A calcium bioluminescence assay for functional analysis of mosquito (Aedes aegypti) and tick (Rhipicephalus microplus) G protein-coupled receptors.
Arthropod hormone receptors are potential targets for novel pesticides as they regulate many essential physiological and behavioral processes. The majority of them belong to the superfamily of G protein-coupled receptors (GPCRs). We have focused on characterizing arthropod kinin receptors from the tick and mosquito. Arthropod kinins are multifunctional neuropeptides with myotropic, diuretic, and neurotransmitter function. Here, a method for systematic analyses of structure-activity relationships of insect kinins on two heterologous kinin receptor-expressing systems is described. We provide important information relevant to the development of biostable kinin analogs with the potential to disrupt the diuretic, myotropic, and/or digestive processes in ticks and mosquitoes. The kinin receptors from the southern cattle tick, Boophilus microplus (Canestrini), and the mosquito Aedes aegypti (Linnaeus), were stably expressed in the mammalian cell line CHO-K1. Functional analyses of these receptors were completed using a calcium bioluminescence plate assay that measures intracellular bioluminescence to determine cytoplasmic calcium levels upon peptide application to these recombinant cells. This method takes advantage of the aequorin protein, a photoprotein isolated from luminescent jellyfish. We transiently transfected the aequorin plasmid (mtAEQ/pcDNA1) in cell lines that stably expressed the kinin receptors. These cells were then treated with the cofactor coelenterazine, which complexes with intracellular aequorin. This bond breaks in the presence of calcium, emitting luminescence levels indicative of the calcium concentration. As the kinin receptor signals through the release of intracellular calcium, the intensity of the signal is related to the potency of the peptide. This protocol is a synthesis of several previously described protocols with modifications; it presents step-by-step instructions for the stable expression of GPCRs in a mammalian cell line through functional plate assays (Staubly et al., 2002 and Stables et al., 1997). Using this methodology, we were able to establish stable cell lines expressing the mosquito and the tick kinin receptors, compare the potency of three mosquito kinins, identify critical amino acid positions for the ligand-receptor interaction, and perform semi-throughput screening of a peptide library. Because insect kinins are susceptible to fast enzymatic degradation by endogenous peptidases, they are severely limited in use as tools for pest control or endocrinological studies. Therefore, we also tested kinin analogs containing amino isobutyric acid (Aib) to enhance their potency and biostability. This peptidase-resistant analog represents an important lead in the development of biostable insect kinin analogs and may aid in the development of neuropeptide-based arthropod control strategies.


Head and Neck Cancer in Saudi Arabia: a Systematic Review.
Head and neck cancer (HNC) is the ninth most common cancer worldwide, and has a poor 5-year survival rate averaging 50%, which has not changed for decades. A high prevalence of HNC has been reported in the southwestern region of Saudi Arabia, as compared to other areas of the country. However, data in regards to HNC are scattered and not well documented. Thus, the aim of this systematic review was to gather all available and updated important information regarding HNC in Saudi Arabia, and highlight the gaps of knowledge in our country with regard to this disease. In addition, suggestions of solutions to overcome the current status and improve our future standard of care to fight HNC are also highlighted. The electronic databases PubMed and Google Scholar using English-language literature were used for this systematic review, using specific inclusion and exclusion criteria and keywords. The search was performed in April 2016 and updated in June 2016. Our search revealed twenty-one studies that fulfilled our inclusion and exclusion criteria and that were conducted in Saudi Arabia. These studies investigated different aspects of HNC, including prevalence, risk factors, biomarkers, and assessed knowledge and awareness of both public and practitioners with regard to HNC. This review uncovered a big gap in our epidemiological data in cancer information in general, and head and neck cancer in particular. In addition, a lack of knowledge and awareness of both the public and health care practitioners hinders the early diagnosis of disease and negatively impact the prognosis, treatment and outcome. The Ministry of Health in Saudi Arabia should develop a more systematic way and adapt policies to gather cancer information in general, and head and neck cancer in particular, from all governmental and private sectors from all over the kingdom, and develop educational programs to raise the knowledge and awareness of HNC in the country.


Genetic analysis of the mode of interplay between an ATPase subunit and membrane subunits of the lipoprotein-releasing ATP-binding cassette transporter LolCDE.
The LolCDE complex, an ATP-binding cassette (ABC) transporter, releases lipoproteins from the inner membrane, thereby initiating lipoprotein sorting to the outer membrane of Escherichia coli. The LolCDE complex is composed of two copies of an ATPase subunit, LolD, and one copy each of integral membrane subunits LolC and LolE. LolD hydrolyzes ATP on the cytoplasmic side of the inner membrane, while LolC and/or LolE recognize and release lipoproteins anchored to the periplasmic leaflet of the inner membrane. Thus, functional interaction between LolD and LolC/E is critically important for coupling of ATP hydrolysis to the lipoprotein release reaction. LolD contains a characteristic sequence called the LolD motif, which is highly conserved among LolD homologs but not other ABC transporters of E. coli. The LolD motif is suggested to be a region in contact with LolC/E, judging from the crystal structures of other ABC transporters. To determine the functions of the LolD motif, we mutagenized each of the 32 residues of the LolD motif and isolated 26 dominant-negative mutants, whose overexpression arrested growth despite the chromosomal lolD(+) background. We then selected suppressor mutations of the lolC and lolE genes that correct the growth defect caused by the LolD mutations. Mutations of the lolC suppressors were mainly located in the periplasmic loop, whereas ones of lolE suppressors were mainly located in the cytoplasmic loop, suggesting that the mode of interaction with LolD differs between LolC and LolE. Moreover, the LolD motif was found to be critical for functional interplay with LolC/E, since some LolD mutations lowered the ATPase activity of LolCDE without affecting that of LolD.


Trends in alcohol and marijuana detected in homicide victims in 9 US states: 2004-2016.
Use of alcohol and other drugs is a major risk factor for assaultive injuries and violent deaths. The purpose of this study was to examine the time trends in the prevalence of alcohol and marijuana detected in homicide victims. We analyzed toxicological testing data for homicide victims (n = 12,638) from the 2004-2016 National Violent Death Reporting System in 9 US states (Colorado, Georgia, Massachusetts, New Jersey, Oregon, Rhode Island, South Carolina, Virginia, and Wisconsin). We used the Cochran-Armitage test for trend to assess the statistical significance of changes in the prevalence of alcohol and marijuana detected in these homicide victims during the study period. Overall, 37.5% of the homicide victims tested positive for alcohol, 31.0% positive for marijuana, and 11.4% positive for both substances. During the study period, the prevalence of marijuana increased from 22.3% (95% confidence interval [CI] = 19.6, 25.0) in 2004 to 42.1% (95% CI = 39.2, 44.9) in 2016 (Z = -15.7; P < .001) while the prevalence of alcohol declined slightly (Z = 1.5; P = 0.143). Marked increases in the prevalence of marijuana were observed in both sexes and across age and racial groups. Marijuana is increasingly detected in homicide victims irrespective of demographic characteristics. Further research is needed to assess the causal role of marijuana use and concurrent use of marijuana and alcohol in homicide victimization.


Placebo- and amitriptyline-controlled evaluation of central nervous system effects of the NK1 receptor antagonist aprepitant and intravenous alcohol infusion at pseudo-steady state.
Recent interest in NK1 receptor antagonists has focused on a potential role in the treatment of drug addiction and substance abuse. In the present study, the potential for interactions between the NK1 receptor antagonist aprepitant and alcohol, given as an infusion at a target level of 0.65 g/L, was evaluated. Amitriptyline was included as positive control to provide an impression of the profile of central nervous system (CNS) effects. In a double-blind, randomized, placebo- and amitriptyline-controlled study, the pharmacokinetics and CNS effects of aprepitant and alcohol were investigated in 16 healthy volunteers. Cognitive and psychomotor function tests included the visual verbal learning test (VVLT), Bond and Lader visual analogue scales (VAS), digit symbol substitution test (DSST), visual pattern recognition, binary choice reaction time, critical flicker fusion (CFF), body sway, finger tapping, and adaptive tracking. Alcohol impaired finger tapping and body sway. Amitriptyline impaired DSST performance, VAS alertness, CFF, body sway, finger tapping, and adaptive tracking. No impairments were found after administration of aprepitant. Co-administration of aprepitant with alcohol was generally well tolerated and did not cause significant additive CNS effects, compared with alcohol alone. Therefore, our study found no indications for clinically relevant interactions between aprepitant and alcohol.


Instantaneous tonometry.
Respiration and arterial pulse cause intraocular pressure to cyclically vary around a mean pressure. Both the respiratory and arterial pulse waves approximate sine waves, and we have represented the IOP cycle as the sum of sinusoidal pressure waves. A rapidly acting tonometer may record any portion of the IOP cycle. We have computed the probability that a single pressure measurement will lie within a given interval around mean IOP and the probability that the mean of several such measurements will lie within a given range of mean pressure. The probability that an IOP estimate will lie in a given range of mean IOP decreases as the IOP cycle amplitude increases but increases as the number of tonometric measurements averaged together increases.


Phenotypic and genotypic analysis of antimicrobial resistance in Nocardia species.
Antimicrobial resistance is common in Nocardia species but data regarding the molecular mechanisms beyond their resistance traits are limited. Our study aimed to determine the species distribution, the antimicrobial susceptibility profiles, and investigate the associations between the resistance traits and their genotypic determinants. The study included 138 clinical strains of Nocardia from nine Israeli microbiology laboratories. MIC values of 12 antimicrobial agents were determined using broth microdilution. WGS was performed on 129 isolates of the eight predominant species. Bioinformatic analysis included phylogeny and determination of antimicrobial resistance genes and mutations. Among the isolates, Nocardia cyriacigeorgica was the most common species (36%), followed by Nocardia farcinica (16%), Nocardia wallacei (13%), Nocardia abscessus (9%) and Nocardia brasiliensis (8%). Linezolid was active against all isolates, followed by trimethoprim/sulfamethoxazole (93%) and amikacin (91%). Resistance to other antibiotics was species-specific, often associated with the presence of resistance genes or mutations: (1) aph(2″) in N. farcinica and N. wallacei (resistance to tobramycin); (ii) blaAST-1 in N. cyriacigeorgica and Nocardia neocaledoniensis (resistance to amoxicillin/clavulanate); (iii) blaFAR-1 in N. farcinica (resistance to ceftriaxone); (iv) Ser83Ala substitution in the gyrA gene in four species (resistance to ciprofloxacin); and (v) the 16S rRNA m1A1408 methyltransferase in N. wallacei isolates (correlating with amikacin resistance). Our study provides a comprehensive understanding of Nocardia species diversity, antibiotic resistance patterns, and the molecular basis of antimicrobial resistance. Resistance appears to follow species-related patterns, suggesting a lesser role for de novo evolution or transmission of antimicrobial resistance.


