ALDOSE REDUCTASE: New Insights for an Old Enzyme.
In the past years aldose reductase (AKR1B1; AR) is thought to be involved in the pathogenesis of secondary diabetic complications such as retinopathy, neuropathy, nephropathy and cataractogenesis. Subsequently, a number of AR inhibitors have been developed and tested for diabetic complications. Although, these inhibitors have found to be safe for human use, they have not been successful at the clinical studies because of limited efficacy. Recently, the potential physiological role of AR has been reassessed from a different point of view. Diverse groups suggested that AR besides reducing glucose, also efficiently reduces oxidative stress-generated lipid peroxidation-derived aldehydes and their glutathione conjugates. Since lipid aldehydes alter cellular signals by regulating the activation of transcription factors such as NF-kB and AP1, inhibition of AR could inhibit such events. Indeed, a wide array of recent experimental evidence indicates that the inhibition of AR prevents oxidative stress-induced activation of NF-kB and AP1 signals that lead to cell death or growth. Further, AR inhibitors have been shown to prevent inflammatory complications such as sepsis, asthma, colon cancer and uveitis in rodent animal models. The new experimental in-vitro and in-vivo data has provided a basis for investigating the clinical efficacy of AR inhibitors in preventing other inflammatory complications than diabetes. This review describes how the recent studies have identified novel plethoric physiological and pathophysiological significance of AR in mediating inflammatory complications, and how the discovery of such new insights for this old enzyme could have considerable importance in envisioning potential new therapeutic strategies for the prevention or treatment of inflammatory diseases.


Interleukin-1 beta down-regulates the expression of metabotropic glutamate receptor 5 in cultured human astrocytes.
Expression of metabotropic glutamate receptor 5 (mGluR5) protein is known to be plastic and to depend critically on the astrocytes' microenvironment. In the present study we investigated whether interleukins, which are involved in the immune response following brain injury, could contribute to the regulation of mGluR5 protein in human astrocytes in culture. Using Western blotting and immunocytochemistry, no detectable changes in the expression of the mGluR5 protein were observed with both interleukin 1beta and interleukin 6 in undifferentiated cultures (growing in serum free media). In contrast, in cultures that had been morphologically differentiated by exposure to epidermal growth factor (EGF), addition of interleukin 1beta (but not interleukin 6) reduced mGluR5 protein expression. In addition, stimulation of phosphoinositide hydrolysis by the selective group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) was reduced after exposure to interleukin 1beta. The suppressive effect on mGluR5 was prevented by the interleukin 1 receptor antagonist. Thus, interleukin 1beta may represent an additional pathway through which mGluR5 expression and function can be modulated in astrocytes under different pathological conditions associated with an inflammatory response.


Design and synthesis of new bifunctional sigma-1 selective ligands with antioxidant activity.
Herein we report the synthesis of new bifunctional sigma-1 (σ1)-selective ligands with antioxidant activity. To achieve this goal, we combined the structure of lipoic acid, a universal antioxidant, with an appropriate sigma aminic moiety. Ligands 14 and 26 displayed high affinity and selectivity for σ1 receptors (Kiσ1 = 1.8 and 5.5 nM; Kiσ2/σ1 = 354 and 414, respectively). Compound 26 exhibited in vivo antiopioid effects on kappa opioid (KOP) receptor-mediated analgesia. In rat liver and brain mitochondria (RLM, RBM), this compound significantly reduced the swelling and the oxidation of thiol groups induced by calcium ions. Our results demonstrate that the tested compound has protective effects against oxidative stress.


Comparison of gluteus maximus and hamstring electromyographic activity and lumbopelvic motion during three different prone hip extension exercises in healthy volunteers.
To compare the surface electromyography (EMG) amplitude of the hip joint, including the gluteus maximus (GM), biceps femoris (BF), and semitendinosus (ST) muscles generated by three different exercises: prone hip extension (PHE), prone table hip extension (PTHE), and prone table hip extension with 90° knee flexion (PTHEK), with compensatory pelvic motions. Repeated-measure within-subject intervention. Sixteen-healthy males (mean age = 23.4 ± 2.2 years). EMG was used to collect EMG signals from the GM, erector spinae (ES), BF, and ST muscles. Furthermore an electromagnetic tracking motion analysis was also performed to measure the compensations. EMG amplitude differed significantly among the three conditions (PHE vs. PTHE vs. PTHEK) (p < 0.05). The mean GM muscle activity increased significantly during the PTHEK (70.93% and 13.75% increases in %MVIC compared with the PHE and PTHE, respectively) (p < 0.01). However, there was no significant difference in the kinematic data for rotation or anterior tilting angle of the pelvis among the three conditions (p > 0.05). These results suggest that the PTHEK can be recommended as an effective method to strengthen the GM muscle without increased BF or ES muscle activities and without compensatory pelvic motions.


Hyperreflective cystoid spaces in diabetic macular oedema: prevalence and clinical implications.
To analyse the prevalence and evolution of hyper-reflective cystoid spaces with decorrelation signal detected using optical coherence tomography angiography (OCTA) in diabetic macular oedema (DMO). A retrospective study of consecutive eyes with DMO imaged using OCTA over a 1-year period was conducted. All eyes with hyper-reflective cystoid spaces at baseline and at least 3 months of follow-up were included in a longitudinal analysis. The prevalence of hyperreflective cystoid spaces with decorrelation signal was of 37% (61/165) in DMO eyes. Hyperreflective foci within hyperreflective cystoid spaces were observed in 85% of eyes. The longitudinal study included 33 eyes (10 observed and 23 treated with intravitreal anti-vascular endothelial growth factor), with a median follow-up of 15 months. The hyperreflective cystoid spaces resolved in 85% of eyes. The mean best-corrected visual acuity remained stable during the follow-up, even in the eyes achieving a resolution of the hyperreflective cystoid spaces. Hard exudates appeared in the area of resolved hyperreflective cystoid spaces in 33% of eyes. Hyperreflective cystoid spaces detected by OCTA affected more than one-third of the DMO eyes. Their disappearance was not associated with any functional improvement and led to the formation of new hard exudate deposits in about one-third of the eyes.


[Nuclear FoxO1 as a bridge between metabolism and mitogenesis].
The transcription factor FoxO1 plays a central role in the metabolic adaptations to fasting. Furthermore, FoxO1 and its homologs encode enzymes buffering ROS (reactive oxygen species) or repairing damaged DNA, and are involved in stalling the ageing process across evolution. Our recent work conducted in primary cultures of rat hepatocytes suggests new mechanisms by which FoxO1 exerts some of these functions. They revealed an unexpected role for FoxO1 in amplifying metabolic, survival, mitogenic and stress signals, and the existence of multiple feed-back loops by which FoxO1 integrates and controls these pathways. Furthermore, these effects were found to be independent of FoxO1 direct binding to DNA.


Sustained virological response in patients with HCV treated with daclatasvir plus sofosbuvir, with or without ribavirin: a large, field-practice study.
The once-daily oral combination of daclatasvir (DCV) and sofosbuvir (SOF), with or without ribavirin (RBV), is effective and well tolerated in patients with hepatitis C virus (HCV). However, further field-practice studies are necessary to investigate the effectiveness and safety of the DCV+SOF combination in diverse subpopulations of patients with HCV, including those who are more challenging to treat such as patients with a genotype 3 (G3) infection. The aim of this retrospective, multicenter, field-practice study was to investigate the therapeutic efficacy and safety of the oral combination of DCV and SOF, with or without RBV (DCV+SOF±RBV), in a large unselected cohort of patients with chronic HCV infection (CHC). Consecutive patients received DCV+SOF±RBV for 12 or 24 weeks. The efficacy endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12). Safety factors were also considered. A total of 620 patients were included in this study; the predominant genotype was G3 (55.3%). Of the total sample, 248 (40%) patients were treated with DCV+SOF+RBV and 372 (60%) did not receive RBV. The majority of patients assessed at week 12 (98%, 596/608) achieved SVR12. Among G3 patients, 98.8% (335/339) achieved SVR12. The most common adverse event was elevated bilirubin (30.6%), recorded in 4.9% of cases as a grade 3-4 adverse event. This study shows the high pan-genotypic effectiveness and safety of the DCV+SOF±RBV combination in a large, unselected sample of CHC patients with G1-4, including a wide proportion of G3 CHC patients.


Protective effect of lutein on spinal cord ischemia-reperfusion injury in rats.
Paraplegia is deterioration in motor or sensory function of the lower limbs that can occur after modification of a thoracoabdominal aortic aneurysm. The purpose of this survey was to determine the protective action of lutein on spinal cord ischemia-reperfusion (I-R) damage. Thirty-five male rats were distributed into five groups: intact, sham, dimethyl sulfoxide (I-R+DMSO), low dose lutein (I-R+0.2 mg/kg lutein), and high dose lutein (I-R + 0.4 mg/kg lutein). Thirty minutes before surgery, a single dose lutein or DMSO was administered to rats of experimental groups. Next, the abdominal aorta was clamped exactly under the left renal artery and proximal to the abdominal aortic bifurcation for 60 min. All animals were evaluated by neurological function and histological and biochemical examinations at 72 hr after I-R. The mean motor deficit index (MDI) scores in lutein groups were lower compared with the DMSO group (P<0.001). Plasma level of malondialdehyde in lutein groups decreased compared with the DMSO group (P<0.05). Plasma level of total antioxidative capacity was increased in the high lutein group compared with low dose lutein and sham groups (P<0.05). Mean number of normal motor neurons in lutein groups was greater compared with the DMSO group (P<0.001). There was a significant negative correlation between MDI scores and the number of normal neurons (r= -0.764, P<0.001). Findings of the present study demonstrate that lutein may support spinal cord neurons from I-R damage.


