A spectrum of mutations in keratins K6a, K16 and K17 causing pachyonychia congenita.
Pachyonychia congenita (PC) is a rare autosomal dominant keratin disorder, subdivided into two major variants, PC-1 and PC-2. Predominant characteristics include hypertrophic nail dystrophy, focal palmoplantar keratoderma and oral leukokeratosis. Multiple steatocystomas that develop during puberty are a useful feature distinguishing PC-2 from PC-1. At the molecular level it has been shown that mutations in keratin K6a or K16 cause PC-1 whereas those in K6b or K17 lead to PC-2. To identify mutations in 22 families presenting with clinical symptoms of either PC-1/focal non-epidermolytic palmoplantar keratoderma (FNEPPK) or PC-2. Mutation analysis was performed on genomic DNA from PC patients by direct sequencing. Here, we report four new missense and five known mutations in K6a; one new deletion and three previously identified missense mutations in K16; plus one known mutation in K17. With one exception, all these heterozygous mutations are within the highly conserved helix boundary motif regions at either end of the keratin rod domain. In one sporadic case, a unique mutation in K16 resulting in deletion of 24bp was found within the central rod domain, in a child with a phenotype predominantly consisting of focal plantar keratoderma. The identification of mutations in cases of PC is prerequisite for future development of gene-specific and/or mutation-specific therapies.


Fish Consumption and Colorectal Cancer Risk: Meta-Analysis of Prospective Epidemiological Studies and Review of Evidence from Animal Studies.
Background: Epidemiological studies on the association between fish consumption and colorectal cancer (CRC) risk have yielded inconsistent results, despite evidence from preclinical studies that long-chain ω-3 polyunsaturated fatty acids inhibit colorectal carcinogenesis. We conducted a meta-analysis of prospective epidemiological studies investigating the association between fish consumption and CRC risk among humans and reviewed studies examining the link between fish components and colorectal carcinogenesis in animal models. Methods: We included studies published until November 2020. We calculated the summary risk ratio (SRR) and 95% confidence intervals (CI) through random effects meta-analysis models in order to summarize evidence from studies among humans. Results: Twenty-five prospective epidemiological studies encompassing 25,777 CRC cases were included. Individuals in the highest (vs. lowest) category of fish consumption had a significantly reduced risk of CRC (SRR 0.94, 95%CI 0.89-0.99). In dose-response meta-analysis, a 50-g increment in the daily consumption of fish was associated with a statistically significant 4% reduction in CRC risk (SRR 0.96, 95%CI 0.92-0.99). Preclinical studies (n = 25) identified multiple mechanisms of action of fish and fish components on colorectal carcinogenesis. Conclusions: Dietary recommendations for cancer prevention should take into account the evidence from epidemiological and preclinical studies that increasing fish consumption may be effective in preventing CRC.


Induction of the SOS response by ICR191 does not influence frameshift mutagenesis at the hisC3076 marker of Salmonella typhimurium.
Reversion of the Salmonella typhimurium frameshift marker hisC3076 by ICR191 and 9-aminoacridine in rec+ and recA1 backgrounds was examined using the standard plate-reversion assay. For both compounds, the level of reversion observed in the recA strain is significantly greater than in the rec+ strain. Thus reversion of hisC3076 is not recA-dependent, but is recA-modulated. The ability of a mutagen (or mutagenic treatment) to induce the recA lexA-dependent SOS response does not therefore imply that mutagenic effects will also be recA-dependent.