Clustering and Percolation in Suspensions of Carbon Black.
High-structured carbon fillers are ubiquitous as the conductive additive comprising suspension-based electrochemical energy storage technologies. Carbon black networks provide the necessary electrical conductivity as well as mechanical percolation in the form of a yield stress. Despite their critical role in determining system performance, a full mechanistic understanding of the relationship between the electrical transport characteristics of the percolated, conductive networks of carbon black, and the rheological properties is lacking, which hinders the rational design and optimization of flowable electrodes and the processing of electrolytes for batteries. Here, we report on the microstructural origin of the rheological and electrical properties of two commonly used conductive additives in neat propylene carbonate. From quiescent mechanical and structural studies, we find that the gelation of these carbon black suspensions is best described by the dynamic arrest of a clustered fluid phase. In contrast, the temperature and frequency dependence of the ac conductivity near this transition shows that mesoscale charge transport is determined by hopping between localized states that does not require a stress-bearing network. This unique combination of microstructural characterization with rheological and electrical measurements enables testing prevailing theories of the connection between electrical and mechanical percolation as well as improving conductive additives to enhance electrochemical performance.


PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia.
High-dose glucocorticoids (GCs) can be a useful treatment for aggressive forms of chronic lymphocytic leukemia (CLL). However, their mechanism of action is not well understood, and resistance to GCs is inevitable. In a minimal, serum-free culture system, the synthetic GC dexamethasone (DEX) was found to decrease the metabolic activity of CLL cells, indicated by down-regulation of pyruvate kinase M2 (PKM2) expression and activity, decreased levels of pyruvate and its metabolites, and loss of mitochondrial membrane potential. This metabolic restriction was associated with decreased size and death of some of the tumor cells in the population. Concomitant plasma membrane damage increased killing of CLL cells by DEX. However, the nuclear receptor peroxisome proliferator activated receptor α (PPARα), which regulates fatty acid oxidation, was also increased by DEX, and adipocyte-derived lipids, lipoproteins, and propionic acid protected CLL cells from DEX. PPARα and fatty acid oxidation enzyme inhibitors increased DEX-mediated killing of CLL cells in vitro and clearance of CLL xenografts in vivo. These findings suggest that GCs prevent tumor cells from generating the energy needed to repair membrane damage, fatty acid oxidation is a mechanism of resistance to GC-mediated cytotoxicity, and PPARα inhibition is a strategy to improve the therapeutic efficacy of GCs.


A single session assessment and psychoeducational intervention for eating disorders: Impact on treatment waitlists and eating disorder symptoms.
Long waitlists are common in eating disorder services and can have a detrimental impact on patients. We examined the effect on waitlist length, attendance, and eating disorder symptoms, of a 75-90 min single session intervention (SSI), attended a median of 16 days after referral to a specialist eating disorders clinic. Sequential referrals (N = 448) to a public outpatient eating disorders program were tracked from referral until a decision was made on patients entering treatment. One group ("SSI cohort") received a protocol incorporating assessment and psychoeducation about eating disorders before being placed on a waitlist, after which they received further assessment and entered treatment. Data on patient flow indices were collected from this cohort and compared to data from a "Pre-SSI" cohort who had not received the SSI. Symptom change was examined in the SSI cohort. Waitlist length reduced and the proportion of referrals attending assessment and being allocated to treatment increased. Eating disorder symptoms and impairment decreased. Underweight patients (Body Mass Index [BMI] < 18.5 kg/m2 ) gained weight. These findings suggest that a single session psychoeducational assessment may reduce waiting times, increase the likelihood of patients entering treatment, and facilitate early reductions in eating disorder symptoms. However, there may be other explanations for the changes observed.


Systemic circulatory adjustments to acute hypoxia and reoxygenation in unanesthetized sheep. Role of renin, angiotensin II, and catecholamine interactions.
The hemodynamic consequences of the hypoxic inhibition of angiotensin-converting enzyme activity were studied in chronically instrumented unanesthetized sheep (n = 8) breathing a hypoxic gas mixture for 60 min (PaO2 = 31 mm Hg) followed by reoxygenation with room air. Changes in cardiac output, vascular pressures, blood flow distribution, arterial pH, PaCO2, PaO2, and arterial levels of plasma renin activity, angiotensin II, bradykinin, and catecholamines were measured at selected time points. Seven additional sheep underwent the same protocol but received saralasin, an angiotensin II receptor blocker beginning at 55 min of hypoxia and extending into the reoxygenation period. During hypoxia, both groups developed identical hemodynamic patterns including a rise in cardiac output (25%), blood pressure (15%), and preferential blood flow distribution to the heart, brain, adrenals, diaphragm, and skeletal muscle, as well as a decrease in the fraction of cardiac output to the kidneys and most of the gut. This was associated with a decrease in angiotensin II concentrations (from 35 to 17 pg/ml) in spite of a doubling in plasma renin activity and catecholamines. Bradykinin levels did not change. Upon reoxygenation, bolus production of angiotensin II (from 17 to 1,819 pg/ml) occurred in spite of a constant level of plasma renin activity. Concurrently, different hemodynamic patterns between control and saralasin groups emerged upon reoxygenation, including an elevation from base line in blood pressure and systemic vascular resistance in the control group. Cardiac work (heart-rate systolic pressure product) in the control group remained elevated upon reoxygenation while coronary blood flow returned to base-line values. Saralasin reduced cardiac work upon reoxygenation and restored the match between coronary blood flow and work. We conclude that plasma renin activity and oxygen tension together govern angiotensin II levels for an optimal level of systemic vasomotor tone during hypoxia. However, upon reoxygenation, bolus production of angiotensin II may result in pathophysiologic circulatory patterns, such as impairment in oxygen delivery to the myocardium proportional to persistently elevated cardiac work in the immediate postresuscitation period.


Impact of an electronic consultant system on hypersensitivity reactions to iodinated radiocontrast media: an observational study.
To evaluate the impact of an electronic consultation support system on the incidence of hypersensitivity reactions to iodinated radiocontrast media (RCM). A retrospective observational study was conducted before and after the introduction of the consultation support system. The 1-year study period was divided into two 6-month periods: before and after 1 December 2012 (baseline and intervention periods, respectively), which was when our consultation support system was introduced. Data from examinations were collected retrospectively from the hospital information centre and problem reporting sheets in the radiology department. The primary outcome was the incidence of RCM reactions before and after the introduction of the consultation support system. Generalised estimating equations were used to account for the correlation between the same patients measured on multiple occasions. There were 317/20,179 (1.6%) and 186/19,873 (0.9%) hypersensitivity reactions during the baseline and intervention periods, respectively. The consultation support system significantly decreased the odds of the occurrence of a RCM reaction (OR=0.59, 95% CI 0.49 to 0.71, p<0.001) compared with baseline. There was also a twofold increase in the premedication rate after initiation of the consultation support system (OR=2.05, 95% CI 1.16 to 3.65 p=0.01). However, there was no significant difference in the recurrence rate between the periods (OR=0.97, 95% CI 0.58 to 1.65, p<0.93). The introduction of the consultation support system reduced the incidence of hypersensitivity reactions to RCM and increased the use of premedication in patients with known hypersensitivity to RCM.


Oral health care among nursing home residents in Avon.
To assess personal oral health care standards among frail, elderly and infirm nursing home residents prior to developing and evaluating a health promotion intervention. Descriptive survey, interview and clinical data. 22 randomly selected nursing homes in the Bristol area. 412 residents with denture(s) and/or natural teeth, and giving informed consent to the study were interviewed about dental attendance and current dental problems. A clinical examination assessed levels of oral and denture hygiene, denture-related stomatitis, gingivitis, calculus and root caries. Less than half the subjects (mean age 84.5 years) were ambulant. Over 70% had not seen a dentist for over 5 years, and 22% reported a current dental problem. Among denture wearers, 82% were unable to clean their dentures; staff cleaned dentures for 64%. Denture-related stomatitis affected 33%, and unhygienic dentures were worn by 95% of subjects. Among dentate subjects (mean number of teeth 11.6), 75% were unable to clean their teeth yet none received regular assistance. On average, two-thirds of each tooth surface were covered in plaque. Gingivitis was moderately severe. Calculus was present in 82% of subjects and root caries in 63% of subjects. Most residents required help with oral health care but many did not receive it. Residents' levels of plaque and associated dental disease were high. Staff did not effectively perform oral health care appropriate to residents' needs. Further research to evaluate an oral health care training programme for care staff is planned.