Cytotoxic activity of endometrial granulated lymphocytes during the menstrual cycle in humans.
CD56+ CD16- granulated lymphocytes, termed endometrial granulated lymphocytes (eGLs), have been suggested to play a role in the maintenance of human pregnancy, although their in vivo function in both pregnant and nonpregnant endometrium remains unknown. The present study compared the cytotoxic activity of CD56+ CD16- eGLs (> 98% purity) positively selected from early and late proliferative-phase, early and late secretory-phase, and menstrual-phase endometrium with that of CD56+ CD16- eGLs purified from first-trimester decidua and CD56+ predominantly CD16+ cells from peripheral blood. From the late proliferative phase onwards, the major histocompatibility complex (MHC)-nonrestricted cytotoxic activity of eGLs was comparable between phases of the menstrual cycle. In contrast, eGLs from early proliferative-phase endometrium displayed significantly lower cytotoxic activity. With the exception of eGLs purified from early proliferative-phase endometrium, the cytotoxic activity of CD56+ CD16- eGLs purified from nonpregnant endometrium was comparable to that of CD56+ CD16- eGLs in decidua and CD56+ predominantly CD16+ cells from peripheral blood. No endogenous lymphokine-activated killer cell activity was detected in eGLs from endometrium or decidua. The present study using highly purified eGLs demonstrates that, with the exception of early proliferative-phase samples, CD56+ CD16- eGLs from nonpregnant endometrium and early pregnancy decidua have cytotoxic activity comparable to that of "classical" natural killer cells from peripheral blood.


A sensitive method for the detection and isolation of recombinants of foot-and-mouth disease virus.
Recombination between temperature-sensitive (ts) mutants of foot-and-mouth disease (FMD) virus was examined, using an infectious centre technique that was more sensitive (approx. 30-fold) than the conventional virus yield test. The test involved a brief incubation of the mixedly infected cells at the permissive temperature to allow recombination to occur followed by assay at the restrictive temperature to select for those cells in which recombination had occurred. With crosses involving widely separated mutations, as many as 28% of the infected cells produced presumptive recombinant plaques. Since each plaque was the result of an independent event, large numbers of different presumptive recombinants could be isolated for further study. Analysis of presumptive recombinant plaques from a variety of crosses showed that, in general, the virus produced had the properties expected of recombinants. An approximate correlation was found between genetic distance, as determined in the yield recombination test, and the percentage of recombinant infectious centres observed. The phenomenon was very sensitive to the balance between the input multiplicities of the two parent viruses and occurred very early in virus replication. The test has considerable potential for the study of genetic interactions in FMD virus, but it would be surprising if this potential was limited to picornaviruses.


The foot microbiome.
The human skin microbiome is represented by bacteria, fungi, viruses, and mites. Every human being possess their own unique skin microbiome because intrinsic and environmental factors have a significant impact on the quality and quantity of microorganism. Every site of the body is a separate microbial niche. The feet are one of the most unique and heterogeneous microbial niches of human body with areas that differ by skin thickness, anatomical features, distribution of sweat glands, pH, and the availability of oxygen. Healthy skin of the foot is inhabited by Corynebacteriaceae, Micrococcaceae, Propionibacteriaceae, Actinobacteria, Clostridiales, Lactobacillaceae, Streptococcaceae, Enterobacteriaceae, Moravellaceae, Neisseriaceae, Pastereullaceae, and Proteobacteria. The most common fungi present on the feet are Malassezzia, Cryptococcus, Aspergillus, Rhodotorula, Epicoccum, Saccharomyces, Candida, Epidermophyton Microsporum, and Trichophyton. The disturbance of the foot microbiome causes dysbiosis and may lead to pitted keratolysis, fungal, and viral infections or even to protothecosis.


Effects of junk-food on food-motivated behavior and NAc glutamate plasticity; insights into the mechanism of NAc calcium-permeable AMPA receptor recruitment.
In rats, eating obesogenic diets increase calcium-permeable AMPA receptor (CP-AMPAR) transmission in the nucleus accumbens (NAc) core, and enhances food-motivated behavior. Interestingly these diet-induced alterations in NAc transmission are pronounced in obesity-prone (OP) rats and absent in obesity-resistant (OR) populations. However, effects of diet manipulation on food motivation, and the mechanisms underlying NAc plasticity in OPs is unknown. Using male selectively-bred OP and OR rats, we assessed food-motivated behavior following ad lib access to chow (CH), junk-food (JF), or 10d of JF followed by a return to chow diet (JF-Dep). Behavioral tests included conditioned reinforcement, instrumental responding, and free consumption. Additionally, optogenetic, chemogenetic, and pharmacological approaches were used to examine NAc CP-AMPAR recruitment following diet manipulation and ex vivo treatment of brain slices. Motivation for food was greater in OP than OR rats, as expected. However, JF-Dep only produced enhancements in food-seeking in OP groups, while continuous JF access reduced food-seeking in both OPs and ORs. Reducing excitatory transmission in the NAc was sufficient to recruit CP-AMPARs to synapses in OPs, but not ORs. In OPs, JF-induced increases in CP-AMPARs occurred in mPFC-, but not BLA-to-NAc inputs. Diet differentially affects behavioral and neural plasticity in obesity susceptible populations. We also identify conditions for acute recruitment of NAc CP-AMPARs; these results suggest that synaptic scaling mechanisms contribute to NAc CP-AMPAR recruitment. Overall, this work improves our understanding of how sugary, fatty food consumption interacts with obesity susceptibility to influence food-motivated behavior. It also extends our fundamental understanding of NAc CP-AMPAR recruitment; this has important implications for motivation in the context of obesity as well as drug addiction.


Mating frequency influences nectar amino acid preference of Pieris napi.
It is generally assumed that butterflies, as is the case with many holometabolous insects, rely primarily on nutrients gathered by larval feeding for somatic maintenance and fecundity. These reserves can be supplemented by adult feeding and in some cases by nuptial gifts passed from the males to the females during mating. Recent findings indicate that female butterflies detect and prefer nectar with high levels of amino acids, thus calling new attention to this nutritive source. Polyandrous species can further supplement their larval stores with additional nuptial gifts. This study examined how mating frequency of the polyandrous butterfly Pieris napi affects the female's preference for nectar amino acids. Females of this species generally detect and prefer nectar mimics containing amino acids. However, nectar amino acid preference is significantly lower in mated females. Furthermore, nectar amino acid preference increases when females are not allowed to remate, whereas the preference of twice-mated females remains constant at a lower level. These results indicate a versatile response of females to nectar amino acids, depending on their nutritional status; they may even switch their source of amino acids between adult feeding and nuptial gifts.


Evaluation of iPod-Based Automated Tinnitus Pitch Matching.
Tinnitus is the perception of sound unrelated to any external source. Diagnostic approaches to assess tinnitus characteristics such as tinnitus pitch are crucial for new attempts of tinnitus therapy. The purpose of this study was to develop and evaluate reliable tinnitus pitch-matching procedures. Existing procedures usually require audiometric equipment and are time consuming. However, some patients with tinnitus find it hard to match their tinnitus in one single session. Therefore, we developed an iPod-based application for self-administered tinnitus pitch matching and compared it with a standardized audiometric procedure. A total of 17 patients with chronic tonal tinnitus participated in two sessions including both pitch-matching procedures. In the conventional audiometric test, the investigator adjusted the frequency and loudness of pure tones led by the responses of the patient. For the iPod-based procedure, we used a recursive two-interval forced-choice test that required no interaction with an investigator. Both procedures included loudness matching and testing for octave confusion. The iPod-based procedure resulted in lower pitch matches as compared with the conventional audiometry. Psychometric qualities such as test-retest reliability of both methods were comparable. Participants rated the iPod-based procedure as easier to perform and more comfortable to use. In conclusion, we find that the use of self-administered tinnitus pitch-matching procedures on a mobile device is feasible and easier in practice without any loss of reliability and validity. A major advantage is the possibility of repeated measurements without expensive equipment and experienced staff. Repeated measurements of tinnitus pitch can provide more information about the stability of the tinnitus perception and may improve the ability of participants to match their tinnitus.


Automatic identification of mixed bacterial species fingerprints in a MALDI-TOF mass-spectrum.
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry has been broadly adopted by routine clinical microbiology laboratories for bacterial species identification. An isolated colony of the targeted microorganism is the single prerequisite. Currently, MS-based microbial identification directly from clinical specimens can not be routinely performed, as it raises two main challenges: (i) the nature of the sample itself may increase the level of technical variability and bring heterogeneity with respect to the reference database and (ii) the possibility of encountering polymicrobial samples that will yield a 'mixed' MS fingerprint. In this article, we introduce a new method to infer the composition of polymicrobial samples on the basis of a single mass spectrum. Our approach relies on a penalized non-negative linear regression framework making use of species-specific prototypes, which can be derived directly from the routine reference database of pure spectra. A large spectral dataset obtained from in vitro mono- and bi-microbial samples allowed us to evaluate the performance of the method in a comprehensive way. Provided that the reference matrix-assisted laser desorption/ionization time-of-flight mass spectrometry fingerprints were sufficiently distinct for the individual species, the method automatically predicted which bacterial species were present in the sample. Only few samples (5.3%) were misidentified, and bi-microbial samples were correctly identified in up to 61.2% of the cases. This method could be used in routine clinical microbiology practice.


CT in transcatheter aortic valve replacement.
Transcatheter aortic valve replacement is a new method to treat patients with symptomatic, severe aortic stenosis who are at high surgical risk. Short- and midterm results have been encouraging, with more than 90,000 procedures performed worldwide. Patient selection, prosthesis sizing, and access strategies heavily rely on noninvasive imaging. Computed tomographic (CT) angiography is increasingly used for peri-interventional evaluation, as this modality allows for objective three-dimensional assessment of the aortic root, evaluation of the iliofemoral access route, and prediction of appropriate projection angles for prosthesis deployment. Compared with two-dimensional imaging techniques, CT provides comprehensive information about aortic annulus anatomy and geometry, supporting appropriate patient selection and prosthesis sizing. Recently, integration of CT measurements into sizing algorithms has been demonstrated to significantly reduce the incidence of paravalvular regurgitation, compared with prosthesis sizing with two-dimensional echocardiography. In addition, CT-based vascular access planning has been shown to reduce vascular access complications. Postprocedural CT imaging allows for the documentation of procedural success, evaluation of prosthesis positioning, and identification of asymptomatic complications. In this article, the rapidly emerging role of CT in the context of transcatheter aortic valve replacement will be described. Online supplemental material is available for this article.


