive and cost-containment programs. To examine the impact of California's pro-competition policies on hospital performance, we grouped the state's short-term hospitals according to the level of competition within their markets. From 1983 through 1985, total inpatient costs (inflation adjusted) increased by less than 1% in hospitals in low-competition markets compared with a decrease of 11.29% in hospitals located in highly competitive markets. After controlling for the effects of the Medicare prospective payment system program, the rate of increase in cost per discharge in hospitals in highly competitive markets was 3.53% lower than the rate of increase in hospitals in low-competition markets during the period from 1983 through 1985. We conclude that these pro-competition policies are having dramatic and potentially far-reaching effects on the nature of hospital competition, leading to increased competition based on price.


COVID-19 vaccine induced poor neutralization titers for SARS-CoV-2 omicron variants in maternal and cord blood.
Maternally derived antibodies are crucial for neonatal immunity. Understanding the binding and cross-neutralization capacity of maternal and cord antibody responses to SARS-CoV-2 variants following COVID-19 vaccination in pregnancy can inform neonatal immunity. Here we characterized the binding and neutralizing antibody profile at delivery in 24 pregnant individuals following two doses of Moderna mRNA-1273 or Pfizer BNT162b2 vaccination. We analyzed for SARS-CoV-2 multivariant cross-neutralizing antibody levels for wildtype Wuhan, Delta, Omicron BA1, BA2, and BA4/BA5 variants. In addition, we evaluated the transplacental antibody transfer by profiling maternal and umbilical cord blood. Our results reveal that the current COVID-19 vaccination induced significantly higher RBD-specific binding IgG titers in cord blood compared to maternal blood for both the Wuhan and Omicron BA1 strain. Interestingly, the binding IgG antibody levels for the Omicron BA1 strain were significantly lower when compared to the Wuhan strain in both maternal and cord blood. In contrast to the binding, the Omicron BA1, BA2, and BA4/5 specific neutralizing antibody levels were significantly lower compared to the Wuhan and Delta variants. It is interesting to note that the BA4/5 neutralizing capacity was not detected in either maternal or cord blood. Our data suggest that the initial series of COVID-19 mRNA vaccines were immunogenic in pregnant women, and vaccine-elicited binding antibodies were detectable in cord blood at significantly higher levels for the Wuhan and Delta variants but not for the Omicron variants. Interestingly, the vaccination did not induce neutralizing antibodies for Omicron variants. These results provide novel insight into the impact of vaccination on maternal humoral immune response and transplacental antibody transfer for SARS-CoV-2 variants and support the need for bivalent boosters as new variants emerge.


Hydrocarbons in Upland Groundwater, Marcellus Shale Region, Northeastern Pennsylvania and Southern New York, U.S.A.
Water samples from 50 domestic wells located <1 km (proximal) and >1 km (distal) from shale-gas wells in upland areas of the Marcellus Shale region were analyzed for chemical, isotopic, and groundwater-age tracers. Uplands were targeted because natural mixing with brine and hydrocarbons from deep formations is less common in those areas compared to valleys. CH4-isotope, predrill CH4-concentration, and other data indicate that one proximal sample (5% of proximal samples) contains thermogenic CH4 (2.6 mg/L) from a relatively shallow source (Catskill/Lock Haven Formations) that appears to have been mobilized by shale-gas production activities. Another proximal sample contains five other volatile hydrocarbons (0.03-0.4 μg/L), including benzene, more hydrocarbons than in any other sample. Modeled groundwater-age distributions, calibrated to 3H, SF6, and 14C concentrations, indicate that water in that sample recharged prior to shale-gas development, suggesting that land-surface releases associated with shale-gas production were not the source of those hydrocarbons, although subsurface leakage from a nearby gas well directly into the groundwater cannot be ruled out. Age distributions in the samples span ∼20 to >10000 years and have implications for relating occurrences of hydrocarbons in groundwater to land-surface releases associated with recent shale-gas production and for the time required to flush contaminants from the system.