A graphical representation model for telemedicine and telehealth center sustainability.
This study shows the creation of a graphical representation after the application of a questionnaire to evaluate the indicative factors of a sustainable telemedicine and telehealth center in São Paulo, Brazil. We categorized the factors into seven domain areas: institutional, functional, economic-financial, renewal, academic-scientific, partnerships, and social welfare, which were plotted into a graphical representation. The developed graph was shown to be useful when used in the same institution over a long period and complemented with secondary information from publications, archives, and administrative documents to support the numerical indicators. Its use may contribute toward monitoring the factors that define telemedicine and telehealth center sustainability. When systematically applied, it may also be useful for identifying the specific characteristics of the telemedicine and telehealth center, to support its organizational development.


m-Chlorophenylpiperazine challenge in borderline personality disorder: relationship of neuroendocrine response, behavioral response, and clinical measures.
We have previously found that a subgroup of patients with impulsive personality disorders respond to m-chlorophenylpiperazine (m-CPP) administration with a distinctive spacy/high behavioral reaction and with increased cortisol responses. In this report we analyzed the relationship between behavioral and neuroendocrine responses to m-CPP in an enlarged sample of patients with borderline personality disorder (BPD). We also assessed the association of behavioral and neuroendocrine responses with clinical symptoms and with m-CPP blood levels. We found that in BPD patients the presence of a spacy/high behavioral response was significantly associated with increased prolactin and cortisol responses to m-CPP. In BPD patients increased m-CPP levels were significantly associated with neuroendocrine hypersensitivity and with a spacy/high behavioral response, while in controls increased m-CPP levels were not significantly associated with neuroendocrine hypersensitivity but were significantly associated with dysphoric behavioral responses. Taken together with previous work on m-CPP in obsessive-compulsive disorder, these results are partially consistent with the hypothesis that compulsive and impulsive symptoms fall at opposite ends of a phenomenologic and neurobiologic spectrum.


A Novel Biomolecule-Mediated Reduction of Graphene Oxide: A Multifunctional Anti-Cancer Agent.
Graphene oxide (GO) is a monolayer of carbon atoms that form a dense honeycomb structure, consisting of hydroxyl and epoxide functional groups on the two accessible sides and carboxylic groups at the edges. In contrast, graphene is a two-dimensional sheet of sp2-hybridized carbon atoms packed into a honeycomb lattice. Graphene has great potential for use in biomedical applications due to its excellent physical and chemical properties. In this study, we report a facile and environmentally friendly approach for the synthesis of reduced graphene oxide (rGO) using uric acid (UA). The synthesized uric acid-reduced graphene oxide (UA-rGO) was fully characterized by ultraviolet-visible (UV-Vis) absorption spectra, X-ray diffraction (XRD), dynamic light scattering (DLS), Fourier transform infrared (FTIR), scanning electron microscopy (SEM), and Raman spectroscopy. GO and UA-rGO induced a dose-dependent decrease in cell viability and induced cytotoxicity in human ovarian cancer cells. The results from this study suggest that UA-rGO could cause apoptosis in mammalian cells. The toxicity of UA-rGO is significantly higher than GO. Based on our findings, UA-rGO shows cytotoxic effects against human ovarian cancer cells, and its synthesis is environmentally friendly. UA-rGO significantly inhibits cell viability by increasing lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, activation of caspase-3, and DNA fragmentation. This is the first report to describe the comprehensive effects of UA-rGO in ovarian cancer cells. We believe that the functional aspects of newly synthesized UA-rGO will provide advances towards various biomedical applications in the near future.


Effectiveness of additional transmalar Kirschner wire fixation for a zygoma fracture.
The purpose of this study was to verify the effectiveness of transmalar Kirschner wire fixation as additional fixation for the treatment of zygoma fractures. The authors compared two methods for zygoma fixation at the frontozygomatic suture from both theoretical and clinical viewpoints: miniplate fixation (plate fixation) and miniplate fixation with an additional transmalar Kirschner wire fixation (wire plus plate fixation). For the theoretical study, the authors produced zygoma fractures on 20 skull simulation models; these were generated on the basis of computed tomographic data of actual dry skulls. In their simulation surgery, they fixed the fractured zygoma with the above-mentioned two fixation methods, producing 20 plate fixation models and 20 wire plus plate fixation models. A 10-kgf load was then applied on the fractured zygoma in the anteroposterior and superoinferior directions. Finally, the stresses around the fixation screws and the deviation of the zygoma were calculated using finite element analysis. For the clinical study, the authors compared the postoperative zygoma alignment based on computed tomography of six patients treated with plate fixation and eight patients treated with wire plus plate fixation using a visual analogue scale. In the theoretical study, the wire plus plate fixation models demonstrated a significant decrease in both the stresses around the screws and the deviation of the fractured bone compared with the plate fixation models. In the clinical study, the visual analogue scale scores for the wire plus plate fixation group were significantly higher than those for the plate fixation group. Because the additional transmalar Kirschner wire fixation can effectively increase the stability of the fractured zygoma that has been fixed with one miniplate, it should be recommended as an effective technique for the treatment of complicated zygoma fractures.


Long-term prognostic factors of chronic central serous chorioretinopathy after half-dose photodynamic therapy: A 3-year follow-up study.
To evaluate the long-term efficacy and factors involved in the recurrence and persistence of subretinal fluid (SRF) after half-dose photodynamic therapy (PDT) for chronic central serous chorioretinopathy (CSC). In this retrospective observational case series, 79 eyes (73 patients) with chronic CSC were treated with half-dose PDT and followed up for at least 3 years. They were divided into successful (64 eyes) and unsuccessful (15 eyes) groups based on SRF absorption and disease recurrence after one PDT session. Age, best-corrected visual acuity (BCVA), central foveal thickness, neuroretinal thickness, height of SRF, subfoveal choroidal thickness, window defect area detected by fluorescein angiography, and PDT spot area were compared between the groups. Factors associated with PDT success and BCVA at 3 years were investigated. LogMAR BCVA improved from 0.21±0.24 to 0.08±0.16 (P<0.001) at 3 years after PDT. Compared with the unsuccessful group, the successful group had a significantly younger mean age (50.5±9.7 vs. 56.5±9.1 years, P = 0.032) and better baseline BCVA (0.18±0.23 vs. 0.32±0.25, P = 0.034). Other parameters were not significantly different. Multivariate analyses showed that unsuccessful PDT was significantly associated with lower baseline BCVA (P = 0.026) and older age (P = 0.029) and that BCVA at 3 years after PDT was positively associated with baseline BCVA (P<0.001). Half-dose PDT has a long-term efficacy in chronic CSC. Relatively early PDT may improve anatomic and functional outcomes of chronic CSC.


Shared decision-making between health care providers and patients at a tertiary hospital diabetic Clinic in Tanzania.
Patients' participation in decision making regarding their treatment is defined in ethical, legal and human rights standards in the provision of care that concerns health providers and the entire community. This study was conducted to document experiences of patients and health care providers on shared decision making. This study employed a phenomenological study design using in-depth interview technique. Study participants were diabetic patients visiting the clinic and healthcare providers working at Muhimbili National Hospital. Data was collected using the semi-structured interview guide with open-ended questions using an audio digital recorder. Content analysis method was used during analysis whereby categories were reached through the process of coding assisted by Nvivo 12 software. Participants in this study expressed the role of shared decision-making in the care of patients with diabetes, with report of engagement of patients by health care providers in making treatment decisions. Participants reported no use of decision-making aids; however, health education tools were reported by participants to be used for educating patients. Limited time, patient beliefs and literacy were documented as barriers of effective engagement of patients in decision making by their healthcare providers. Engagement of patients in decision-making was noted in this study as experienced by participants of this study. Time, patient beliefs and patient literacy were documented as barriers for patients engagement, therefore diabetic clinic at Muhimbili National Hospital need to devise mechanisms for ensuring patients involvement in treatment decisions.


Further studies of the effects of inhaled glucocorticoids on pituitary-adrenal function in healthy adults.
We compared the effects of increasing doses of beclomethasone dipropionate (BDP) and fluocortin butylester (FCB) on several indices of pituitary-adrenal function in healthy adult subjects. Significant depression of urinary free cortisol excretion and the response to metyrapone was seen only at the highest dose (1600 mg/day) of BDP. This depression was not reflected by frequent measurement of the serum cortisol concentration. FCB used well in excess of its presumed therapeutic dose range showed no evidence of any effect on pituitary-adrenal function. These results confirm that at high doses BDP causes pituitary adrenal suppression. Differences from studies showing reduced adrenal function in children on BDP doses of 400 to 800 mg/day probably reflect differences in the dose per kilogram of body weight. Since the use of FCB was not accompanied by any adverse side effects or evidence of reduced pituitary-adrenal function, it may be a variable alternative for asthmatics who require high doses of inhaled glucocorticoid.


Enhanced expressions of microvascular smooth muscle receptors after focal cerebral ischemia occur via the MAPK MEK/ERK pathway.
MEK1/2 is a serine/threonine protein that phosphorylates extracellular signal-regulated kinase (ERK1/2). Cerebral ischemia results in enhanced expression of cerebrovascular contractile receptors in the middle cerebral artery (MCA) leading to the ischemic region. Here we explored the role of the MEK/ERK pathway in receptor expression following ischemic brain injury using the specific MEK1 inhibitor U0126. Rats were subjected to a 2-h middle cerebral artery occlusion (MCAO) followed by reperfusion for 48-h and the ischemic area was calculated. The expression of phosphorylated ERK1/2 and Elk-1, and of endothelin ETA and ETB, angiotensin AT1, and 5-hydroxytryptamine 5-HT1B receptors were analyzed with immunohistochemistry using confocal microscopy in cerebral arteries, microvessels and in brain tissue. The expression of endothelin ETB receptor was analyzed by quantitative Western blot. We demonstrate that there is an increase in the number of contractile smooth muscle receptors in the MCA and in micro- vessels within the ischemic region. The enhanced expression occurs in the smooth muscle cells as verified by co-localization studies. This receptor upregulation is furthermore associated with enhanced expression of pERK1/2 and of transcription factor pElk-1 in the vascular smooth muscle cells. Blockade of transcription with the MEK1 inhibitor U0126, given at the onset of reperfusion or as late as 6 hours after the insult, reduced transcription (pERK1/2 and pElk-1), the enhanced vascular receptor expression, and attenuated the cerebral infarct and improved neurology score. Our results show that MCAO results in upregulation of cerebrovascular ETB, AT1 and 5-HT1B receptors. Blockade of this event with a MEK1 inhibitor as late as 6 h after the insult reduced the enhanced vascular receptor expression and the associated cerebral infarction.