Differential and dynamic regulation of miR398 in response to ABA and salt stress in Populus tremula and Arabidopsis thaliana.
MicroRNAs (miRNAs) are endogenous small RNAs of ~22 nucleotides (nt) that play a key role in down regulation of gene expression at the post-transcriptional level in plants and animals. Various studies have identified numerous miRNAs that were either up regulated or down regulated upon stress treatment. Here, we sought to understand the temporal regulation of miRNAs in different plant species under abscisic acid (ABA) and salt (NaCl) stress. Our results showed that the regulation of miR398 in response to ABA and salt stress was more dynamic in plants than previously reported. In poplars, miR398 was first induced upon 3-4 h of ABA or salt stress. However, this induction declined after 48 h and finally accumulated again over a prolonged stress (72 h). We referred to this kind of regulation as dynamic regulation. In contrast, such dynamic regulation of miR398 under salt stress was completely absent in Arabidopsis, in which miR398 was steadily and unidirectionally suppressed. Interestingly, ABA treatment caused a deviate dynamic regulation of miR398 in Arabidopsis, showing an opposite response as compared to that in poplars. We referred to the difference in regulation between Arabidopsis and poplars as differential regulation. Furthermore, the expression of the miR398 target, copper superoxide dismutase1 (CSD1), was in reverse correlation with the miR398 level, suggesting a control of this specific target expression predominantly by miR398 under abiotic stress. Together, these data consistently show a correlated regulation between miR398 and its representative target, CSD1, by ABA and salt stresses, and raise the possibility that regulation of miRNAs in plants is twofold: a dynamic regulation within a plant species and a differential regulation between different plant species.


Quasi-Experimental Evaluation of LifeCourse on Utilization and Patient and Caregiver Quality of Life and Experience.
Whole-person care is a new paradigm for serious illness, but few programs have been robustly studied. We sought to test the effect of LifeCourse (LC), a person-centered program for patients living with serious illness, on health-care utilization, care experience, and quality of life, employing a quasi-experimental design with a Usual Care (UC) comparison group. The study was conducted 2012 to 2017 at an upper-Midwest not-for-profit health-care system with outcomes measured every 3 months until the end of life. Enrolled patients (N = 903) were estimated to be within 3 years of end of life and diagnosed with 1+ serious illness. Exclusion criteria included hospice enrollment at time of screening or active dying. Community health workers (CHWs) delivered standardized monthly 1-hour home visits based on palliative care guidelines and motivational interviewing to promote patients' physical, psychosocial, and financial well-being. Primary outcomes included health-care utilization and patient- and caregiver-experience and quality of life. Patients were elderly (LC 74, UC 78 years) and primarily non-Hispanic, white, living at home with cardiovascular disease as the primary diagnosis (LC 69%, UC 57%). A higher proportion of LC patients completed advance directives (N = 173, 38%) than UC patients (N = 66, 15%; P < .001). LifeCourse patients who died spent more days in hospice (88 ± 191 days) compared to UC patients (44 ± 71 days; P = .018). LifeCourse patients reported greater improvements than UC in communication as part of the care experience ( P = .016). Implementation of person-centered programs delivered by CHWs is feasible; inexpensive upstream expansion of palliative care models can yield benefits for patients and caregivers. Trial Registration: Trial NCT01746446 was registered on November 27, 2012 at ClinicalTrials.gov .


Perceptions of the impact of non-standard work schedules on health in Australian graduates: an exploratory study.
Non-standard working hours are associated with negative health outcomes. However, little is known about the early years of exposure to non-standard work hours, or whether workers new to these work schedules perceive their work as impacting their health. This limits our ability to develop meaningful intervention strategies for transitioning into non-standard work hour schedules. This exploratory study investigated whether recent Australian graduates in various non-standard workhour schedules perceive that their work schedule negatively impacts their health. The responses of 120 graduates within four years of completing their tertiary qualification collected from an online survey were analysed. Graduates were asked whether they perceived their work arrangements as impacting their health. Significantly more of those who were engaged in non-standard work schedules or worked beyond contracted hours perceived their working arrangements as having an impact on their health. This study highlights the importance of studying workers' perceptions of the impact of work hours on health, particularly when workers may be experiencing good global health but be at risk for negative health outcomes in future.


Subjective memory complaints in the elderly: depressive symptoms and future dementia.
Population studies indicate that subjective memory complaints by elderly people are correlated with cognitive performance. These complaints have some predictive power regarding the development of dementia. The present study attempted to replicate this finding, and investigated which variables determine subjective memory complaints. Participants in the Amsterdam Study of the Elderly (n = 2114; 65-84 years of age), who were not demented and had a normal MMSE score (> 23) at baseline, were re-examined after four years. Subjective complaints were measured using a previously developed scale. Dementia and depression were measured using the Geriatric Mental State Schedule (GMS). Premorbid intelligence was measured by the Dutch Adult Reading Test (DART). Memory complaints at baseline contributed a small but significant amount of diagnostic information with respect to the prediction of future dementia. Depressive symptoms at baseline had no predictive value when these memory complaints were accounted for. Subjective memory complaints were associated with depression, baseline MMSE score, and premorbid intelligence. Subjective memory complaints are not just secondary to depression, but in part reflect realistic self-observations of cognitive decline.


Transplantation: current developments and future directions; the future of clinical islet transplantation as a cure for diabetes.
Islet transplantation is now a therapeutic option for patients with unstable type 1 diabetes mellitus (T1DM) with hypoglycemic unawareness. The benefits of this treatment include improvement in metabolic control with normalization of A1c and prevention of severe hypoglycemia. Insulin independence and improved quality of life can be reproducibly obtained by transplanting adequate islet numbers. Current obstacles to the widespread application of beta-cell replacement therapies include limited islet availability and the need for chronic immunosuppression. The emergence of promising interventions may be of assistance in improving islet recovery and favoring engraftment of smaller islet masses with comparable or better efficacy. In the future, regenerative efforts will contribute to overcoming this limitation as well. Combining these approaches with the development of safe immune interventions to induce self tolerance or to induce the permanent acceptance of transplanted tissues will be necessary to achieve long-term success. The steady progress and promising results of recent clinical trials justifies a great optimism toward the widespread application of beta-cell replacement as a treatment of choice for patients with diabetes.


Prediction of gamma-turns from amino acid sequences.
We predicted gamma-turns from amino acid sequences using the first-order Markov chain theory and enlarged representative data sets corresponding to protein chains selected from the Protein Data Bank (PDB). The following data sets were used for training and deriving the probability values: (1) an initial data set containing 315 protein chains comprising 904 gamma-turns and (2) a later data set in order to include new entries in the PDB, containing 434 protein chains and comprising 1053 gamma-turns. By excluding 93 protein chains that were common to these two training data sets, we generated two mutually exclusive data sets containing 222 and 341 protein chains for testing our predictions. Applying amino acid probability values derived from training data sets on to testing data sets yielded overall prediction accuracies in the range 54-57%. We recommend the use of probability values derived from the data set comprising 315 protein chains that represents more gamma-turns and also provides better predictions.


Osmotic strength blocks sporulation at stage II by impeding activation of early sigma factors in Bacillus subtilis.
In Bacillus subtilis, osmotolerance is a stationary phase-dependent, adaptive response inhibiting sporulation and sharing common regulators with this process. The extent of this inhibition was determined by measuring transcription activity of promoter lacZ fusions to early sigma genes (spoIIG and spoIIA coding for precursors of sigmaE and sigmaF) and to reporters of them (spoIID, spoIIQ and spoIIIG), in the absence and presence of 0.6 M or 1 M NaCl. The transcription activity of these sigma precursors, normally occurring at the onset of the stationary phase, was reduced to 30-50% of their maximal expression in hyperosmotic conditions; expression of genes under their control was, however, more inhibited (<10%). Therefore, sporulation was blocked at the sigma sigmaE and sigmaF activation steps. This assumption was confirmed by electron microscopic examinations of hyperosmotic cultures, which presented asymmetric septa characteristic of stage II mutants. Discussion was focused on the particular composition and/or structure of membranes during hyperosmotic growth and their involvement in the arrest of sporulation.


Seroprevalence of Toxoplasma gondii Infection in Refugee and Migrant Pregnant Women along the Thailand-Myanmar Border.
Toxoplasma gondii primary infection in pregnancy is associated with poor obstetric outcomes. This study aimed to determine the seroprevalence of Toxoplasma infection in pregnant migrant and refugee women from Myanmar attending antenatal care in Thailand. A random selection of 199 residual blood samples from first antenatal screen in 2014-2015 was tested for Toxoplasma IgG and IgM antibodies. Seroprevalence of Toxoplasma infection was 31.7% (95% confidence interval = 25.6-38.4). Avidity testing in the three positive IgM cases indicated all were past infections. Multiparity (≥ 3 children) was significantly associated with higher Toxoplasma seropositivity rates. Seroprevalence of T. gondii infection in this pregnant population is similar to the only other report from Myanmar, where multiparity was also identified as a significant association. Toxoplasma infection is important in pregnant women. Nevertheless, in this marginalized population, this infection may be given less priority, due to resource constraints in providing the most basic components of safe motherhood programs.


Sweet-type star fruit supplementation controls oxidative stress status and enhances the community walking capacity among elderly Thai.
Sweet-type Star fruit (SF) (Averrhoa carambola L.) is seasonal and more available for purchase in many markets in Thailand, when compared to the sour-type. But, its antioxidant activity results and potentially more modified supplement for elderly health during regular exercise in the community are unclear. This study aimed to evaluate the antioxidant activity and physical capacity from supplementation of sweet-type SF among elderly people performing home walking exercise. Mixing SF juice with honey industrially prepared the SF product. Its effects on oxidative stress status and physical capacity were studied in four groups; a supplement with walking exercise (n = 11, 67.00 ± 4.17 years), control (n = 12, aged 67.50 ± 5.58 years), supplementation (n = 11, aged 69.63 ± 7.14 years), and walking exercise (n = 12, aged 67.91 ± 4.33 years). Twenty grams or two teaspoons of supplement in warm water (150 mL) was the guideline for consumption twice daily for 4 weeks. In contrast, the walking exercise was prescribed with moderate intensity for 30 min, 3 days per week. Before and after the 4-week period, the oxidative stress status; glutathione (GSH), ascorbic acid (Vit C), total antioxidant capacity (TAC), and malondialdehyde (MDA), and 6-minute walking distance (6MWD) were evaluated. Results after the 4-week period, showed that Vit C and TAC increased and the MDA decreased significantly in the supplementation group, except the GSH and 6MWD results. The GSH and Vit C slightly decreased in the walking exercise group, whereas, its TAC, MDA and 6MWD increased significantly. Finally, The GSH and Vit C did not decrease and MDA slightly decreased in the combined group, but, their TAC and 6MWD increased significantly. Supplementation of the SF product during walking exercise possibly controls oxidative stress status and may enhance walking capacity.