Effects of Statins on Memory, Cognition, and Brain Volume in the Elderly.
There is widespread consumer concern that statin use may be associated with impaired memory and cognitive decline. This study sought to examine the association between statin use and changes in memory and global cognition in the elderly population over 6 years and brain volumes over 2 years. Interactions between statin use and known dementia risk factors were examined. Prospective observational study of community-dwelling elderly Australians age 70 to 90 years (the MAS [Sydney Memory and Ageing Study], n = 1,037). Outcome measures were memory and global cognition (by neuropsychological testing every 2 years) and total brain, hippocampal and parahippocampal volumes (by magnetic resonance) in a subgroup (n = 526). Analyses applied linear mixed modeling, including the covariates of age, sex, education, body mass index, heart disease, diabetes, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. Interactions were sought between statin use and dementia risk factors. Over 6 years there was no difference in the rate of decline in memory or global cognition between statin users and never users. Statin initiation during the observation period was associated with blunting the rate of memory decline. Exploratory analyses found statin use was associated with attenuated decline in specific memory test performance in participants with heart disease and apolipoprotein Eε4 carriage. There was no difference in brain volume changes between statin users and never users. In community-dwelling elderly Australians, statin therapy was not associated with any greater decline in memory or cognition over 6 years. These data are reassuring for consumers concerned about statin use and risk of memory decline.


Delivery of prevention and care to asthmatic children.
Asthma-induced mortality increases especially among children; asthma induced morbidity impairs their day-to-day life as well as both their physical and psychological development. The treatment of asthma in children should reduce their symptoms. Although asthma medication appears to be efficient in clinical trials such is not the case in clinical practice and public health. The use of drugs and services depends upon the severity of the disease as well as upon cultural, personal and familial factors. These factors are crucial in the spontaneously inconsistent evolution of this disease. The management of asthmatic children should thus aim: 1) to alter behaviors--of both the patients and their parents who are often in charge of the treatment on a day-to-day basis and of the physician in order to organize a comprehensive therapeutic project for the sick children; 2) to enhance the collaboration between the different paramedical people involved in the treatment; 3) to improve the efficiency of the health system to allow it to achieve its goal of providing high-standard, accessible health care.


Induction of tissue factor expression on human umbilical vein endothelial cells by cell-specific HLA class I antibody: preliminary data.
Donor-specific antibodies may play an important role in the development of chronic allograft rejection process. However, the mechanisms leading to intimal vascular proliferation and fibrosis remain poorly understood. The aim of this study was to examine whether donor-specific HLA antibodies induce overexpression of tissue factor (TF) by endothelial cells. HLA typed human umbilical vein endothelial cells (HUVEC) were incubated for 1 to 12 hours with LPS (10 microg/mL), and increasing concentrations (1 to 500 microg/mL) of anti-HLA A1 antibody specific for an antigen expressed by HUVEC and of an anti-HLA A2 antibody for which A2 was not expressed by the HUVEC. Expression of TF mRNA transcripts was quantified using real time Q-RT PCR and TF activity was tested in cell lysates of cultured HUVEC using a chromogenic TF activity assay. HUVEC-specific anti-HLA A1 antibody at low concentrations (10 microg/mL) induced both a significant increase of TF mRNA transcripts after 1 hour of incubation and TF activity after 3 hours incubation compared to incubation with medium alone or with the nonspecific anti-HLA A2 antibody (n = 4 for all experiments, P < .05). These data show for the first time that specific anti-HLA antibody can induce overexpression of TF on endothelial cells. TF, a transmembrane glycoprotein involved not only in the onset of the coagulation cascade, but also in cell proliferation and anti-apoptotic processes, may play a role in the development of alloantibody-induced chronic rejection.


One-Step Visible Light Photoredox-Catalyzed Purine C8 Alkoxylation with Alcohol.
A cross-dehydrogenation coupling reaction between purines and alcohols, induced by visible light, using an acridinium photocatalyst and air as the sole oxidant, to synthesize a series of C8-alkoxy purine derivatives was developed. This protocol is a green and novel method to construct the C8-O bond on a purine ring with high step and atom economy.