Pollen tube development in Petunia hybrida following compatible and incompatible intraspecific matings.
Pollen tubes formed following compatible and incompatible intraspecific matings in Petunia have been examined with light and electron microscopes. Compatible and incompatible tubes develop in an identical fashion on the stigma but, on entry into the top 1 mm of the stylar transmitting tissue changes occur both to the cytology of the tubes and their rates of growth. The early cytological changes are common to tubes of both compatibilities but, although both types of tube accelerate on entry into the style, incompatible tubes grow more slowly than compatible. Cytological differences became apparent between compatible and incompatible tubes following a short period of growth in the style, the latter possessing thicker cell walls and a cytoplasm packed with both organelles and reserves. Incompatible tubes subsequently burst or simply cease growth and die. The characteristic image afforded by this cytoplasm resembles that or burst or dead compatible tubes, except in that proportions of the cell components may differ. These data are discussed in terms of current models proposed to explain pollen tube growth and the operation of the self-incompatibility response in Petunia.


Neuropsychological and quality of life outcome after thalamic stimulation for essential tremor.
To evaluate short-term effects of unilateral thalamic deep brain stimulation (DBS) on cognition, mood state, and quality of life in patients with essential tremor (ET). Unilateral thalamotomy and thalamic DBS are effective in alleviating refractory tremor contralateral to the side of surgery. Thalamotomy can lead to cognitive morbidity, and DBS might be a preferable surgical intervention given potential avoidance or reversibility of such morbidity. Although unilateral thalamic DBS is cognitively safe and leads to quality of life improvement in PD, its neurobehavioral effects in ET are unknown. Forty patients with ET were administered a broad neuropsychological test battery, measures of mood state, and generic and disease-specific quality of life measures approximately 1 month before and 3 months after surgery (left hemisphere, 38 patients). Unilateral thalamic DBS was associated with significant improvements in tremor and dominant-hand fine visuomotor coordination. Statistically significant but clinically modest gains were observed on tasks of visuoperceptual and constructional ability, visual attention, delayed word list recognition, and prose recall. Only lexical verbal fluency declined significantly after surgery. Patients rated themselves as less anxious after surgery, and they perceived their quality of life as improved significantly. In particular, patients reported improved quality of life with respect to activities of daily living, stigma, emotional well-being, and communication. Unilateral thalamic DBS for ET is cognitively safe and associated with improvements in anxiety and quality of life in the near term and in the absence of operative complications. Patients were better able to carry out activities of daily living after surgery, and they reported improvement in several psychosocial domains of quality of life.


[Efficacy of disodium cromolyn in adult chronic asthma].
Disodium cromolyn is effective in preventing asthma, but its steroid sparing effect remains controversial. In this prospective cross-over study, we used two different brands of disodium cromolyn, Intal and Ticromil, each for 4 weeks on 7 adult patients with chronic asthma. The dosage was 20 mg qid via a special inhaler. The whole course of the study was 12 weeks for each patient, including 2 run-in weeks and 2 wash-out weeks. Patients were followed up by the same physician at outpatient clinics every 2 weeks to measure FEV1, FVC, peak expiratory flow rate (PEFR), and reversibility after bronchodilator. The physician also assessed the severity of the patients' symptoms via a special score system. Patients recorded symptom severity and frequency of medications at home on daily diary cards. Patients also measured PEFR twice a day. At the end of the treatment, FEV1 was improved more in Intal group; daily prednisolone dosage was markedly reduced in Ticromil group; PEFR was improved in both group; but neither symptom severity nor airway reversibility was significantly changed. When two groups were calculated as a whole, PEFR increased significantly from 294 +/- 20 l/min to 342 +/- 19 l/min (p = 0.0225). The daily prednisolone dosage reduced from 5.87 +/- 0.91 mg to 3.91 +/- 0.60 mg in the 3rd week and to 4.05 +/- 0.63 mg in the 4th week. The differences between these 2 dosages and the baseline dosage were statistically significant (both p < 0.05). Side effects were minimal in all patients. We concluded that after the use of disodium cromolyn for 4 weeks, PEFR was markedly improved and daily prednisolone dosage was also significantly reduced.


Lipid asymmetry of a model mitochondrial outer membrane affects Bax-dependent permeabilization.
The presence of an asymmetric distribution of lipids in biological membranes was first described ca. 50 years ago. While various studies had reported the role of loss of lipid asymmetry on signaling processes, its effect on membrane physical properties and membrane-protein interactions lacks further understanding. The recent description of new technologies for the preparation of asymmetric model membranes has helped to fill part of this gap. However, the major effort so far has been on plasma membrane models. Here we describe the preparation of liposomes mimicking the mitochondria outer membrane (MOM) in regard to its lipid composition and asymmetry. By employing the methyl-β-cyclodextrin-catalyzed lipid exchange technology and accurate quantification of lipid asymmetry with head group-specific probes we showed the successful preparation of a MOM model bearing a physiologically relevant lipid composition and asymmetry. In addition, by a direct comparison with its lipid symmetrical counterpart it is shown that asymmetric models were more resistant to tBid-promoted Bax-permeabilization, suggesting a role played by MOM lipid asymmetry on the mitochondria pathway of apoptosis. The barrier imposed by lipid asymmetry on membrane permeabilization was in part due to a decrease in the concentration of membrane-bound proteins, which was likely a consequence of the two mutually-dependent properties; i.e., the lower electrostatic surface potential and the higher molecular packing imposed by lipid asymmetry. It is proposed that MOM lipid asymmetry imparts different physical properties on the membrane and might add an additional component of regulation in intricate mitochondrial processes.


Dynamics of human replication protein A subunit distribution and partitioning in the cell cycle.
Human replication protein A (RPA) is a three-sub-unit protein complex involved in DNA replication, repair, and recombination. To gain insight into the dynamics of subunit assembly, we examined the subcellular distribution of RPA subunits (p70, p34, and p11) during the cell cycle. All three subunits colocalized in G1 and S phases, showing a diffuse nuclear distribution in G1 but a dot-like nuclear pattern in S phase. During S phase, the subunits showed a pattern reminiscent of the replication granules/factories described by others as sites of replication machinery. In meta-phase, p70 preferentially associated with the spindle poles, p34 was found on chromosomes, and p11 remained in the cytoplasm. In telophase, p70 and p34 appeared in the forming daughter nuclei; p11 remained in the cytoplasm until G1. Among the three subunits only p34 was associated with the nuclear matrix and this association persisted throughout the cell cycle. We conclude that (i) RPA complex assembly is differentially regulated, (ii) the replication machinery may be anchored to the nuclear matrix, and (iii) RPA subunits partition during mitosis and sort into daughter nuclei by different routes.


Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase.
Little is known about the impact of pretreatment drug resistance (PDR) on the efficacy of second generation integrase inhibitors. We sequenced pretreatment plasma specimens from the ADVANCE trial (NCT03122262). Our primary outcome was 96-week virologic success, defined as a sustained viral load <1000 copies/mL from 12 weeks onwards, <200 copies/mL from 24 weeks onwards, and <50 copies/mL after 48 weeks. Here we report how this outcome was impacted by PDR, defined by the World Health Organization (WHO) mutation list. Of 1053 trial participants, 874 (83%) have successful sequencing, including 289 (33%) randomized to EFV-based therapy and 585 (67%) randomized to DTG-based therapy. Fourteen percent (122/874) have ≥1 WHO-defined mutation, of which 98% (120/122) are NNRTI mutations. Rates of virologic suppression are lower in the total cohort among those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001), and for those on EFV-based treatment (60% [12/20] vs 86% [214/248], P = 0.002) and for those on DTG-based treatment (61/92 [66%] vs 84% [391/465] P < 0.001, P for interaction by regimen 0.49). Results are similar in multivariable models adjusted for clinical characteristics and adherence. NNRTI resistance prior to treatment is associated with long-term failure of integrase inhibitor-containing first-line regimens, and portends high rates of first-line failure in sub Saharan Africa.


Minimizing intracochlear trauma during cochlear implantation.
Several clinical trials have now demonstrated the feasibility and benefit of ipsilateral bimodal electric and acoustic stimulation of the auditory system for patients with varying degrees of hearing loss. Surgical techniques employed as a part of these investigations have been similar and focus on the implementation of atraumatic surgical principles. Each procedural step aims at minimizing intracochlear damage. A cochleostomy site inferior and slightly anterior to the round window membrane forms the basis for creating an opening into the scala tympani that avoids the critical structures of the inner ear. Electrode arrays have also been developed and refined to allow for relatively limited insertion-related damage. Using these specialized approaches, hearing preservation rates approaching 90% have been achieved. While impressive, this number reflects the conservation of only some degree of residual hearing. Complete preservation of hearing without any loss in pure tone thresholds and/ or discrimination abilities remains unusual, especially in subjects that have received a full-turn insertion. Thus, further work is clearly needed to optimize surgical protocols in an attempt to achieve total hearing preservation in all cases. A variety of biological and technological areas of investigation hold promise for fulfilling these goals. This report will review the current state of hearing preservation cochlear implantation as it relates to combined ipsi-lateral bimodal or electric acoustic stimulation.


What is the best technique for urethroplasty?
There is no clear evidence that determines which type of urethroplasty to perform under which particular circumstance. To review the options for urethroplasty at different sites in the urethra and for different types of stricture indicating which procedure should be used in which circumstances according to the best available evidence. Recent publications have been reviewed and supplemented with the authors' personal experience. Currently, in the developed world, the most common types of stricture are relatively short and are situated in the bulbar urethra. There is good evidence that these are best treated by excision and end-to-end anastomosis if they are short enough or by patch urethroplasty using a buccal mucosal graft if they are longer. Distal penile urethral strictures are the next most common type of stricture, but the evidence base is weaker, although there is agreement that penile strictures due to lichen sclerosus often require a staged approach to reconstruction, again using buccal mucosal grafts. Urethroplasty for pelvic fracture urethral injury is an altogether different type of technique for an altogether different type of pathology. There is good evidence that this is best treated by bulbo-prostatic anastomotic urethroplasty. Other types of strictures and salvage surgery have no good evidence base and are specialised areas where experience and judgement are necessary. The evidence base for urethral surgery has been developed for the more common types of urethral strictures in the last 20 yr, but it is still as much an art as it is a science.