An introduction to extended-wear contact lenses.
Extended wear contact lenses are now a reality. Unfortunately, the physiological basis for their apparent success is less based on knowledge than wishful thinking. This paper discusses both what we know and what we don't know with the goal of giving the practitioner in the field a global view of this important and controversial procedure.


Clinical features of herpes genitalis.
In a recent survey reported on by the Centers for Disease Control, herpes genitalis was the presenting complaint behind more than 35,000 visits to two clinics in major cities. Herpes genitalis is probably more prevalent today than any other sexually transmitted disease. Type 2 virus accounts for most infections seen; however, type 1 infections are reported more and more often as time passes. Also, there is now evidence suggesting that subclinical infection occurs in women with no antibodies to herpes simplex virus type 1. Meningitis and encephalitis are infrequent sequelae to primary infection, and when encephalitis occurs, the mortality has been reported to be as high as 70% of cases. Mortality in disseminated herpes simplex infection during pregnancy can reach 50% for mother and fetus. In general, signs and symptoms of recurrent infection are milder than those of primary infection.


Molecular and antigenic characterization of porcine rotavirus YM, a possible new rotavirus serotype.
In 1983, we isolated a porcine rotavirus (strain YM) that was prevalent in several regions of Mexico, as judged by the frequency of its characteristic electropherotype. By a focus reduction neutralization test, rotavirus YM was clearly distinguished from prototype rotavirus strains belonging to serotypes 1 (Wa), 2 (S2), 3 (SA11), 4 (ST3), 5 (OSU), and 6 (NCDV). Minor, one-way cross-neutralization (1 to 5%) was observed when antisera to the various rotavirus strains were incubated with rotavirus YM. In addition, the YM virus was not neutralized by neutralizing monoclonal antibodies with specificity to serotypes 1, 2, 3, and 5. The subgroup of the virus was determined to be I by enzyme-linked immunosorbent assay. To characterize the serotype-specific glycoprotein of the virus at the molecular level, we cloned and sequenced the gene coding for VP7. Comparison of the deduced amino acid sequence with reported homologous sequences from human and animal rotavirus strains belonging to six different serotypes further supported the distinct immunological identity of the YM VP7 protein.


Extension of the association structure in joint models to include weighted cumulative effects.
Motivated by a study measuring diabetes-related risk factors and complications, we postulate an extension to the standard formulation of joint models for longitudinal and survival outcomes, wherein the longitudinal outcome has a cumulative effect on the hazard of the event, weighted by recency. We focus on the relationship between the biomarker HbA1c and the development of sight threatening retinopathy, since the impact of the HbA1c marker on the risk of sight threatening retinopathy is expected to be cumulative, with the evolution of the HbA1c marker over time contributing to progressively greater damage to the vascular structure of the retina. Opting for a parametric approach, we propose the use of the normal and skewed normal probability density functions as weight functions, estimating the relevant parameters directly from the data. The use of the recency-weighted cumulative effect specification allows us to incorporate differences in the development of the longitudinal profile over time in the calculation of hazard ratios between subjects. The proposed functions provide us with parameters with clinically relevant interpretations while retaining a degree of flexibility. In addition, they also allow answering of important clinical questions regarding the relative importance of various segments of the biomarkers history in the estimation of the risk of the event. Copyright © 2017 John Wiley & Sons, Ltd.


Lively Minds: improving health and development through play-a randomised controlled trial evaluation of a comprehensive ECCE programme at scale in Ghana.
Many children in developing countries grow up in environments that lack stimulation, leading to deficiencies in early years of development. Several efficacy trials of early childhood care and education (ECCE) programmes have demonstrated potential to improve child development; evidence on whether these effects can be sustained once programmes are scaled is much more mixed. This study evaluates whether an ECCE programme shown to be effective in an efficacy trial maintains effectiveness when taken to scale by the Government of Ghana (GoG). The findings will provide critical evidence to the GoG on effectiveness of a programme it is investing in, as well as a blueprint for design and scale-up of ECCE programmes in other developing countries, which are expanding their investment in ECCE programmes. This study is a cluster randomised controlled trial, in which the order that districts receive the programme is randomised. A minimum sample of 3240 children and 360 schools will be recruited across 72 district school cohort pairs. The primary outcomes are (1) child cognitive and socioemotional development measured using the International Development and Early Learning Assessment tool, the Strengths and Difficulties Questionnaire, and tasks from the Harvard Laboratory for Development Studies; (2) child health (measured using height/weight for age, height-for-weight Z scores). Secondary outcomes include (1) maternal mental health, (using Kessler-10 and Warwick Edinburgh Mental Wellbeing Scale) and knowledge of ECCE practices; (2) teacher knowledge, motivation and teaching quality (measured with classroom observation); (3) parental investment (using the Family Care Index and Home Observation Measurement of the Environment and the Child-Parent Relationship Scale); (4) water, sanitation, and hygiene (WASH) practices; (5) acute malnutrition (using mid-upper arm circumference). We will estimate unadjusted and adjusted intent-to-treat effects. Study protocols have been approved by ethics boards at the University College London (21361/001), Yale University (2000031549) and Ghanaian Health Service Ethics Review Committee (028/09/21). Results will be made available to participating communities, funders, the wider public and other researchers through peer-reviewed journals, conference presentations, social and print media and various community/stakeholder engagement activities. ISRCTN15360698, AEARCTR-0008500.


A case in favor of aneurysmographic studies: a perforating artery originating from the dome of a basilar tip aneurysm.
A posterior perforating artery originating from the dome of a basilar tip aneurysm is reported. The exact origin of this perforator was identified by selective aneurysmography only. This observation provides an argument favoring the consideration of aneurysmographic studies before treatment of large aneurysms located in proximity to areas of normal perforating arteries.


Normal blood supply of the canine patella.
The normal blood supply of the canine patella was evaluated, using microangiography and correlated histology. Arterioles entered the cortex of the patella at multiple sites along the medial, lateral, and dorsal aspects. The body of the patella was vascularized uniformly, with many arterioles that branched and anastomosed extensively throughout the patella. The patella was not dependent on a single nutrient artery for its afferent supply, but had an extensive interior vascular network. These factors should ensure rapid revascularization and healing of patellar fractures, provided appropriate fracture fixation is achieved.


Induced Expression of CYP51a and HK1 Genes Associated with Penconazole and Fludioxonil Resistance in the Potato Pathogen Fusarium oxysporum.
Preventing antifungal resistance development and identifying pathogens with high, medium, and low risk of resistance development to a particular fungicide or fungicide class is crucial in the fight against phytopathogens. We characterized the sensitivity of potato wilt-associated Fusarium oxysporum isolates to fludioxonil and penconazole and assessed the effect of these fungicides on the expression of fungal sterol-14-α-demethylase (CYP51a) and histidine kinase (HK1) genes. Penconazole stunted the growth of F. oxysporum strains at all concentrations used. While all isolates were susceptible to this fungicide, concentrations of up to 1.0 μg/mL were insufficient to cause a 50% inhibition. At low concentrations (0.63 and 1.25 μg/mL), fludioxonil stimulated growth in F. oxysporum. With an increase in the concentration of fludioxonil, only one strain (F. oxysporum S95) exhibited moderate sensitivity to the fungicide. Interaction of F. oxysporum with penconazole and fludioxonil leads to respective elevated expressions of the CYP51a and HK1 genes, which upsurge with increasing concentration of the fungicides. The data obtained indicate that fludioxonil may no longer be suitable for potato protection and its continuous use could only lead to an increased resistance with time.


Reactivity and Enantioselectivity in NHC Organocatalysis Provide Evidence for the Complex Role of Modifications at the Secondary Sphere.
Secondary-sphere interactions are often harnessed to control reactivity and selectivity in organometallic and enzymatic catalysis. Yet, such strategies have only recently been explicitly applied in the context of organocatalytic systems. Although increased stability, reproducibility, and selectivity were obtained in previous work using this approach, the precise mechanistic pathway promoted by secondary-sphere modification in organocatalysis remained unclear. Herein, we report a comprehensive mechanistic study on the origin of the unique reactivity patterns and stereocontrol observed with boronic acids (BAs) as secondary-sphere modifiers of N-heterocyclic carbene (NHC) organocatalysts. Kinetic experiments revealed partial order in catalyst upon the addition of BA and unusual preactivation behavior, indicating the presence of stable off-cycle catalyst aggregation and BA-base adducts. These hypotheses were supported both by computations and by a series of NMR and nonlinear effect experiments. Furthermore, computations indicated a rate-limiting, water-assisted hydrogen atom transfer mechanism. This finding led to a considerable enhancement in the experimental reaction rate while maintaining excellent enantioselectivity by adding catalytic amounts of water. Finally, computations and racemization experiments uncovered an uncommon Curtin-Hammett-controlled enantioselectivity in the presence of secondary-sphere modifiers.


Solution for pseudoscopic problem in integral imaging using phase-conjugated reconstruction of lens-array holographic optical elements.
We propose an optical pseudoscopic to orthoscopic conversion method for integral imaging using a lens-array holographic optical element (LAHOE), which solves the pseudoscopic problem. The LAHOE reconstructs an array of diverging spherical waves when a probe wave with the phase-conjugated condition is imposed on it, while an array of converging spherical waves is reconstructed in ordinary reconstruction. For given pseudoscopic elemental images, the array of the diverging spherical waves integrates the orthoscopic three-dimensional images without a distortion. The principle of the proposed method is verified by the experiments of displaying the integral imaging on the LAHOE using computer generated and optically acquired elemental images.