Selection, design, and engineering of therapeutic antibodies.
mAbs account for an increasing portion of marketed human biological therapeutics. As a consequence, the importance of optimal selection, design, and engineering of these not only has expanded in the past 2 decades but also is now coming into play as a competitive factor. This review delineates the 4 basic areas for optimal therapeutic antibody selection and provides examples of the increasing number of considerations necessary for, and options available for, antibody design. Though some of the advances in antibody technology (eg, antibodies derived from phage-display libraries) have already made it to market, other more recent advances, such as engineering antibodies for enhanced effector functions, may not be far behind, especially given the increasing competition for therapeutic antibodies to the same target (eg, anti-CD20 and anti-TNF-alpha).


Nothing in medicine makes sense, except in the light of evolution.
The practice of medicine is a fruitful marriage of classic diagnostic and healing arts with modern advancements in many relevant sciences. The scientific aspects of medicine are rooted in understanding the biology of our species and those of other organisms that interact with us in health and disease. Thus, it is reasonable to paraphrase Dobzhansky, stating that, "nothing in the biological aspects of medicine makes sense except in the light of evolution." However, the art and science of medicine are also rooted in the unusual cognitive abilities of humans and the cultural evolutionary processes arising. This explains the rather bold and inclusive title of this essay. The near complete absence of evolution in medical school curricula is a historical anomaly that needs correction. Otherwise, we will continue to train generations of physicians who lack understanding of some fundamental principles that should guide both medical practice and research. I here recount my attempts to correct this deficiency at my own medical school and the lessons learned. I also attempt to summarize what I teach in the limited amount of time allowed for the purpose. Particular attention is given to the value of comparing human physiology and disease with those of other closely related species. There is a long way to go before the teaching of evolution can be placed in its rightful context within the medical curriculum. However, the trend is in the right direction. Let us aim for a day when an essay like this will no longer be relevant.


Cap-assisted endoscopic treatment of esophageal food bolus impaction and/or foreign body ingestion: a systematic review and meta-analysis.
Esophageal food bolus and/or foreign body (FB) impaction is a common gastrointestinal emergency. This meta-analysis reports on the pooled outcomes of cap-assisted endoscopic removal of esophageal FB. We conducted a comprehensive search of several databases (inception to February 2022) to identify studies reporting on the use of a cap in the endoscopic treatment of esophageal FB ingestion. A random effects model was used to calculate the pooled odds ratio (OR) and mean difference (MD), and I2 values were used to assess the heterogeneity. Six studies were analyzed that included 677 patients treated with cap-assisted and 694 with conventional endoscopy. The cap-assisted method demonstrated statistically significant superiority regarding technical success (pooled OR 7.1, 95% confidence interval [CI] 1.9-26.9; P=0.004), en bloc removal (pooled OR 26.6, 95%CI 17.6-40.2; P<0.001), as well as a significantly shorter procedure time (4.6 min, 95%CI -6.5 to -2.8; P<0.001), compared to conventional methods. Better technical success was achieved with the cap-assisted method performed under anesthesia (OR 8.7, 95%CI 1.6-47.7; P=0.01); however, a shorter procedure time was noted for the cap-assisted method without anesthesia (MD -1.5, 95%CI -2.7 to -0.4; P=0.01). Pooled adverse events were comparable. Pooled OR for mucosal tear was significantly lower with cap in food bolus impaction (OR 0.07, 95%CI 0.01-0.38; P=0.02). Cap-assisted endoscopic removal of esophageal FB is associated with better technical success and en bloc removal, and a shorter procedure time compared to conventional methods, with comparable adverse events.