"Roaming" dynamics in CH3CHO photodissociation revealed on a global potential energy surface.
We present a quasiclassical trajectory study of the photodissociation of CH3CHO to molecular and radical products, CH4 + CO and CH3 + HCO, respectively, using global ab initio-based potentials energy surfaces. The molecular products have a well-defined potential barrier transition state (TS) but the dynamics exhibit strong deviations from the TS pathway to these products. The radical products are formed via a variational TS. Calculations are reported at total energies corresponding to photolysis wavelengths of 308, 282, 264, 248 and 233 nm. The results at 308 nm focus on a comparison with experiment [Houston, P. L.; Kable, S. H. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 16079] and the elucidation of the nature and extent of non-TS reaction dynamics to form the molecular products, CH4 + CO. At the other wavelengths the focus is the branching ratio of these products and the radical products, CH3 + HCO.


Levels of antithrombin III, alpha 2-macroglobulin, and alpha 1-antitrypsin in acute ischemic heart disease.
Since measurements of AT III and other possible coagulation inhibitors might provide an index of hypercoagulability, the goal was to measure over a 3-month period individual changes in blood levels of AT III, alpha 2-microglobulin, and alpha 1-antitrypsin in 51 patients with acute ischemic heart disease who were admitted to a Coronary Care Unit with the following diagnosis: unstable angina (26 patients), acute transmural myocardial infarction (20 patients), or subendocardial myocardial infarction (5 patients). Some patients received prophylactic antithrombotic therapy. AT III was measured by the von Kaulla, Owen, Thrombo-Screen, chromogenic, immunodiffusion, and immunoelectrophoretic methods. Alpha 2-macroglobulin and alpha 1-antitrypsin were measured by immunodiffusion. All inhibitors were measured on three different occasions: (1) on admission to hospital, (1) day of departure from hospital, and (3) at 3 months after hospitalization. Alpha 1-antitrypsin showed a significant increase compared to the control and remained elevated during the 3-month interval. Compared to normal control values, AT III was found to be significantly diminished when measured by one functional method (von Kaulla) in all three blood samples from patients with unstable angina and transmural myocardial infarction and by one immunological method (immunodiffusion) in patients with unstable angina, transmural myocardial infarction, and subendocardial myocardial infarction. Most methods determining functional AT III detected a significant increase 3 months after the acute ischemic episode; this rise was observed more often in patients with myocardial infarction than in those with unstable angina. Stepwise discriminant analysis separated the patients of the three groups. Subcutaneous heparin has no significant effect on AT III levels. Unexplained discrepancies still exist between the results obtained by various functional and immunological methods for determining AT III. It appears, however, that methods measuring functional AT III seem to be more suited than immunological methods to detect changes in AT III levels that might occur during and after an acute episode of ischemic heart disease.


Therapeutic alliance perceptions and medication adherence in patients with bipolar disorder.
Despite the dissemination of practice guidelines for bipolar disorder, outcomes remain suboptimal, largely due to poor treatment adherence. The episodic nature of bipolar disorder disrupts appropriate patient-provider dynamics, interfering with appropriate care. Maintaining a beneficial therapeutic alliance with providers is one important strategy for improving adherence. We examine the association between adherence and therapeutic environment perceptions among veterans with bipolar disorder. Participants were recruited from the Continuous Improvement for Veterans in Care--Mood Disorders (CIVIC-MD) study (N=435). Individual items and a summary score from the Health Care Climate Questionnaire (HCCQ) for bipolar disorder solicited patient evaluations of their therapeutic environment. Multivariable logistic analyses examined the association between therapeutic alliance and two measures of adherence (missed medication days and intrapersonal barriers), adjusting for relevant patient characteristics. Adherence difficulty was reported on both measures, with substantial differences between perceived barriers and actual medication behavior. Significantly fewer minority veterans endorsed good adherence than white patients (59% versus 77%), although no ethnic differences were noted in therapeutic environment perceptions. Multivariable results indicated that positive therapeutic alliance was associated with better adherence (HCCQ effect sizes 13-20%). Notably, patients reporting providers encouraged "staying in regular contact" were more likely to be adherent, as were patients whose "providers regularly review their progress". Generalizability from observational study; adherence defined by cross-sectional patient self-report. The observed association between medication adherence and therapeutic alliance with bipolar treatment supports intervention efforts to strengthen the patient-provider relationship, a bond likely to yield positive clinical outcomes.