[Effects of Chinese herbal medicine Guanxinkang on expression of PPARγ-LXRα-ABCA1 pathway in ApoE-knockout mice with atherosclerosis].
To observe the effects of Guanxinkang (GXK) decoction, a compound traditional Chinese herbal medicine, on expressions of peroxisome proliferator-activated receptor γ (PPARγ), liver X receptor α (LXRα) and ATP-binding cassette transporter A1 (ABCA1) in apolipoprotein E (ApoE)-knockout mice with atherosclerosis. Fourteen 6-week-old C57BL/6 J mice were used as normal control group. Seventy 6-week-old ApoE-knockout mice receiving a high-cholesterol diet to induce atherosclerosis were randomly divided into untreated group, simvastatin group and low-dose (concentration of crude drugs at 0.864 g/mL), medium-dose (crude drugs at 1.728 g/mL) and high-dose (crude drugs at 3.456 g/mL) GXK groups. After treated with the drugs for eight weeks continuously, the livers and aortas of mice were separated. The expressions of PPARγ, LXRα and ABCA1 were measured by real-time quantitative polymerase chain reaction and Western blotting respectively. Compared with the normal control group, mRNAs and proteins of PPARγ, LXRα and ABCA1 over-expressed in the untreated group (P<0.05). After the treatment, GXK decoction and simvastatin decreased the expressions of PPARγ, LXRα and ABCA1 (P<0.05). High-dose GXK decoction had more marked effects than low- and medium-dose GXK and simvastatin. The PPARγ-LXRα-ABCA1 pathway is involved in lipid regulation and inflammation activities. Over-expression of the genes has complicated effects on atherosclerosis in ApoE-knockout mice with high-cholesterol diet. GXK decoction has anti-inflammatory and anti-matrix metalloproteinase activities by regulating PPARγ, LXRα and ABCA1 interactions in the ApoE-knockout mice.


Effects of the COVID-19 Pandemic on the Mental Health of Healthcare Providers: A Comparison of a Psychiatric Hospital and a General Hospital.
Before the COVID-19 pandemic, healthcare providers (HCPs) were already experiencing a higher prevalence of mental health disorders compared with non-healthcare professionals. Here, we report on the psychosocial functioning and stress resilience of HCPs who worked during the COVID-19 pandemic in a large-sized psychiatric facility and a large acute care hospital, both located in central Ontario, Canada. Participants completed five validated psychometric instruments assessing depression, anxiety, and stress (The Depression, Anxiety, and Stress Scale-21, DASS-21); work-related quality of life (Work-Related Quality of Life Scale, WRQoL); resilience (Connor-Davidson Resilience Scale, CD-RISC); anxiety about the novel coronavirus (Coronavirus Anxiety Scale, CAS); and loneliness (UCLA Loneliness Scale, ULS). Participants from the psychiatric hospital (n = 94) were sampled during the easing of restrictions after the first wave in Ontario, and participants from the acute care hospital (n = 146) were sampled during the height of the second wave in Ontario. Data showed that HCPs from the acute care hospital and psychiatric hospital reported similar scores on the psychometric scales. There were also no significant differences in psychometric scale scores between medical disciplines at the acute care hospital. Among all HCPs, being a nurse predicted better quality of life (p = 0.01) and greater stress resilience (p = 0.031). These results suggest that HCPs' psychological symptoms are similar across the hospital settings sampled. Compared to other HCPs, nurses may show a unique resiliency to the pandemic. We suggest that emergencies such as the COVID-19 pandemic have a pervasive effect on HCPs. It is important to address HCPs' mental health needs in terms of crisis management and improve resilience among all HCPs during the inter-crisis period before a new challenge arrives.


A new decision tree for diagnosis of osteoarthritis in primary care: international consensus of experts.
Although osteoarthritis (OA) is managed mainly in primary care, general practitioners (GPs) are not always trained in its diagnosis, which leads to diagnostic delays, unnecessary resource utilization, and suboptimal patient outcomes. To address this situation, an International Rheumatologic Board (IRB) of 8 experts from 3 continents developed guidelines for the diagnosis of OA in primary care. The focus was three major topologies: hip, knee, and hand/finger OA. The IRB used American College of Rheumatology diagnostic criteria. Care pathways based on clinical and radiological findings were developed to identify intervention thresholds for GPs/specialists. To optimize usefulness in the primary care setting, the guidelines were formatted as an uncomplicated, but comprehensive one-page decision tree for each topology, highlighting key aspects of the evaluation process and incorporating red flags. In a two-phase validation stage, the draft guidelines were evaluated by rheumatologists and GPs for project execution, content and perceived benefit. The strength of the guidelines lies in their user-friendly diagram and potential for broad application. Such guidelines will allow GPs to make an easy but definite diagnosis of OA and offer clear guidance about situations requiring an expert opinion. The guidelines have potential to improve patient outcomes and reduce the number of unnecessary procedures. This project demonstrated the feasibility of developing easy-to-use and effective visual decision trees to facilitate the diagnosis and management of OA of the hip, knee and hand/finger in primary care. The next step should be to conduct a large impact study of implementation of these recommendations in the diagnostic management of OA in general practice in different areas.


Elevated plasma free fatty acids are associated with sudden death: a prospective community-based evaluation at the time of cardiac arrest.
In cohort studies, elevated levels of plasma nonesterified free fatty acids (NEFAs) have been associated with increased risk of sudden cardiac death (SCD) in men, but blood samples were drawn several years before SCD. To confirm this relationship by evaluating levels of plasma NEFAs at the time of the SCD event in a group of both men and women. From the ongoing Oregon Sudden Unexpected Death Study, we compared levels of plasma NEFAs in 149 SCD cases presenting with ventricular fibrillation (mean age 64 ± 12 years; 73% men) and 149 age- and sex-matched controls with coronary artery disease. Plasma was processed from blood drawn at the time of arrest (cases) and at a routine visit (controls). The levels of plasma NEFAs were compared after categorizing into quartiles on the basis of control values. Conditional logistic regression was used to predict adjusted odds ratio for SCD associated with plasma NEFA levels per increased quartile. The plasma NEFA levels were significantly higher in SCD cases than in controls (median 0.39 mmol/L [interquartile range 0.28-0.60 mmol/L] vs 0.32 mmol/L [interquartile range 0.20-0.49 mmol/L]; P = .002). There were no significant differences in body mass index, smoking, and diabetes. The odds ratio for SCD was 1.42 (95% confidence interval 1.14-1.78) per quartile increase in the plasma NEFA level (P = .002). Individuals with plasma NEFA levels above the prespecified cutoff point of 0.32 mmol/L were at increased risk of SCD (odds ratio 2.00; 95% confidence interval 1.20-3.34; P = .008). These findings strengthen the role of plasma NEFA as a potential biomarker for the assessment of SCD risk.


On the induction of injury in tomato under continuous light: circadian asynchrony as the main triggering factor.
Unlike other species, when tomato plants (Solanum lycopersicum L.) are deprived of at least 8h of darkness per day, they develop a potentially lethal injury. In an effort to understand why continuous light (CL) is injurious to tomato, we tested five factors, which potentially could be responsible for triggering the injury in CL-grown tomato: (i) differences in the light spectral distribution between sunlight and artificial light, (ii) continuous light signalling, (iii) continuous supply of light for photosynthesis, (iv) continuous photo-oxidative pressure and (v) circadian asynchrony - a mismatch between the internal circadian clock frequency and the external light/dark cycles. Our results strongly suggest that continuous-light-induced injury does not result from the unnatural spectral distribution of artificial light nor from the continuity of light per se. Instead, circadian asynchrony seems to be the main factor inducing the CL-induced injury, but the mechanism is not by the earlier hypothesised circadian pattern in sensitivity for photoinhibition. Here, however, we show for the first time diurnal fluctuations in sensitivity to photoinhibition during normal photoperiods. Similarly, we also report for the first time diurnal and circadian rhythms in the maximum quantum efficiency of PSII (Fv/Fm) and the parameter F0.


The reuse of genetic information in research and informed consent.
Important advances in genetics research have been made in recent years. Such advances have facilitated the availability of huge amounts of genetic information that could potentially be reused beyond the original purpose for which such information was obtained. Any such reuse must meet certain ethical criteria to ensure that the dignity, integrity, and autonomy of the individual from whom that information was obtained are protected. The aim of this paper is to reflect on these criteria through a critical analysis of the literature. To guarantee these values, ethical criteria need to be established in several respects. For instance, the question must be posed whether the information requires special attention and protection (so-called genetic exceptionalism). Another aspect to bear in mind is the most appropriate type of consent to be given by the person involved, on the one hand favouring research and the reuse of genetic information while on the other protecting the autonomy of that person. Finally, there is a need to determine what protection such reuse should have in order to avoid detrimental consequences and protect the rights of the individual. The main conclusions are that genetic information requires special care and protection (genetic exceptionalism) and that broad consent is the most practical and trustworthy type of consent for the reuse of genetic information.


Galanin inhibits gastrin release from isolated rat gastric G-cells.
Enzymatically isolated rat gastric mucosal cells (0.25% G-cells) were separated by counterflow elutriation, yielding a fraction in which the G-cell content was relatively enriched to 1.4%. In this fraction, basal gastrin release (mean +/- SE) was 31.1 +/- 1.3 pg.10(6) cells-1.60 min-1 and was stimulated by 10(-8) M neuromedin C (222.3 +/- 18.1% of basal), 10(-4) M carbachol (227.5 +/- 25.9%), 10(-6) M 12-O-tetradecanoylphorbol-13-acetate (TPA) (196.3 +/- 14.7%), and 10(-3) M dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) (193.9 +/- 6.8%), respectively. The neuropeptide galanin was tested at 10(-10) to 10(-7) M. Galanin had no effect on basal gastrin release but reduced the responses to neuromedin C, carbachol, TPA, and DBcAMP. IC50 ranged between 1 X 10(-10) and 8.6 X 10(-10) M galanin. Although in the relatively enriched G-cell fraction D-cells were not detectable by immunocytochemistry, a low rate of somatostatin release was still measured by radio-immunoassay (5.3 +/- 0.5 pg.10(6) cells-1.60 min-1). However, galanin failed to increase this rate under basal conditions or in response to any of the stimulants tested. These results favor the assumption that galanin might exert a direct inhibitory effect on rat gastric G-cells. Galanin seems to interfere at an intracellular mechanism(s), which is induced by neuromedin C and carbachol and which is commonly activated by protein kinase C- and cAMP-mediated stimulation.