Sphingosine 1-phosphate-dependent trafficking of peritoneal B cells requires functional NFkappaB-inducing kinase in stromal cells.
We previously reported that sphingosine 1-phosphate (S1P) regulates peritoneal B-cell trafficking and subsequent intestinal IgA production, but the underlying mechanisms remain obscure. We demonstrate here that nuclear factor kappaB-inducing kinase (NIK) is involved in the regulation of S1P-mediated trafficking of peritoneal B cells. Although peritoneal B cells from NIK-mutated alymphoplasia (aly) mice expressed type 1 S1P receptor (S1P(1)) at comparable levels and demonstrated normal migration toward S1P, aly peritoneal B cells showed decreased sensitivity to FTY720, an S1P(1) modulator. NIK-mutated stromal cells showed decreased levels of adhesion molecules (VCAM-1 and ICAM-1) and increased CXCL13 expressions, leading to impaired ability to support S1P-mediated emigration, but not immigration, of peritoneal B cells. Therefore, aly peritoneal B cells exhibited normal S1P-mediated peritoneal B-cell trafficking from peritoneum to intestine for IgA production when they were transferred into severe combined immunodeficient or wild-type mice. However, S1P-mediated emigration of wild-type B cells from the aly peritoneal cavity was impaired without affecting their immigration from the blood. Further, transfer of wild-type stromal cells into the peritoneum restored S1P-mediated trafficking of aly peritoneal B cells. These findings suggest that NIK in stromal cells has a specific role in the regulation of S1P-mediated trafficking of peritoneal B cells.


Maxillomandibular arch width differences at estimated centers of resistance: Comparison between normal occlusion and skeletal Class III malocclusion.
To evaluate the differences in maxillomandibular transverse measurements at either the crown or the estimated center of resistance (CR), and to compare values between normal occlusion and Class III malocclusion groups. Dental casts and computed tomography (CT) data from 30 individuals with normal occlusion and 30 with skeletal Class III malocclusions were evaluated. Using the casts, dental arch widths (DAWs) were measured from the cusp tips, and basal arch widths (BAWs-cast) were measured as the distance between the points at the mucogingival junction adjacent to the respective cusp tips. The BAWs determined from CT (BAWs-CT) images were measured from the estimated CRs of the teeth. None of the DAW measurements or maxillomandibular DAW differences showed statistically significant intergroup differences. In contrast, the maxillary BAWs-CT and BAWs-cast were lesser in the Class III malocclusion group than in the normal occlusion group. The mandibular BAWs-CT were significantly greater in the Class III malocclusion group than in the normal occlusion group. Moreover, the maxillomandibular BAW differences on both CT and cast showed significant intergroup differences in all transverse measurements. The maxillomandibular DAW differences showed no significant intergroup differences. In contrast, the maxillomandibular BAW differences on both CT and cast showed significant intergroup differences in all transverse measurements. The maxillomandibular BAW differences at the estimated CRs, measured using CT or casts, can reveal underlying transverse maxillary basal arch deficiencies in patients with skeletal Class III malocclusions.


Incidence of postoperative symptomatic epidural hematoma in spinal decompression surgery.
Neurological deterioration due to spinal epidural hematoma (SEH) is a rare but significant complication of spinal surgery. The frequency of hematoma evacuation after spinal surgery is reportedly 0.1%-3%. The objective of this study was to investigate the symptomatology of SEH and the frequency of evacuation for each surgical procedure after spinal decompression surgery. This is a retrospective study of 26 patients who underwent SEH evacuation after spinal decompression surgery between 1986 and 2005. During this period, 6356 spinal decompression surgeries were performed. The factors studied were the frequency of SEH evacuation for each surgical procedure, symptoms, time to SEH evacuation, comorbidities, and neurological recovery. The frequency of SEH evacuation was 0.41% (26 of 6356) for all operations. The frequency for each surgical procedure was 0% (0 of 1568) in standard lumbar discectomy, 0.50% (8 of 1614) in lumbar laminectomy, 0.67% (8 of 1191) in posterior lumbar interbody fusion, 4.46% (5 of 112) in thoracic laminectomy, 0.44% (4 of 910) in cervical laminoplasty, and 0.21% (1 of 466) in cervical anterior spinal fusion. Nine patients had comorbidities involving hemorrhage. Spinal epidural hematoma evacuation was performed between 4 hours and 8 days after the initial operation. Whereas severe paralysis was observed within 24 hours in most patients undergoing cervical and/or thoracic surgery, half of the patients undergoing lumbar surgery had symptoms of SEH such as leg pain or bladder dysfunction after suction drain removal. The shorter the period to evacuation, the better were the results of neurological recovery. Postoperative SEH was most frequent after thoracic laminectomy. In cervical and thoracic surgeries, symptoms of SEH were noted within 24 hours, mostly severe paralysis, and almost half of the lumbar surgery patients had symptoms after suction drain removal.


Differential expression of the enolase gene under in vivo versus in vitro growth conditions of Aeromonas hydrophila.
Aeromonas hydrophila is an emerging human pathogen that leads to gastroenteritis and other invasive diseases. By using a murine peritoneal culture (MPC) model, we identified via restriction fragment differential display PCR (RFDDPCR) five genes of A. hydrophila that were differentially expressed under in vivo versus in vitro growth conditions. The gene encoding enolase was among those five genes that were differentially up regulated. Enolase is a glycolytic enzyme and its surface expression was recently shown to be important in the pathogenesis of a gram-positive bacterium Streptococcus pyogenes. By Western blot analysis and Immunogold staining, we demonstrated secretion and surface expression of enolase in A. hydrophila. We also showed that the whole cells of A. hydrophila had strong enolase activity. Using an enzyme-linked immunosorbant assay and sandwich Western blot analysis, we demonstrated binding of enolase to human plasminogen, which is involved in the fibrinolytic system of the host. We cloned the A. hydrophila enolase gene, which exhibited 62% homology at the DNA level and 57% homology at the amino acid level when compared to S. pyogenes enolase. This is a first report describing the increased expression of enolase gene in vivo that could potentially contribute to the pathogenesis of A. hydrophila infections.


Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases.
Members of the potassium channel tetramerization domain (KCTD) family are soluble non-channel proteins that commonly function as Cullin3 (Cul3)-dependent E3 ligases. Solution studies of the N-terminal BTB domain have suggested that some KCTD family members may tetramerize similarly to the homologous tetramerization domain (T1) of the voltage-gated potassium (Kv) channels. However, available structures of KCTD1, KCTD5 and KCTD9 have demonstrated instead pentameric assemblies. To explore other phylogenetic clades within the KCTD family, we determined the crystal structures of the BTB domains of a further five human KCTD proteins revealing a rich variety of oligomerization architectures, including monomer (SHKBP1), a novel two-fold symmetric tetramer (KCTD10 and KCTD13), open pentamer (KCTD16) and closed pentamer (KCTD17). While these diverse geometries were confirmed by small-angle X-ray scattering (SAXS), only the pentameric forms were stable upon size-exclusion chromatography. With the exception of KCTD16, all proteins bound to Cul3 and were observed to reassemble in solution as 5 : 5 heterodecamers. SAXS data and structural modelling indicate that Cul3 may stabilize closed BTB pentamers by binding across their BTB-BTB interfaces. These extra interactions likely also allow KCTD proteins to bind Cul3 without the expected 3-box motif. Overall, these studies reveal the KCTD family BTB domain to be a highly versatile scaffold compatible with a range of oligomeric assemblies and geometries. This observed interface plasticity may support functional changes in regulation of this unusual E3 ligase family.


FGF inhibits neurite outgrowth over monolayers of astrocytes and fibroblasts expressing transfected cell adhesion molecules.
We have cultured cerebellar neurons on monolayers of cortical astrocytes in control medium or medium containing recombinant basic fibroblast growth factor (FGF). FGF was found to inhibit neurite outgrowth, with a significant effect seen at 0.5 ng/ml and a maximal effect at 10 ng/ml. FGF increased the production of arachidonic acid (AA) in cerebellar neurons, and when added directly to cultures or generated endogenously via activation of phospholipase A2 using melittin, this second messenger could mimic the inhibitory effect of FGF. FGF and AA could also specifically inhibit neurite outgrowth stimulated by three cell adhesion molecules (NCAM, N-cadherin and L1) expressed in transfected fibroblasts, or in the case of L1 bound to a tissue culture substratum. These data demonstrate that, in certain cellular contexts, FGF can act as an inhibitory cue for axonal growth and that arachidonic acid is the second messenger responsible for this activity. We discuss the possibility that arachidonic acid inhibits neurite outgrowth by desensitising the second messenger pathway underlying neuronal responsiveness to cell adhesion molecules.


Altered triglyceride and phospholipid metabolism predates the diagnosis of gestational diabetes in obese pregnancy.
Gestational diabetes (GDM), a common pregnancy complication associated with obesity and long-term health risks, is usually diagnosed at approximately 28 weeks of gestation. An understanding of lipid metabolism in women at risk of GDM could contribute to earlier diagnosis and treatment. We tested the hypothesis that altered lipid metabolism at the beginning of the second trimester in obese pregnant women is associated with a diagnosis of GDM. Plasma samples from 831 participants (16-45 years, 15-18 weeks gestation, BMI ≥ 30) from the UPBEAT study of obese pregnant women were used. The lipid, sterol and glyceride fraction was isolated and analysed in a semi-quantitative fashion using direct infusion mass spectrometry. A combination of uni-, multi-variate and multi-variable statistical analyses was used to identify candidate biomarkers in plasma associated with a diagnosis of GDM (early third trimester; IADPSG criteria). Multivariable adjusted analyses showed that participants who later developed GDM had a greater abundance of several triglycerides (48:0, 50:1, 50:2, 51:5, 53:4) and phosphatidylcholine (38:5). In contrast sphingomyelins (32:1, 41:2, 42:3), lyso-phosphatidylcholine (16:0, 18:1), phosphatidylcholines (35:2, 40:7, 40:10), two polyunsaturated triglycerides (46:5, 48:6) and several oxidised triglycerides (48:6, 54:4, 56:4, 58:6) were less abundant. We concluded that both lipid and triglyceride metabolism were altered at least 10 weeks before diagnosis of GDM. Further investigation is required to determine the functional consequences of these differences and the mechanisms by which they arise.