Therapeutic trials with oral colchicine in psoriasis.
Twenty-two psoriatic patients were treated orally with the antichemotactic agent, colchicine, at a dosage of 0.02 mg per kg per day for a duration of 2-4 months. Complete clearing or marked improvement were noted in 8 of the 9 patients, in whom thin papules and thin plaques were the predominant type of lesion. Much less favorable results were obtained in patients with chronic, stable, thick plaque-type disease, although decreased scaliness, erythema and infiltration and marked diminution of the pruritus were observed in almost all of the cases. A considerable improvement of the joint pains was noted in each of the 8 patients who suffered from arthralgias. Five additional patients with extensive, chronic, stable plaque-type psoriasis were given oral colchicine immediately after complete clearing of their skin lesions with Goeckerman's method or with methotrexate. Four of them continued to take colchicine for 8-9 months and during that time they remained free of significant skin disease. These findings lend support to the hypothesis that the migration of the activated psoriatic neutrophils into the skin could be an important factor in the initiation and possibly also in the perpetuation of the psoriatic lesions. Closely controlled, long-term studies conducted in large numbers of patients are warranted in order to determine the exact therapeutic role of oral colchicine in the long-term management of psoriasis.


The use of Eucalyptus tereticornis Sm. (Myrtaceae) oil (leaf extract) as a natural larvicidal agent against the malaria vector Anopheles stephensi Liston (Diptera: Culicidae).
Secondary metabolites obtained from the indigenous plants with proven mosquito control potential can be used as an alternative to synthetic insecticides under the integrated vector control. The essential oil extract from the forest redgum, Eucalyptus tereticornis Sm. (Myrtaceae) was tested against mature and immature mosquito vector Anopheles stephensi Liston (Diptera) under laboratory condition. The extract showed strong larvicidal, pupicidal and adulticidal activity. The leaf oil extracts showed high bioactivity at high doses. Results obtained from the laboratory experiment showed that the leaf extracts suppressed the pupal and adult activity of Anopheles stephensi at higher doses. In general, first and second instar larvae were more susceptible to all treatments. Clear dose -response relationships were established with the highest dose of 160ppm plant extract evoking almost 100% mortality. The results obtained suggest that, in addition to their medicinal activities, E. tereticornis can also serve as a natural mosquitocide.


Pharmacokinetics, pharmacodynamics, and safety of metrifonate in patients with Alzheimer's disease.
Metrifonate is converted nonenzymatically to 2.2, dimethyl dichlorovinyl phosphate (DDVP), an inhibitor of acetylcholinesterase (AChE). This 21-day, randomized, double-blind, placebo-controlled trial of metrifonate in patients with Alzheimer's disease (n = 27) evaluated four doses, each administered orally once daily. All patients received a loading dose (LD) for 6 days followed by a maintenance dose (MD) for 15 days. The treatment groups were: panel 1, LD = 1.5 mg/kg (75-135 mg), MD = 0.25 mg/kg (12.5-25 mg); panel 2, LD = 2.5 mg/kg (125-225 mg), MD = 0.40 mg/kg (20-35 mg); panel 3, LD = 4.0 mg/kg (200-335 mg), MD = 0.65 mg/kg (30-60 mg); and panel 4, LD = 4.0 mg/kg (200-335 mg), MD = 1.0 mg/kg (50-90 mg). All metrifonate doses were well tolerated. Most adverse events were mild to moderate in intensity, gastrointestinal in nature, and transient. Mean area under the concentration-time curve (AUC) and maximum concentration (Cmax) for both metrifonate and DDVP increased in relation to dose. Metrifonate and DDVP had similar, largely dose-independent mean values for time to Cmax (tmax) and half-life (t1/2). There was little or no accumulation of either metrifonate or DDVP with long-term administration. After 21 days of treatment, mean percent erythrocyte AChE inhibition was 14%, 35%, 66%, 77%, and 82% for placebo and panels 1 through 4, respectively. Cognitive improvement was observed with the two highest metrifonate doses. These results reflect favorable safety and pharmacokinetic profiles for the use of metrifonate in the treatment of Alzheimer's disease.