Claudication pain and hemodynamic responses to exercise in younger and older peripheral arterial disease patients.
Claudication patients who are candidates for exercise can frequently walk to maximal pain without experiencing exaggerated blood pressure and heart rate, as well as other clinical symptoms. However, these concomitant problems are more likely to become apparent as patients age. Consequently, this study compared the claudication and hemodynamic responses to exercise in younger and older peripheral arterial disease patients. Forty younger (mean age 60.4 yr, range 55-62) and 51 older (mean age 75.5 yr, range 73-81) patients with stable claudication symptoms performed a progressive treadmill walking test to maximal leg pain. The times to onset and to maximal claudication pain, peripheral hemodynamic measurements (oximetry, ankle systolic pressure, and ankle-to-brachial systolic pressure index), and central hemodynamic measurements (heart rate and brachial blood pressures) were obtained. Onset and maximal claudication pain occurred 71 sec and 126 sec sooner (p < .05) in the older group, respectively. Greater reductions (p < .05) in foot transcutaneous oxygen tension, ankle systolic pressure, and ankle-to-brachial systolic pressure index were obtained during and following exercise in the older group. Furthermore, smaller increases (p < .05) in heart rate, brachial blood pressures, mean arterial pressure, and rate-pressure product were noted during exercise in the older group. Greater impairment in the peripheral hemodynamic measurements occurs without exaggerated heart rate and blood pressure responses in older claudication patients who walk to maximal leg pain compared with younger patients.


Concurrent and Lagged Relations between Emotion Regulation and Affect in Adolescents' Daily Life.
A better understanding of emotion regulation (ER) within daily life is a growing focus of research. This study evaluated the average use of two ER strategies (cognitive reappraisal and expressive suppression) and concurrent and lagged relationships between these two ER strategies and affect (positive and negative affect) in the daily lives of adolescents. We also investigated the role of the same strategies at the trait level on these within-person relationships. Thirty-three adolescents provided 1,258 reports of their daily life by using the Experience Sampling Method for one week. Regarding the relative use of ER strategies, cognitive reappraisal (M = 2.87, SD = 1.58) was used more often than expressive suppression (M = 2.42, SD = 1.21). While the use of both strategies was positively correlated when evaluated in daily life (p = .01), the same did not occur at the trait level (p = .37). Multilevel analysis found that ER strategies were concurrently related to affect (p < .01), with the exception of cognitive reappraisal-positive affect relationship (p = .11). However, cognitive reappraisal predicted higher positive affect at the subsequent sampling moment ( β = 0.07, p = .03). The concurrent associations between cognitive reappraisal and negative affect vary as function of the use of this strategy at the trait level (β = 0.05, p = .02). Our findings highlighted the complex associations between daily ER strategies and affect of a normative sample of adolescents.


Does gender discrimination exist in a gynecology training program in a private hospital?
Does gender discrimination by attending physicians exists in a residency in regard to residents' opportunities to perform complete/operative management of hysterectomies versus just being surgical assistants? The program studied is a 4-year program in obstetrics and gynecology residency with 3 residents per year. All cases involving a resident were recorded in a computer program designed by one of the authors (C.S.M.) to collect data for Residency Review Committee reports. Data were able to be sorted in a variety of methods including level of management, date of procedure, Physicians' Current Procedural Terminology codes, and attending physician name or resident name. Only intrafascial and extrafascial hysterectomies for benign disease were included in the study. Data were collected from July 1, 1996 to March 31, 1997. Five hundred and forty-nine hysterectomies with residents participating as primary surgeon (complete/operative management) or surgical assistant were performed during the study period. Complete/operative management was performed by the resident in 82.5% of cases while the resident was surgical assistant in 17.5%. Male residents were responsible for complete/operative management in 81.6% of cases and female residents in 83.2% of cases (P = 0.33). Male attending physicians were more likely to allow residents (male or female) to participate as the primary surgeon in abdominal hysterectomies (95.3%) and vaginal hysterectomies (68.5%) than female attending physicians (abdominal, 87.0% and vaginal, 57.3%) (P < 0.001 and P = 0.006, respectively). Although male attending physicians were more likely than female attending physicians to allow residents to perform complete/operative management, there was no discrimination as to whether the resident in question was male or female. When determining the level of management private gynecologists will allow residents to perform they do not practice gender discrimination.


Localized loss of Ca2+ homeostasis in neuronal dendrites is a downstream consequence of metabolic compromise during extended NMDA exposures.
Excessive Ca(2+) loading is central to most hypotheses of excitotoxic neuronal damage. We examined dendritic Ca(2+) signals in single CA1 neurons, injected with fluorescent indicators, after extended exposures to a low concentration of NMDA (5 microM). As shown previously, NMDA produces an initial transient Ca(2+) elevation of several micromolar, followed by recovery to submicromolar levels. Then after a delay of approximately 20-40 min, a large Ca(2+) elevation appears in apical dendrites and propagates to the soma. We show here that this large delayed Ca(2+) increase is required for ultimate loss of membrane integrity. However, transient removal of extracellular Ca(2+) for varying epochs before and after NMDA exposure does not delay the propagation of these events. In contrast to compound Ca(2+) elevations, intracellular Na(+) elevations are monophasic and were promptly reversed by the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]. MK-801 applied after the transient Ca(2+) elevations blocked the delayed propagating Ca(2+) increase. Even if applied after the propagating response was visualized, MK-801 restored resting Ca(2+) levels. Propagating Ca(2+) increases in dendrites were delayed or prevented by (1) reducing extracellular Na(+), (2) injecting ATP together with the Ca(2+) indicator, or (3) provision of exogenous pyruvate. These results show that extended NMDA exposure initiates degenerative signaling generally in apical dendrites. Although very high Ca(2+) levels can report the progression of these responses, Ca(2+) itself may not be required for the propagation of degenerative signaling along dendrites. In contrast, metabolic consequences of sustained Na(+) elevations may lead to failure of ionic homeostasis in dendrites and precede Ca(2+)-dependent cellular compromise.


The Need for Extracorporeal Membrane Oxygenation in Adults Undergoing Congenital Heart Surgery: Impact and Trends of Utilization.
Adults with congenital heart disease (ACHD) represent a population with unique health-care needs. Many patients require cardiac surgery, with some requiring postoperative extracorporeal membrane oxygenation (ECMO). This study aimed to identify the risk factors for the need of postoperative ECMO and characterize the impact of ECMO on admission characteristics. Data from the 2005-2012 iterations of the Nationwide Inpatient Sample were used. ACHD admissions over 18 years with a documented cardiac surgery were included. Univariate analysis was conducted to compare the characteristics between those requiring ECMO and those who did not. Regression analysis was done to identify the independent risk factors associated with ECMO and to determine the impact of ECMO on length, cost, and mortality of the admission. A total of 186,829 admissions were included. Of these, 446 (0.2%) admissions required ECMO. Those with acute kidney injury, double-outlet right ventricle, or total anomalous pulmonary venous connection were more likely to require ECMO. ECMO was also significantly more utilized in patients undergoing septal defect repair, complete repair of tetralogy of Fallot, atrial switch, and heart transplant. The use of ECMO significantly increased length, cost, and mortality of stay. Overall mortality was 62.6% in the ECMO group. ECMO is only needed in a small proportion of postoperative ACHD patients. The use of ECMO significantly increases cost, length of stay and mortality in these patients. Improved identification of postoperative ACHD patients who are more likely to survive ECMO may facilitate improved survival and decreased resource utilization.


Knowledge of risk factors and warning signs of stroke.
In this review, we have summarized the findings of fifteen studies of knowledge of stroke warning signs and risk factors in both high- and low-risk populations. In general, there appears to be low levels of knowledge of both risk factors and stroke warning signs among the communities studied. Using free recall, between 20% and 30% of respondents could not name a single risk factor, and between 10% and 60% could not name a single warning sign of stroke. Providing survey respondents with a list of potential warning signs substantially improved the identification of warning signs. Respondents in older age groups and having lower levels of educational attainment tended to have less knowledge of risk factors and warning signs of stroke than those in younger age groups and those with more education. Public campaigns to improve stroke knowledge are needed, particularly in the older age groups where the risk of stroke is greater.


A spoon full of studies helps the comparison go down: a comparative analysis of Tulving's spoon test.
Mental time travel refers to the ability to cast one's mind back in time to re-experience a past event and forward in time to pre-experience events that may occur in the future. Tulving (2005), an authority on mental time travel, holds that this ability is unique to humans. Anticipating that comparative psychologists would challenge this claim, Tulving (2005) proposed his spoon test, a test specifically designed to assess whether non-human animals are capable of mental time travel. A number of studies have now employed the spoon test to assess mental time travel in non-human animals. Here, we review the evidence for mental time travel in primates. To provide a benchmark, we also review studies that have employed the spoon test with preschool children. The review demonstrates that if we compare the performance of great apes to that of preschool children, and hold them to the same criteria, the data suggest mental travel is present but not ubiquitous in great apes.