High PCB residues in birds from the Sheboygan River, Wisconsin.
Organochlorine residues were measured in the carcasses and, in some cases, brains and stomach contents of four species of birds collected along the Sheboygan River, Wisconsin during the years 1976 to 1980. Polychlorinated biphenyls (PCBs) were high in all samples and were the contaminants of greatest concern. Carcass residues ranged from 23 to 218 ppm PCBs on a wet weight basis; these are levels associated with reproductive impairment in laboratory studies with some birds. Food items in the stomachs of collected birds contained from 12 to 58 ppm PCBs, indicating a heavy contamination of food sources. The brain of one bird contained 220 ppm PCBs, a level that is not in the lethal range but is very high. Birds feeding in the contaminated portions of the Sheboygan River may have been harmed by high PCB levels.


Enantioselective alkenylation of aldimines catalyzed by a rhodium-diene complex.
An efficient rhodium-catalyzed asymmetric addition reaction of potassium alkenyltrifluoroborates to N-nosylaldimines has been developed. Under optimal conditions, the reactions proceeded with good to excellent yields and excellent enantioselectivities (97 → 99% ee). The utility of this method is demonstrated by the formal synthesis of (-)-aurantioclavine.


Material strategies and considerations for serologic testing of global infectious diseases.
The SARS-CoV-2 pandemic has brought to light multiple considerations when approaching infectious diseases on the global level. These range from diagnostic platforms, to therapeutics, and prevention agents. In this article, we focus on the engineering platforms and considerations when applying serologic assays to multiple geographic locations, climates with varying endemic virus repertoires, and different laboratory and clinical resource settings. Serologic assays detect antibodies that react against viral proteins, suggesting prior infection and correlative of an increased likelihood of immunity to future infection. As these assays are focused on the human immune response to a pathogen, and humans are variable, there are a number of important engineering steps to optimize assay performance, from sample collection, to assay execution and data analysis. Moving forward, a global approach to infectious disease detection and prevention is necessary to prevent the spread of future viruses with pandemic potential.


Multi-Scale Label-free Human Brain Imaging with Integrated Serial Sectioning Polarization Sensitive Optical Coherence Tomography and Two-Photon Microscopy.
The study of neurodegenerative processes in the human brain requires a comprehensive understanding of cytoarchitectonic, myeloarchitectonic, and vascular structures. Recent computational advances have enabled volumetric reconstruction of the human brain using thousands of stained slices, however, tissue distortions and loss resulting from standard histological processing have hindered deformation-free reconstruction of the human brain. The development of a multi-scale and volumetric human brain imaging technique that can measure intact brain structure would be a major technical advance. Here, we describe the development of integrated serial sectioning Polarization Sensitive Optical Coherence Tomography (PSOCT) and Two Photon Microscopy (2PM) to provide label-free multi-contrast imaging, including scattering, birefringence and autofluorescence of human brain tissue. We demonstrate that high-throughput reconstruction of 4×4×2cm3 sample blocks and simple registration of PSOCT and 2PM images enable comprehensive analysis of myelin content, vascular structure, and cellular information. We show that 2μm in-plane resolution 2PM images provide microscopic validation and enrichment of the cellular information provided by the PSOCT optical property maps on the same sample, revealing the sophisticated capillary networks and lipofuscin filled cell bodies across the cortical layers. Our method is applicable to the study of a variety of pathological processes, including demyelination, cell loss, and microvascular changes in neurodegenerative diseases such as Alzheimer's disease (AD) and Chronic Traumatic Encephalopathy (CTE).


Prevalence of antibodies to infectious bursal disease virus serotypes I and II in 75 Ohio chicken flocks.
Serum samples from 75 Ohio layer flocks were tested for antibodies to infectious bursal disease virus (IBDV) serotypes I and II using a virus-neutralization test. Infectious bursal disease had been diagnosed in three of the 75 flocks. Antibody titers to serotype I were detected in 77% of the flocks, and antibody titers to serotype II were detected in 47% of the flocks. Of the eight flocks known to have been vaccinated using a serotype I IBDV vaccine, all had antibody titers to serotype I, and four had antibody titers to serotype II. Eleven of 17 known unvaccinated flocks had antibodies to serotype I, and seven had antibodies to serotype II.


Caffeic acid phenethyl ester reduces spinal cord injury-evoked locomotor dysfunction.
Caffeic acid phenethyl ester (CAPE) is a component of propolis, which is a substance taken from the hives of honeybees, and is known to exhibit an anti-inflammatory activity. Such activity has been thought to be partly based on its potential and specific inhibitory activities toward nuclear factor-κB, a transcription factor. Therefore, in the present study, we evaluated the effect of CAPE on functional locomotor recovery after spinal cord injury (SCI) caused by hemi-transection, because inflammatory responses are a major cause of the secondary injury observed following SCI and play a pivotal role in regulating the pathogenesis of acute and chronic SCI. When CAPE was i.p.-administered at a dosage of 10 µmol/kg, it enhanced the recovery of locomotor function and reduced the lesion size while suppressing the expression of the mRNAs for a pro-inflammatory cytokine interleukin-1β and the inflammatory enzymes, inducible nitric oxide synthase and cyclooxygenase-2. These results suggest CAPE to be a promising therapeutic tool for reducing the secondary neuronal damage following primary physical injury to the spinal cord.


ClpE from Lactococcus lactis promotes repression of CtsR-dependent gene expression.
The heat shock response in bacterial cells is characterized by rapid induction of heat shock protein expression, followed by an adaptation period during which heat shock protein synthesis decreases to a new steady-state level. In this study we found that after a shift to a high temperature the Clp ATPase (ClpE) in Lactococcus lactis is required for such a decrease in expression of a gene negatively regulated by the heat shock regulator (CtsR). Northern blot analysis showed that while a shift to a high temperature in wild-type cells resulted in a temporal increase followed by a decrease in expression of clpP encoding the proteolytic component of the Clp protease complex, this decrease was delayed in the absence of ClpE. Site-directed mutagenesis of the zinc-binding motif conserved in ClpE ATPases interfered with the ability to repress CtsR-dependent expression. Quantification of ClpE by Western blot analysis revealed that at a high temperature ClpE is subjected to ClpP-dependent processing and that disruption of the zinc finger domain renders ClpE more susceptible. Interestingly, this domain resembles the N-terminal region of McsA, which was recently reported to interact with the CtsR homologue in Bacillus subtilis. Thus, our data point to a regulatory role of ClpE in turning off clpP gene expression following temporal heat shock induction, and we propose that this effect is mediated through CtsR.


Packing Effect on Latex Film Dissolution: A UV-Visible Study.
Latex films with various thicknesses are formed from pyrene (P) labeled poly (methyl methacrylate) (PMMA) latex particles sterically stabilized by poly isobutylene (PIB). Annealings of latex films were performed above T(g) at elevated temperatures up to 270 degrees C for 30 min time intervals. The UV-Visible (UVV) technique was used for monitoring latex film formation and dissolution. It was observed that thicker films formed more transparent films than thinner films. Absorption of solvent molecules (chloroform) into the annealed latex film was followed by diffusion of PMMA chains into a solvent reservoir. Diffusion of pyrene-labeled PMMA chains was monitored in real time by the absorbance change of pyrene in the polymer-solvent mixture. A diffusion model with a moving boundary was employed to quantify real-time UVV data. Diffusion coefficients of PMMA chains were measured and found to be between 2.6 x 10(-9) and 9.7 x 10(-13) cm(2) s(-1) for the latex films in various thicknesses. It is observed that thicker and more transparent films dissolved much faster than the thinner and turbid films; i.e., highly packed films dissolve more easily. Copyright 1999 Academic Press.


Structure-activity relationship studies of antiviral N-quinolin-4-yl-N'-benzylidenehydrazine derivatives by discriminant analysis.
The classification technique of linear discriminant analysis (LDA) is applied for studying the structure-activity relationship among antiviral N-quinolin-4-yl-N'-benzylidenehydrazine (II) derivatives. The total hydrophilicity of substituents in the benzylidene moiety along with 4 indicator variables is found to significantly (p less than 0.001) discriminate 25 inactive congeners of (II) from 28 active congeners with more than 80% posterior classification ratio. The predictive stability of the discriminant functions is established by the leave-one-out procedure. In the light of the posterior probabilities of assignment calculated from these functions it is observed that ethoxy group at position 7 and methoxy group at positions 8 and 6 in the quinoline system favour activity while a methoxy group at ortho or para position in the phenyl ring decreases activity. In view of the finer classification within the active class the three-group analysis is also performed using LDA and the adaptive-least-squares techniques.


New vistas in the molecular chemistry of thorium: low oxidation state complexes.
Although the molecular chemistry of thorium is dominated by the +4 oxidation state accounts of Th(iii) complexes have continued to increase in frequency since the first structurally characterised example was reported thirty years ago. The isolation of the first Th(ii) complexes in 2015 and exciting recent Th(iii) and Th(ii) reactivity studies both indicate that this long-neglected area is set to undergo a rapid expansion in research activity over the next decade, as previously seen since the turn of the millennium for analogous U(iii) small molecule activation chemistry. In this perspective article, we review synthetic routes to Th(iii) and Th(ii) complexes and summarise their distinctive physical properties. We provide a near-chronological discussion of these systems, focusing on structurally characterised examples, and cover complementary theoretical studies that rationalise electronic structures. All reactivity studies of Th(iii) and Th(ii) complexes that have been reported to date are described in detail.


Rabies and other lyssavirus diseases.
The full scale of the global burden of human rabies is unknown, owing to inadequate surveillance of this fatal disease. However, the terror of hydrophobia, a cardinal symptom of rabies encephalitis, is suffered by tens of thousands of people each year. The recent discovery of enzootic European bat lyssavirus infection in the UK is indicative of our expanding awareness of the Lyssavirus genus. The main mammalian vector species vary geographically, so the health problems created by the lyssaviruses and their management differ throughout the world. The methods by which these neurotropic viruses hijack neurophysiological mechanisms while evading immune surveillance is beginning to be unravelled by, for example, studies of molecular motor transport systems. Meanwhile, enormous challenges remain in the control of animal rabies and the provision of accessible, appropriate human prophylaxis worldwide.