Concentration-dependent half-lives of polychlorinated biphenyl in sera from an occupational cohort.
Polychlorinated biphenyls (PCBs) are carcinogenic. Estimating PCB half-life in the body based on levels in sera from exposed workers is complicated by the fact that occupational exposure to PCBs was to commercial PCB products (such as Aroclors 1242 and 1254) comprised of varying mixtures of PCB congeners. Half-lives were estimated using sera donated by 191 capacitor manufacturing plant workers in 1976 during PCB use (1946-1977), and post-exposure (1979, 1983, and 1988). Our aims were to: (1) determine the role of covariates such as gender on the half-life estimates, and (2) compare our results with other published half-life estimates based on exposed workers. All serum PCB levels were adjusted for PCB background levels. A linear spline model with a single knot was used to estimate two separate linear equations for the first two serum draws (Equation A) and the latter two (Equation B). Equation A gave half-life estimates of 1.74 years and 6.01 years for Aroclor 1242 and Aroclor 1254, respectively. Estimates were 21.83 years for Aroclor 1242 and 133.33 years for Aroclor 1254 using Equation B. High initial body burden was associated with rapid PCB elimination in workers at or shortly after the time they were occupationally exposed and slowed down considerably when the dose reached background PCB levels. These concentration-dependent half-life estimates had a transition point of 138.57 and 34.78 ppb for Aroclor 1242 and 1254, respectively. This result will help in understanding the toxicological and epidemiological impact of exposure to PCBs in humans.


Succinobucol versus probucol: higher efficiency of succinobucol in mitigating 3-NP-induced brain mitochondrial dysfunction and oxidative stress in vitro.
This study evaluated and compared the potential protective effects of probucol and succinobucol, two lipid-lowering compounds with anti-inflammatory and antioxidant properties, on oxidative stress and mitochondrial dysfunction induced by 3-nitropropionic acid (3-NP, a succinate dehydrogenase (SDH) inhibitor largely used as model of Huntington's disease) in rat brain mitochondria-enriched synaptosomes. 3-NP caused significant inhibition of mitochondrial complex II activity, induced mitochondrial dysfunction and oxidative stress. Probucol and succinobucol prevented oxidative stress, but only succinobucol was able to prevent the mitochondrial dysfunction induced by 3-NP. Succinobucol, which did not recover complex II inhibition, was able to protect against 3-NP-induced decreased of MTT reduction, indicating that SDH is not the only enzyme responsible for MTT reduction. The present findings suggest that succinobucol might be a novel strategy to slow or halt oxidative events in neurodegenerative conditions.


Adenosine-induced cyclic AMP increase in pig lymphocytes is not related to adenylate cyclase stimulation.
Adenosine-cyclic AMP relationships have been studied in pig mesenteric lymph node lymphocytes. The early 2--3-fold increase in cyclic AMP accumulation elicited by adenosine and 2-chloroadenosine, an adenosine deaminase-resistant analogue, could not be correlated to similar effects on the adenylate cyclase activity of disrupted cell preparations, but rather to the competitive inhibition of the low Km (0.17 muM) cyclic AMP phosphodiesterase. The existence of adenosine receptors coupled to lymphocyte adenylate cyclase, which had been proposed by several authors, could not be confirmed by this study Adenosine-cyclic AMP relationships do not appear to be involved in concanavalin A stimulation of pig lymphocytes.


The Impact of Exercise Training and Supplemental Oxygen on Peripheral Muscles in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.
Exercise training is a cornerstone of the treatment of chronic obstructive pulmonary disease, whereas the related interindividual heterogeneity in skeletal muscle dysfunction and adaptations are not yet fully understood. We set out to investigate the effects of exercise training and supplemental oxygen on functional and structural peripheral muscle adaptation. In this prospective, randomized, controlled, double-blind study, 28 patients with nonhypoxemic chronic obstructive pulmonary disease (forced expiratory volume in 1 second, 45.92% ± 9.06%) performed 6 wk of combined endurance and strength training, three times a week while breathing either supplemental oxygen or medical air. The impact on exercise capacity, muscle strength, and quadriceps femoris muscle cross-sectional area (CSA) was assessed by maximal cardiopulmonary exercise testing, 10-repetition maximum strength test of knee extension, and magnetic resonance imaging, respectively. After exercise training, patients demonstrated a significant increase in functional capacity, aerobic capacity, exercise tolerance, quadriceps muscle strength, and bilateral CSA. Supplemental oxygen affected significantly the training impact on peak work rate when compared with medical air (+0.20 ± 0.03 vs +0.12 ± 0.03 W·kg -1 , P = 0.047); a significant increase in CSA (+3.9 ± 1.3 cm 2 , P = 0.013) was only observed in the training group using oxygen. Supplemental oxygen and exercise-induced peripheral desaturation were identified as significant opposing determinants of muscle gain during this exercise training intervention, which led to different adaptations of CSA between the respective subgroups. The heterogenous functional and structural muscle adaptations seem determined by supplemental oxygen and exercise-induced hypoxia. Indeed, supplemental oxygen may facilitate muscular training adaptations, particularly in limb muscle dysfunction, thereby contributing to the enhanced training responses on maximal aerobic and functional capacity.