Prevalence of multiple forms of autoimmunity in Egyptian patients with Turner syndrome: relation to karyotype.
Our study aimed to investigate: the prevalence of autoantibodies related to organ-specific disease; the prevalence of some autoimmune diseases (AID) in Egyptian Turner syndrome (TS) patients; and the association of autoimmunity with patients' karyotypes. Eighty TS patients were subjected to history, auxological assessment and measurement of antithyroid peroxidase antibody (ATPOAb), antithyroglobulin antibody (ATGAb), anti-tissue transglutaminase IgA antibodies (ATTIgAAb), anti-glutamic acid decarboxylase-65 antibodies (GAD-65-Ab) and anti-adrenal cortex antibodies (AACAb). Of the 80 TS patients, 54 (67.5%) were seropositive for one or more autoantibodies. Thirty-five percent were positive for ATPOAb, 15% for ATGAb, 12.5% for ATTIgAAb, 3.75% for Anti-GAD-65Ab and 1.25% for AACAb. There was a non-significant association between the 45,X karyotype and overall prevalence of autoantibodies (p=0.20), while IsoXq was associated with increased prevalence of ATPOAb (p<0.01), ATGAb (p=0.01) and anti-GAD-65Ab (p=0.02). Thus, female TS patients face a high prevalence of autoimmunity and associated AID.


Mutagenic inverted repeat assisted genome engineering (MIRAGE).
Here we describe a one-step method to create precise modifications in the genome of Saccharomyces cerevisiae as a tool for synthetic biology, metabolic engineering, systems biology and genetic studies. Through homologous recombination, a mutagenesis cassette containing an inverted repeat of selection marker(s) is integrated into the genome. Due to its inherent instability in genomic DNA, the inverted repeat catalyzes spontaneous self-excision, resulting in precise genome modification. Since this excision occurs at very high frequencies, selection for the integration event can be followed immediately by counterselection, without the need for growth in permissive conditions. This is the first time a truly one-step method has been described for genome modification in any organism.


HIF-1α inhibits IDH-1 expression in osteosarcoma.
Recently, hypoxia inducible factor-1 (HIF-1) was reported to be correlated with isocitrate dehydrogenase 1 (IDH-1) in several types of tumors. However, the expression and significance of HIF-1 and IDH-1 in osteosarcoma is still unknown. In the present study, the expression levels of IDH-1 and HIF-1α in 35 formalin-fixed paraffin-embedded sections from osteosarcoma patients were investigated by immunohistochemistry. The expression levels of IDH-1 and HIF-1α in human osteosarcoma cell lines (MG-63 and 143B) were further detected by western blotting under normal and hypoxic conditions. In addition, HIF-1α was downregulated via lentiviral vector‑mediated RNA interference (RNAi) in the MG-63 human osteosarcoma cell line. The results revealed that HIF-1α was negatively correlated with IDH-1 in the osteosarcoma tissues. Both in MG-63 and 143B cell lines, the expression of HIF-1α was increased while IDH-1 was decreased under a hypoxic condition compared to normal conditions. HIF-1α downregulation promoted IDH-1 expression in the MG-63 cell line under either normal or hypoxic conditions. In conclusion, our findings suggest that HIF-1α inhibits IDH-1 in osteosarcoma and consequently increases the incidence of osteosarcoma.


Dual Role of the Histone Variant H2A.Z in Transcriptional Regulation of Stress-Response Genes.
The influence of the histone variant H2A.Z on transcription remains a long-standing conundrum. Here, by analyzing the actin-related protein6 mutant, which is impaired in H2A.Z deposition, and by H2A.Z profiling in stress conditions, we investigated the impact of this histone variant on gene expression in Arabidopsis thaliana We demonstrate that the arp6 mutant exhibits anomalies in response to osmotic stress. Indeed, stress-responsive genes are overrepresented among those hyperactive in arp6. In wild-type plants, these genes exhibit high levels of H2A.Z in the gene body. Furthermore, we observed that in drought-responsive genes, levels of H2A.Z in the gene body correlate with transcript levels. H2A.Z occupancy, but not distribution, changes in parallel with transcriptional changes. In particular, we observed H2A.Z loss upon transcriptional activation and H2A.Z gain upon repression. These data suggest that H2A.Z has a repressive role in transcription and counteracts unwanted expression in noninductive conditions. However, reduced activity of some genes in arp6 is associated with distinct behavior of H2A.Z at their +1 nucleosome, which exemplifies the requirement of this histone for transcription. Our data support a model where H2A.Z in gene bodies has a strong repressive effect on transcription, whereas in +1 nucleosomes, it is important for maintaining the activity of some genes.