Acetate kinase: a triple-displacement enzyme.
Facts relating to the mechanism of phosphoryl transfer by acetate kinase (ATP:acetate phosphotransferase, EC 18.104.22.168) are reviewed. They point to the existence of at least one experimentally established phosphoenzyme (E-P) intermediate on the reaction pathway. Sterically, the phosphoryl transfer occurs with a net inversion of the configuration of the phosphorus atom. These facts are best in accord with a triple-displacement mode of action for acetate kinase, with two E-P intermediates and three steric inversions on phosphorus. It follows that a second E-P for acetate kinase must exist.


Liver-related effects of chronic hepatitis C antiviral treatment.
More than five years ago, the treatment of hepatitis C virus infection was revolutionized with the introduction of all-oral direct-acting antiviral (DAA) drugs. They proved highly efficient in curing patients with chronic hepatitis C (CHC), including patients with cirrhosis. The new DAA treatments were alleged to induce significant improvements in clinical outcome and prognosis, but the exact cause of the expected benefit was unclear. Further, little was known about how the underlying liver disease would be affected during and after viral clearance. In this review, we describe and discuss the liver-related effects of the new treatments in regards to both pathophysiological aspects, such as macrophage activation, and the time-dependent effects of therapy, with specific emphasis on inflammation, structural liver changes, and liver function, as these factors are all related to morbidity and mortality in CHC patients. It seems clear that antiviral therapy, especially the achievement of a sustained virologic response has several beneficial effects on liver-related parameters in CHC patients with advanced liver fibrosis or cirrhosis. There seems to be a time-dependent effect of DAA therapy with viral clearance and the resolution of liver inflammation followed by more discrete changes in structural liver lesions. These improvements lead to favorable effects on liver function, followed by an improvement in cognitive dysfunction and portal hypertension. Overall, the data provide knowledge on the several beneficial effects of DAA therapy on liver-related parameters in CHC patients suggesting short- and long-term improvements in the underlying disease with the promise of an improved long-term prognosis.


Propagation of longitudinal leaky surface waves under periodic metal grating structure on lithium tetraborate.
The dispersion properties of longitudinal leaky surface waves propagating under the periodic Al strip grating on lithium tetraborate (Li(2)B(4)O(7); LBO) are described theoretically and experimentally for applications of the mode to high frequency SAW devices. A theoretical method developed here is based on Floquet's theorem using space harmonics as an orthogonal function set and real boundary integral equations derived from the method of weighted residuals for a period of each region, i.e., substrate, metal, and free space. The boundary integral equations are solved by using the Galerkin procedure. The periodic strip gratings with both single-electrodes and double-electrodes are investigated, considering the convergency of the numerical computation for the number of the space harmonics. As a result, the propagation loss for shorted gratings was found to be relatively low in the thickness range of the Al strip below about 1% for the single-electrodes and 2% for the double-electrodes, although it greatly increases for a thickness over 2% for the single-electrodes and 3% for the double-electrodes.


[Factors influencing nerve regeneration].
This paper describes the most important cellular and molecular factors that influence nerve regeneration. The first prerequisite for axonal regeneration is survival of the neuron. This depends on neuron type, age, and the degree and proximity of the injury to the cell body. Spinal motoneurons are less susceptible to injury-induced death than cranial motoneurons and sensory neurons. The surviving neurons undergo changes characteristic of a switch from a transmitting mode to a growing mode. They produce various neurotrophic factors and their receptors influencing the neuron and the non-neuronal cells such as Schwann cells. The distal nerve stump undergoes degenerative processes including removal of axons and phagocytosis of myelin debris, the so-called Wallerian degeneration. Until the second day phagocytosis is done by Schwann cells, hematogenous macrophages invade the distal stump at the second day and phagocyte the whole debris within two weeks. Devoid of axonal contact, the myelinating Schwann cells switch their function from myelination to growth support for the regenerating axons, including cell proliferation, downregulation of myelin components and upregulation of neurotrophic factors. Additionally, the Schwann cells form the so-called Bands of Büngner, cell columns serving as pathway for the growing axon. Trophic factors, cell adhesion molecules and extracellular matrix influence the neuron, the growing axon and the endorgan as well as the non-neuronal cells such as Schwann cells, fibroblasts and macrophages. Application of drugs or trophic substances to enhance nerve regeneration after trauma and reconstruction is in the very beginning, and thus requires further experimental and clinical studies. Experimentally, FK 506 was found to support axonal regeneration after crush lesions and nerve grafting. Growth factors are currently administered clinically in other neurological diseases.


An adolescent female African elephant (Loxodonta africana) gave birth to an abnormal calf.
Maternal nutrition and the uterine environment can influence placental development in mammals, leading to the birth of abnormal infants who often experience difficulties in independent standing. This article documents an adolescent female African elephant (Loxodonta africana) giving birth to an African elephant calf with a shoulder height below the mean, and its inability to stand for the first 10 h after birth, a time span that significantly exceeds the average duration for independent standing. Through the implementation of assisted feeding and assisted standing measures, the calf eventually achieved independent standing and nursing from its mother after 27 h and subsequent catch-up growth at 5 months of age. This study presents the first case report on the growth parameters during pregnancy of an adolescent African elephant, the birth and care (feeding, assisted standing) of a small African elephant calf with the inability to stand alone and nurse independently for several hours, highlighting pregnancy may influence the growth of cows during their ongoing growth and development phase, the calf's survival and subsequent catch-up growth at 5 months of age. These findings offer valuable insights into the care of abnormal African elephant calves.


β-Blockers for Autism-Help or Hindrance?
A renewed interest in the use of β-blockers for neurodevelopmental disorders has recently resurfaced, notably as an addition to the limited psychopharmacological armamentarium of autism spectrum disorders (ASD). In this clinical perspective, authors decently argue this use could be advantageous and multi-folded for this population.


[The content of histamine and tyramine dependent of microbiological quality of salted herring stored at different temperatures].
Twenty six samples of salted herring from Warsaw food market were analyzed. Herrings in high-salted brine (with 26% content of salt) were stored for 21 days at temperature of 4 degrees C and 22 degrees C; low-salted (16% content of salt in brine) herring were stored for 42 days at temperature of 4 degrees C and 22 degrees C. Microbiological contamination level was assessed by standard methods for fish products, and biogenic amines--histamine and tyramine content by spectrofluorometric methods. There was no level change of both amines in high-salted herrings. Significant increase of tyramine content was observed in low-salted samples, depending on the time of storage. The highest level of tyramine up to 318 mg/kg--was observed after 6 weeks of storage. Histamine content increased in low-salted sampled up to 35 mg/kg during the period of storage. Aerobic microflora in the amount up to 10(6)/g was detected during storage of low-salted samples. Such level changes were not observed in high-salted herring samples.


Update on indications, complications, and outcomes of scleral contact lenses.
The role of scleral contact lenses (SCLs) has increasingly expanded since the first lens was fitted more than a century ago. While it was initially prescribed for the management of severely compromised corneas, the indications for modern SCL use have expanded to include less severe diseases. In this review, we aimed to provide an up-to-date overview of the current indications, complications, and outcomes for the various types of SCLs. In this narrative review, we thoroughly searched the PubMed/MEDLINE database for literature published from January 1980 to November 2021. Only relevant up-to-date English references were included. Furthermore, the figures in this manuscript were derived from our unit's patient documentation. Currently, SCLs can successfully be used to manage ocular surface diseases, visually rehabilitate irregular corneas, and correct irregular refractive errors. Although newer materials have yielded the same visual outcomes with fewer complications, these consequences still occur in approximately one-third of contact lens wearers, including difficulties in insertion and/or removal, discomfort or pain, and developing either halos, blurriness, or haze. Even though most of these complications are minor and can be easily treated, a good practice is essential to avoid sight-threatening complications such as microbial keratitis. SCLs are indispensable in ophthalmic clinics. The development of better-quality SCLs has increased the number of indications and improved the achievable visual rehabilitation. The future of developing improvements in SCL design, materials, and fit, and the expansion of their indication range is promising.


Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism.
In the central nervous system, tissue-type plasminogen activator (tPA) has been associated with both pro-death and prosurvival actions on neurons. In most cases, this has been related to exogenous tPA. In the present study, we addressed the influence of endogenous tPA. We first observed an increased transcription of tPA following either in vivo global brain ischemia in rats or in vitro oxygen glucose deprivation (OGD) on mice and rats hippocampal slices. Hippocampal slices from tPA-deficient mice were more sensitive to OGD than wild-type slices. Pharmacological approaches targeting the known receptors of tPA revealed that only the inhibition of phosphorylation of epidermal growth factor receptors (EGFRs) prevented the neuroprotective effect of endogenous tPA. This study shows that ischemic hippocampal neurons overproduce endogenous tPA as an intend to protect themselves from ischemic death, by a mechanism involving an activation of EGFRs. Thus, strategies contributing to promote either endogenous production of tPA or its associated EGFR-linked signaling pathway may have beneficial effects following brain injuries such as stroke.


Resection of Carotid Body Tumors in Patients of Advanced Age: Experience From a Single Center.
Resection of carotid body tumor (CBT) in patients of advanced ages has not been appreciated. This study aims to assess the clinical characteristics and perioperative comorbidities for CBT resection in patients of advanced age and to validate the application of an "isolated island" technique for extirpation of CBT. Eight patients of advanced age (≥60 years) who underwent CBT resection were enrolled as the study group (SG). Another 29 patients of younger age (<45 years old) underwent CBT extirpation were assigned as the control group (CG). The perioperative issues were compared between these 2 groups. The "isolated island" technique was successfully applied for resection of CBT in all 37 patients. The prevalence of Shamblin classification I, II, and III tumors in the SG was 12.5%, 62.5%, and 25%; whereas in the CG was 10.3%, 55.2%, and 34.5%, respectively. Bilateral CBT was observed in 7 patients of the CG and none in the SG. Vascular reconstruction was required for 1 (12.5%) patient in the SG, while it was required for 8 (27.6%) patients in the CG. Postoperative vocal cord palsy occurred in 37.5% of patients in SG, whereas the vocal cord palsy (34.5%) and dysphagia (6.9%) were commonly encountered in CG. In addition to postoperative length of stay (P = .004), no significant difference for operative time, intraoperative blood loss, or mortality were observed between these 2 groups (P > .05). Extirpation of CBT in patients of advanced age is rationale in appropriately selected patients. The "isolated island" technique is safe for CBT resection with seemingly low complication rates.