New Perspectives on Non-invasive Blood Pressure Measurement.
Noninvasive blood pressure (NIBP) devices are calibrated against validated auscultation sphygmomanometers using Korotkoff sounds. This study aimed to investigate the timing of Korotkoff sounds in relation to pulse appearance in the brachial artery and values of intra-arterial blood pressure. Experiments were carried out on 15 participants, (14 males, 64.3 ± 10.4 years; one female, 86 yo), undergoing coronary angiography. A conventional occluding cuff, with a microphone for Korotkoff sounds, was placed on the upper arm (on the brachial artery). Intra-arterial blood pressure (IABP) was measured below the cuff with a fluid-filled catheter inserted via the radial artery and an external transducer. Finger photoplethysmography was used to measure brachial pulse wave velocity (PWV). Korotkoff sounds were processed electronically and custom algorithms identified the cuff pressure (CP) at which the first and last Korotkoff sounds were heard. PWV and max slope of the IABP pressure pulse were recorded to estimate arterial stiffness. The brachial artery closed at a CP of 132.0 ± 17.1 mmHg. Systolic and diastolic blood pressure (SBP and DBP) were 147.6 ± 14.3 and 72.7 ± 10.1 mmHg; mean pressure (MP, 100.1 ± 10.4 mmHg) was similar to MP derived from the peak of the oscillogram (98.5 ± 13.6 mmHg). Difference between IABP and CP recorded at first and last occurrence of Korotkoff sounds were, SBP: 19.0 ± 8.3 (range 2-29) mmHg, DBP: 4.0 ± 4.3 (range 2-12) mmHg. SBP derived from the onset of Korotkoff sounds can underestimate IABP by up to 19 mmHg. Since Korotkoff sounds are the recommended method mandated by the universal standard for the validation of blood pressure measuring devices, these errors are propagated through to all NIBP measurement devices irrespective of whether they use auscultatory or oscillometric methods.


The seroepidemiology of Lyme borreliosis in zoo animals in Germany.
We conducted the first seroepidemiological study to evaluate the exposure of zoo animals to Borrelia burgdorferi s.l. in German zoos and wildlife parks. A total of 1487 individuals representing 148 ungulate and carnivore species belonging to 19 families were examined using a non-species dependent ELISA. Specific antibodies were detected in 154 (10.4%) animals; 168 (11.3%) sera produced borderline results. The percentage of seropositive individuals was related to species and origin (zoo), and increased with age of the animals. Sex and season did not influence seroprevalence. Examination of 600 ticks (Ixodes ricinus; caught from vegetation in the zoos) by darkfield microscopy and indirect immunofluorescence technique revealed infection rates within the range typical for Central Europe. The results substantiate that there is an infection risk for zoo animals. A differential diagnosis of Lyme borreliosis should be taken into account in case of suspicious clinical symptoms and possible contact to ticks.


Improving survival for childhood cancer in Slovakia.
Data from the National Cancer Registry of Slovakia were used to evaluate survival for 2,958 childhood cancer patients registered between 1968 and 1987 and aged 0-14 years at diagnosis. Actuarial survival rates were computed for children diagnosed in 4 successive 5-year periods and compared. Overall 5-year survival rose from 20% for the period 1968-1972 to 46% for the period 1983-1987. The increase was statistically significant in age groups 1-4, 5-9 and 10-14 years. Survival for children aged less than l year also increased slightly, but this was not statistically significant. In most of the major diagnostic groups, survival increased markedly. Five-year survival rose significantly for leukaemias, lymphomas, CNS neoplasms, Wilms' tumours, bone tumours, soft-tissue sarcomas and germ-cell tumours. Despite this progress, survival in Slovakia remains lower than the corresponding figures from registries in Western Europe and the United States.


The interaction between cell adhesion molecule L1, matrix metalloproteinase 14, and adenine nucleotide translocator at the plasma membrane regulates L1-mediated neurite outgrowth of murine cerebellar neurons.
We have identified the adenine nucleotide translocator (ANT) isoforms ANT1 and ANT2 that are present in the plasma membrane of mouse cerebellar neurons as novel binding partners of the cell adhesion molecule L1. The direct interaction between ANT and L1 is mediated by sites within the fibronectin type III domains of L1 and the first and third extracellular loops of the ANT proteins. We also show that L1 interacts with the ANT binding partner matrix metalloprotease 14 (MMP14) and that the ANT proteins bind directly to the L1 interaction partner glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Moreover, we provide evidence that the functional interplay between L1, ANT proteins, MMP14, and GAPDH at the plasma membrane mediates L1-induced neurite outgrowth of cerebellar neurons. Disruption of this interplay by ANT inhibitors, ANT-derived synthetic peptides, and/or function-blocking MMP14 and ANT antibodies leads to alterations in L1-dependent neurite outgrowth. Stimulation of L1-mediated signaling in cerebellar neurons triggers transient ATP secretion via ANT proteins and leads to transient src family-dependent tyrosine phosphorylation of L1, ANT1, ANT2, and MMP14. Thus, our results indicate that plasma membrane-localized ANT1 and ANT2 regulate L1-mediated neurite outgrowth in conjunction with MMP14.


Event-Triggered Adaptive Dynamic Programming for Continuous-Time Systems With Control Constraints.
In this paper, an event-triggered near optimal control structure is developed for nonlinear continuous-time systems with control constraints. Due to the saturating actuators, a nonquadratic cost function is introduced and the Hamilton-Jacobi-Bellman (HJB) equation for constrained nonlinear continuous-time systems is formulated. In order to solve the HJB equation, an actor-critic framework is presented. The critic network is used to approximate the cost function and the action network is used to estimate the optimal control law. In addition, in the proposed method, the control signal is transmitted in an aperiodic manner to reduce the computational and the transmission cost. Both the networks are only updated at the trigger instants decided by the event-triggered condition. Detailed Lyapunov analysis is provided to guarantee that the closed-loop event-triggered system is ultimately bounded. Three case studies are used to demonstrate the effectiveness of the proposed method.


Conscious emotional experience emerges as a function of multilevel, appraisal-driven response synchronization.
In this paper we discuss the issue of the processes potentially underlying the emergence of emotional consciousness in the light of theoretical considerations and empirical evidence. First, we argue that componential emotion models, and specifically the Component Process Model (CPM), may be better able to account for the emergence of feelings than basic emotion or dimensional models. Second, we advance the hypothesis that consciousness of emotional reactions emerges when lower levels of processing are not sufficient to cope with the event and regulate the emotional process, particularly when the degree of synchronization between the components reaches a critical level and duration. Third, we review recent neuroscience evidence that bolsters our claim of the central importance of the synchronization of neuronal assemblies at different levels of processing.


[A rapid radionuclide method for clinical assessment of gastric juice proteolytic activity and acidity].
A new method for radionuclide measurement of gastric juice proteolytic activity (GJPA) is described. GJPA is determined according to the time of dissolution of the protein capsule filled with 99mTc-pertechnetate solution. In vitro experiments made with 342 samples of gastric juice revealed a correlation (p1 less than 0.01) between the time of dissolution of the 99mTc-pertechnetate capsule and proteolytic activity measured according to Metta's method. No correlation was established between GJPA (measured by Metta's method and by radionuclide method) and gastric juice acidity (p greater than 0.05). In 63 patients examined, the time of capsule dissolution was 15 to 18 minutes with GJPA being normal, 8 to 14 minutes (p less than 0.01) with elevated parameters of GJPA, and 19 to 37 minutes (p less than 0.01) with GJPA being reduced. The given method is a physiological one, sufficiently precise and can be recommended for a screening analysis of GJPA.


Spatial Distribution of PM2.5 Mass and Number Concentrations in Paris (France) from the Pollutrack Network of Mobile Sensors during 2018-2022.
The presence of particulate matter smaller than 2.5 µm in diameter (PM2.5) in ambient air has a direct pejorative effect on human health. It is thus necessary to monitor the urban PM2.5 values with high spatial resolution to better evaluate the different exposure levels that the population encounters daily. The Pollutrack network of optical mobile particle counters on the roofs of hundreds of vehicles in Paris was used to produce maps with a 1 km2 resolution (108 squares to cover the Paris surface). The study was conducted during the 2018-2022 period, showing temporal variability due to different weather conditions. When averaging all the data, the highest air pollution was found along the Paris motorway ring. Also, the mean mass concentrations of PM2.5 pollution increased from southwest to northeast, due to the typology of the city, with the presence of canyon streets, and perhaps due to the production of secondary aerosols during the transport of airborne pollutants by the dominant winds. The number of days above the new daily threshold of 15 µg.m-3 recommended by the WHO in September 2021 varies from 3.5 to 7 months per year depending on the location in Paris. Pollutrack sensors also provide the number concentrations for particles greater than 0.5 µm. Using number concentrations of very fine particles instead of mass concentrations corresponding to the dry residue of PM2.5 is more representative of the pollutants citizens actually inhale. Some recommendations for the calibration of the sensors used to provide such number concentrations are given. Finally, the consequences of such pollution on human health are discussed.


Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma.
Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient ( NCT01970358 ). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.


[The role of mass morphological study of placenta for prognosis of infectious processes in newborns].
The results of the long-term morphological study of a great number of placentas in the cities of St. Petersburg and Novgorod have been summarized. These results show frequent occurrence of infection of various etiology. The efficiency of revealing the risk groups among newborns is documented by a considerable decrease of infant mortality in Novgorod (from 20.6 in 1986 to 11.9 in 1996). The same phenomenon is demonstrated in St. Petersburg where a decrease in the incidence of intrauterine infections was noted at the autopsy material. A detailed study of catamnesis of children infected in utero showed an increase of minor neurological symptoms and higher incidence of acute respiratory viral infections.