Development of Pharmacy Practice in European Countries-The Polish Perspective.
Polish pharmacy practice and the distribution of medicinal products in some European countries are still going through a significant transformation. Changes postulated by the pharmacists should strengthen their role, and the place of community pharmacies in the health care system in the context of-among others-the introduction and popularization of pharmaceutical care. Subsequently, these efforts may essentially ensure the professional independence of the pharmacists. The introduction of pharmaceutical care to the pharmacy practice in all European countries will help to improve the quality of patient care and treatment outcomes, and will lead to a better allocation of available resources. Herewith, we present an important voice in the international debate, showing the current changes in the pharmacy practice in Poland, a European Union (EU)-member from 2004. Indeed, this paper presents the perspective of the country in which the position of pharmaceutical care is not well-established, and the role of the pharmacist is still limited to dispensing medicinal products, more than decade after it joined EU.


Spillover effect of Japanese long-term care insurance as an employment promotion policy for family caregivers.
We evaluate a spillover effect of the Japanese public long-term care insurance (LTCI) as a policy to stimulate family caregivers' labor force participation. Using nationally representative data from 1995 to 2013, we apply difference-in-difference propensity score matching to investigate the spillover effect in two periods: before and after the introduction of the LTCI in 2000 and before and after its major amendment in 2006. Our results show that the LTCI introduction has significant and positive spillover effects on family caregivers' labor force participation and the effects vary by gender and age. In contrast, the LTCI amendment is found to have generally negative spillover effects on their labor force participation. We draw attention to these spillover effects, as expanding labor market supply to sustain the economy would be a priority for Japan and other rapidly aging countries in the coming decades.


Sustainability of religious communities.
This article focuses on the relationship between church population and sustainability. We carried out the study on a sample of Presbyterian churches in South Korea, and implemented dynamic optimization of the church population based on the Susceptible-Infected-Recovered (SIR) epidemic model. In particular, System Dynamics (SD) and Agent-Based Model (ABM) simulations are performed for a prototype model with key parameters that contribute to church growth. Potential parameters reflecting sustainability for churches trigger dramatic growth in church populations. We categorized five dimensions of sustainability with various multi-dimensional indicators in order to measure the level of sustainability, and we obtained the values of the indicators by analyzing a number of news articles searched with a text mining technique. As time-dependent values of sustainability are imposed on the generic SD model for church population dynamics as sustainable potential parameters, the optimized result reproduces specific features for the church population. We discuss the roles of key parameters for sustainable church growth, and the contributions of the churches to sustainability.


Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice.
-ATP-sensitive potassium (K(ATP)) channels were discovered in ventricular cells, but their roles in the heart remain mysterious. K(ATP) channels have also been found in numerous other tissues, including vascular smooth muscle. Two pore-forming subunits, Kir6.1 and Kir6.2, contribute to the diversity of K(ATP) channels. To determine which subunits are operative in the cardiovascular system and their functional roles, we characterized the effects of pharmacological K(+) channel openers (KCOs, ie, pinacidil, P-1075, and diazoxide) in Kir6.2-deficient mice. Sarcolemmal K(ATP) channels could be recorded electrophysiologically in ventricular cells from Kir6.2(+/+) (wild-type [WT]) but not from Kir6.2(-/-) (knockout [KO]) mice. In WT ventricular cells, pinacidil induced an outward current and action potential shortening, effects that were blocked by glibenclamide, a K(ATP) channel blocker. KO ventricular cells exhibited no response to KCOs, but gene transfer of Kir6.2 into neonatal ventricular cells rescued the electrophysiological response to P-1075. In terms of contractile function, pinacidil decreased force generation in WT but not KO hearts. Pinacidil and diazoxide produced concentration-dependent relaxation in both WT and KO aortas precontracted with norepinephrine. In addition, pinacidil induced a glibenclamide-sensitive current of similar magnitude in WT and KO aortic smooth muscle cells and comparable levels of hypotension in anesthetized WT and KO mice. In both WT and KO aortas, only Kir6.1 mRNA was expressed. These findings indicate that the Kir6.2 subunit mediates the depression of cardiac excitability and contractility induced by KCOs; in contrast, Kir6.2 plays no discernible role in the arterial tree.


Determinants of hepatitis C virus treatment completion and efficacy in drug users assessed by meta-analysis.
Hepatitis C virus (HCV)-infected drug users (DUs) have largely been excluded from HCV care. We conducted a systematic review and meta-analysis of the literature on treatment completion and sustained virologic response (SVR) rates in DUs. We assessed the effects of different treatment approaches and services to promote HCV care among DUs as well as demographic and viral characteristics. Studies of at least 10 DUs treated with pegylated interferon/ribavirin that reported SVR were analyzed. Heterogeneity was assessed (Cochran test) and investigated (meta-regression), and pooled rates were estimated (random effects). Thirty-six studies comprising 2866 patients were retrieved. The treatment completion rate among DUs was 83.4% (95% confidence interval [CI], 77.1%-88.9%). Among studies that included addiction-treated and untreated patients during HCV therapy, the higher the proportion of addiction-treated patients, the higher the HCV treatment completion rate (P < .0001). After adjusting for human immunodeficiency virus (HIV)/HCV coinfection, sex, and treatment of addiction, support services during antiviral therapy increased treatment completion (P < .0001). The pooled SVR rate was 55.5% (95% CI, 50.6%-60.3%). Genotype 1/4 (P = .0012) and the proportion of HIV-coinfected DUs (P = .0173) influenced the SVR rate. After adjusting for HCV genotype 1/4 and HIV/HCV coinfection, the SVR rate was positively correlated with involvement of a multidisciplinary team (P < .0001). Treatment of addiction during HCV therapy results in higher treatment completion. Our pooled SVR rate is similar to that obtained in registration trials in the general population. Treatment of addiction during HCV therapy will likely be important for HCV-infected DUs undergoing treatment with more complex regimens including direct-acting antivirals.


Bacteria and the growing threat of multidrug resistance for invasive cardiac interventions.
Invasive cardiovascular procedures which include heart transplantations, congenital heart surgery, coronary artery bypass grafts, cardiac valve repair and replacement, and interventional cardiac electrophysiology procedures represent common mechanisms to treat a variety of cardiovascular diseases across the globe. The majority of these invasive approaches employ antibiotics as a regular and obligatory feature of the invasive procedure. Although the growing incidence of bacterial resistance to currently used antibiotics threatens to curtail the use of all interventional surgical techniques, it remains an underappreciated threat within the arsenal of cardiovascular therapies. It is reasonable to expect that the continued overuse of antibiotics and the frequent management of coronavirus disease 2019 (COVID-19) infected patients with high doses of antibiotics will inevitably accentuate the rise of multidrug resistance. The purpose of this article is to heighten awareness of the role of bacterial infections in cardiovascular disease, the use of antibiotics in today's cardiovascular surgical theaters, the threat facing cardiovascular surgery should multidrug resistance continue to rise unabated, and the development of new antibiotic platforms to solve this problem.


The cognitive triad and suicide intent in depressed in-patients.
Daily ratings of self-esteem, hopelessness and suicide intent were made by senior psychiatric residents on 60 patients hospitalized for depression. Both hopelessness and low self-esteem correlated highly with suicide intent and both contributed independently to suicide intent. This suggested that self-esteem may be important in the development of suicide intent as well as hopelessness.


Ethnic differences in arterial wave reflections and normative equations for augmentation index.
Data regarding ethnic differences in wave reflections, which markedly affect the central pressure profile, are very limited. Furthermore, because age, heart rate, and body height are strong determinants of augmentation index, relating single measurements to normative data (in which augmentation index values correspond with average population values of its determinants) is challenging. We studied subject-level data from 10 550 adults enrolled in large population-based studies. In a healthy reference sample (n=3497), we assessed ethnic differences in augmentation index (ratio of second/first systolic peaks) and generated equations for adjusted z scores, allowing for a standardized comparison between individual augmentation index measurements and the normative population mean from subjects of the same age, sex, ethnic population, body height, and heart rate. After adjustment for age, body height, heart rate, and mean arterial pressure, African blacks (women: 154%; men: 138%) and Andean Hispanics (women: 152%; men: 133%) demonstrated higher central (aortic) augmentation index values than British whites (women: 140%; men: 128%), whereas American Indians (women: 133%; men: 122%) demonstrated lower augmentation index (all P<0.0001), without significant differences between Chinese and British whites. Similar results were found for radial augmentation index. Nonlinear ethnic/sex-specific equations for z scores were successfully generated to adjust individual augmentation index values for age, body height, and heart rate. Marked ethnic differences in augmentation index exist, which may contribute to ethnic differences in hypertensive organ damage. Our study provides normative data that can be used to complement the interpretation of individual hemodynamic assessments among men and women of various ethnic populations, after removing the effect of various physiological determinants.


Management of acute supraventricular tachycardia in children.
Recently, a 3-year-old patient in my practice urgently needed to go to the emergency department. The patient was found to have supraventricular tachycardia (SVT) and needed immediate treatment with adenosine. What evidence is currently available for management of SVT in children? Supraventricular tachycardia is a common cardiac condition in the pediatric population that manifests as a narrow QRS complex tachycardia on electrocardiography. Symptoms may range from palpitations, poor feeding, and irritability to more substantial hemodynamic instability. Patients who are hemodynamically stable can benefit from interventions such as vagal maneuvers, which can be done in the office. Such maneuvers include the Valsalva maneuver, stimulation of the diving reflex (for infants), and unilateral carotid sinus massage. Other children may need pharmacologic therapies to restore normal heart rhythm, which usually consists of a rapid intravenous injection of adenosine under monitoring. For patients who are hemodynamically unstable, emergency cardioversion may be needed.