Estimated MP2 and CCSD(T) interaction energies of n-alkane dimers at the basis set limit: comparison of the methods of Helgaker et al. and Feller.
The MP2 (the second-order Møller-Plesset calculation) and CCSD(T) (coupled cluster calculation with single and double substitutions with noniterative triple excitations) interaction energies of all-trans n-alkane dimers were calculated using Dunning's [J. Chem. Phys. 90, 1007 (1989)] correlation consistent basis sets. The estimated MP2 interaction energies of methane, ethane, and propane dimers at the basis set limit [EMP2(limit)] by the method of Helgaker et al. [J. Chem. Phys. 106, 9639 (1997)] from the MP2/aug-cc-pVXZ (X=D and T) level interaction energies are very close to those estimated from the MP2/aug-cc-pVXZ (X=T and Q) level interaction energies. The estimated EMP2(limit) values of n-butane to n-heptane dimers from the MP2/cc-pVXZ (X=D and T) level interaction energies are very close to those from the MP2/aug-cc-pVXZ (X=D and T) ones. The EMP2(limit) values estimated by Feller's [J. Chem. Phys. 96, 6104 (1992)] method from the MP2/cc-pVXZ (X=D, T, and Q) level interaction energies are close to those estimated by the method of Helgaker et al. from the MP2/cc-pVXZ (X=T and Q) ones. The estimated EMP2(limit) values by the method of Helgaker et al. using the aug-cc-pVXZ (X=D and T) are close to these values. The estimated EMP2(limit) of the methane, ethane, propane, n-butane, n-pentane, n-hexane, n-heptane, n-octane, n-nonane, and n-decane dimers by the method of Helgaker et al. are -0.48, -1.35, -2.08, -2.97, -3.92, -4.91, -5.96, -6.68, -7.75, and -8.75 kcal/mol, respectively. Effects of electron correlation beyond MP2 are not large. The estimated CCSD(T) interaction energies of the methane, ethane, propane, and n-butane dimers at the basis set limit by the method of Helgaker et al. (-0.41, -1.22, -1.87, and -2.74 kcal/mol, respectively) from the CCSD(T)/cc-pVXZ (X=D and T) level interaction energies are close to the EMP2(limit) obtained using the same basis sets. The estimated EMP2(limit) values of the ten dimers were fitted to the form m0+m1X (X is 1 for methane, 2 for ethane, etc.). The obtained m0 and m1 (0.595 and -0.926 kcal/mol) show that the interactions between long n-alkane chains are significant. Analysis of basis set effects shows that cc-pVXZ (X=T, Q, or 5), aug-cc-pVXZ (X=D, T, Q, or 5) basis set, or 6-311G** basis set augmented with diffuse polarization function is necessary for quantitative evaluation of the interaction energies between n-alkane chains.


Temporal Trends and Geographic Variations in Dementia Mortality in China Between 2006 and 2012: Multilevel Evidence From a Nationally Representative Sample.
We aimed to explore the temporal trends and geographic variations in dementia mortality in China. Annual dementia mortality counts (years 2006 to 2012) in 161 counties and districts (Disease Surveillance Points, DSP) were extracted from the nationally representative China Mortality Surveillance System and stratified by 5-year age group (aged >65), sex, and time. These counts were linked to annually adjusted denominator populations. Multilevel negative binomial regression with random intercepts and slopes were used to investigate spatiotemporal variation in dementia mortality. Dementia mortality varied over 2-fold between DSPs (median rate ratio: 2.59). Significant variation in DSP slopes through time (variance 0.075, SE 0.020) indicated spatiotemporal variations. Mortality rates were significantly higher in the east (rate ratio 2.28; 95% confidence intervals, 1.45-3.60) compared with the north. There was a declining trend in 2 (east and northwest) of the 7 regions. Dementia mortality decreased by 15% in urban areas but increased by 24% in rural areas. Our findings indicate that regional inequalities in dementia mortality are salient, and the increase in mortality rates in rural areas is an emerging public health challenge in China. Tailored preventive health strategies should be in place to narrow down this avoidable and wholly unnecessary inequality.


Pharmacological inhibition of TGFβ as a strategy to augment the antitumor immune response.
There is considerable evidence suggesting that a variety of malignancies utilize the TGFβ cytokine to evade immune surveillance mechanisms to facilitate tumor growth and metastatic progression. The recently developed large- and small-molecule TGFβ inhibitors have demonstrated antitumor efficacy in several preclinical tumor models. Further investigation has revealed these agents to be critically dependent upon the host's immune system, suggesting that the inhibition of TGFβ may overcome the immunosuppressive tumor microenvironment and, ultimately, augment the antitumor immune response. These findings strongly support combining this strategy with other immunotherapeutic approaches for the treatment of metastatic cancer. This review discusses the immunoregulatory and antitumor properties of these pharmacological inhibitors of TGFβ signaling as either independent agents or in combination with various immunotherapeutic strategies, their potential side effects, as well as additional avenues of research that may be necessary for their eventual clinical application.


Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds.
Increased formation of MG (methylglyoxal) and related protein glycation in diabetes has been linked to the development of diabetic vascular complications. Diabetes is also associated with impaired wound healing. In the present study, we investigated if prolonged exposure of rats to MG (50-75 mg/kg of body weight) induced impairment of wound healing and diabetes-like vascular damage. MG treatment arrested growth, increased serum creatinine, induced hypercholesterolaemia (all P < 0.05) and impaired vasodilation (P < 0.01) compared with saline controls. Degenerative changes in cutaneous microvessels with loss of endothelial cells, basement membrane thickening and luminal occlusion were also detected. Acute granulation appeared immature (P < 0.01) and was associated with an impaired infiltration of regenerative cells with reduced proliferative rates (P < 0.01). Immunohistochemical staining indicated the presence of AGEs (advanced glycation end-products) in vascular structures, cutaneous tissue and peripheral nerve fibres. Expression of RAGE (receptor for AGEs) appeared to be increased in the cutaneous vasculature. There were also pro-inflammatory and profibrotic responses, including increased IL-1beta (interleukin-1beta) expression in intact epidermis, TNF-alpha (tumour necrosis factor-alpha) in regions of angiogenesis, CTGF (connective tissue growth factor) in medial layers of arteries, and TGF-beta (transforming growth factor-beta) in glomerular tufts, tubular epithelial cells and interstitial endothelial cells. We conclude that exposure to increased MG in vivo is associated with the onset of microvascular damage and other diabetes-like complications within a normoglycaemic context.


Patient care outcomes of a tobacco use registry in an academic family practice.
While the potential benefit of a chronic disease registry for tobacco use is great, outcome reports have not been generated. We examined the effect of implementing a tobacco use registry, including a decision support tool, on treatment outcomes within an academic family medicine clinic. A chart review of 200 patients who smoked and attended the clinic before and after registry implementation assessed the number of patients with clinic notes documenting (1) counseling for tobacco use, (2) recommendations for cessation medication, (3) a set quit date, (4) referrals to the on-site Nicotine Dependence Program (NDP) and/or QuitlineNC, and (5) pneumococcal vaccine. Data from the NDP, QuitlineNC, and clinic billing records before and after implementation compared the number of clinic-generated QuitlineNC fax referrals, new scheduled appointments for the NDP, and visits coded for tobacco counseling reimbursement. Significant increases in documentation occurred across most chart review variables. Significant increases in the number of clinic-generated fax referrals to QuitlineNC (from 27 to 96), initial scheduled appointments for the NDP (from 84 to 148), and coding for tobacco counseling (from 101 to 287) also occurred when compared with total patient visits during the same time periods. Patient attendance at the NDP (52%) and acceptance of QuitlineNC services (31%) remained constant. The tobacco use registry's decision support tool increased evidenced-based tobacco use treatment (referrals, medications, and counseling) for patients at an academic family medicine clinic. This novel tool offers standardized care for all patients who use tobacco, ensuring improved access to effective tobacco use counseling and medication treatments.


Is West Africa Approaching a Catastrophic Phase or is the 2014 Ebola Epidemic Slowing Down? Different Models Yield Different Answers for Liberia.
An unprecedented epidemic of Zaire ebolavirus (EBOV) has affected West Africa since approximately December 2013, with intense transmission on-going in Guinea, Sierra Leone and Liberia and increasingly important international repercussions. Mathematical models are proving instrumental to forecast the expected number of infections and deaths and quantify the intensity of interventions required to control transmission; however, calibrating mechanistic transmission models to an on-going outbreak is a challenging task owing to limited availability of epidemiological data and rapidly changing interventions. Here we project the trajectory of the EBOV epidemic in Liberia by fitting logistic growth models to the cumulative number of cases. Our model predictions align well with the latest epidemiological reports available as of October 23, and indicates that the exponential growth phase is over in Liberia, with an expected final attack rate of ~0.1-0.12%. Our results indicate that simple phenomenological models can provide complementary insights into the dynamics of an outbreak and capture early signs of changes in population behavior and interventions. In particular, our results underscore the need to treat the effective size of the susceptible population as a dynamic variable rather than a fixed quantity, due to reactive changes in transmission throughout the outbreak. We show that predictions from the logistic model are more variable in the earlier stages of an epidemic (such as the EBOV epidemics in Sierra Leone and Guinea). More research is warranted to compare the performances of mechanistic and phenomenological approaches for disease forecasts, before such predictions can be fully used by public health authorities.


From hand maiden to right hand--the birth of nursing in America.
AT THE ONSET of the American Civil War, women were asked to leave their homes and serve as suppliers and caregivers for the armies on both sides of the conflict. MANY WOMEN suddenly found themselves in situations that required real strength, stamina, and fortitude, and some found an inner strength as they organized others to provide care. WOMEN LIKE Dorthea Dix and Clara Barton were among the first to champion the ability of and the need for women to provide nursing care, which until then had been a male bastion. THIS ARTICLE, which is the second in a two-part series on nursing during the Civil War, tells how Dorthea Dix, Clara Barton, and other women worked to establish nursing as a viable career choice for women in the United States.


Transdiagnostic Brain Mapping in Developmental Disorders.
Childhood learning difficulties and developmental disorders are common, but progress toward understanding their underlying brain mechanisms has been slow. Structural neuroimaging, cognitive, and learning data were collected from 479 children (299 boys, ranging in age from 62 to 223 months), 337 of whom had been referred to the study on the basis of learning-related cognitive problems. Machine learning identified different cognitive profiles within the sample, and hold-out cross-validation showed that these profiles were significantly associated with children's learning ability. The same machine learning approach was applied to cortical morphology data to identify different brain profiles. Hold-out cross-validation demonstrated that these were significantly associated with children's cognitive profiles. Crucially, these mappings were not one-to-one. The same neural profile could be associated with different cognitive impairments across different children. One possibility is that the organization of some children's brains is less susceptible to local deficits. This was tested by using diffusion-weighted imaging (DWI) to construct whole-brain white-matter connectomes. A simulated attack on each child's connectome revealed that some brain networks were strongly organized around highly connected hubs. Children with these networks had only selective cognitive impairments or no cognitive impairments at all. By contrast, the same attacks had a significantly different impact on some children's networks, because their brain efficiency was less critically dependent on hubs. These children had the most widespread and severe cognitive impairments. On this basis, we propose a new framework in which the nature and mechanisms of brain-to-cognition relationships are moderated by the organizational context of the overall network.