Revisiting the clinical trial history and regulatory mechanisms in Nepal in the context of COVID-19 pandemic.
Presence of Nepal in global clinical trials has been visibly negligible despite the history of conducting large scaled randomized controlled trial on Hepatitis E vaccine decades ago. Majority of the problem is attributed to the lack of collaborative work, financial and human resource constrains. COVID-19 pandemics seems to have triggered urgency among the authorities of Nepal leading to a substantial increase in the number of clinical trials in collaboration with national and international organizations/institutions. Immediately after detection of the first COVID-19 case on 13 January 2020, the Ethical Review Board (ERB) of NHRC received several research proposals, subsequently leading to the approval of the first clinical trial for COVID-19 on 01 July 2020 to investigate potential of traditional Ayurveda based medicine for COVID treatment. Soon, number of other clinical trial proposals received approval and implemented in the country, however budgetary allocation from the Government of Nepal (GON) was prioritized for COVID-19 outrage management and vaccination coverage only. Collaborations with various international institutions played a significant role in the successful implementation of large-scale clinical trials in the country and further laid the path for future. In this review paper we present the recent developments in clinical trials in Nepal, budgetary allocation from the government and the mechanisms in place for regulation of clinical research in the country along with challenges and way forward.


Isomorphic Fluorescent Nucleosides Facilitate Real-Time Monitoring of RNA Depurination by Ribosome Inactivating Proteins.
Ribosome-inactivating proteins, a family of highly cytotoxic proteins, interfere with protein synthesis by depurinating a specific adenosine residue within the conserved α-sarcin/ricin loop of eukaryotic ribosomal RNA. Besides being biological warfare agents, certain RIPs have been promoted as potential therapeutic tools. Monitoring their deglycosylation activity and their inhibition in real time have remained, however, elusive. Herein, we describe the enzymatic preparation and utility of consensus RIP hairpin substrates in which specific G residues, next to the depurination site, are surgically replaced with tz G and th G, fluorescent G analogs. By strategically modifying key positions with responsive fluorescent surrogate nucleotides, RIP-mediated depurination can be monitored in real time by steady-state fluorescence spectroscopy. Subtle differences observed in preferential depurination sites provide insight into the RNA folding as well as RIPs' substrate recognition features.


Laparoscopic appendectomy conversion rates two decades later: an analysis of surgeon and patient-specific factors resulting in open conversion.
The role of laparoscopy in appendicitis has gained increased popularity but remains controversial. Despite more than 20 y of experience in laparoscopy, the nationwide laparoscopic appendectomy (LA) conversion rate is reportedly 8.6%. We sought to analyze the impact of patient-specific and surgeon-specific factors that may contribute to open conversion during LA. A retrospective analysis of 745 LAs (49.9% females and 50.1% males; average age of 37.8 y performed at a large tertiary community teaching hospital over a 5-y period (May 2004-October 2008) was performed. The overall conversion rate for the study period was 4.16% (n = 31). The most common reason for open conversion was severe acute inflammation (38.7%). Among converted cases, 77.42% had no prior abdominal surgery and only 25.81% of cases were converted due to adhesions. Females and patients ≥ 65-y-old had a higher likelihood of open conversion (4.30% versus 4.02%, P < 0.99 and 9.26% versus 3.76%, P < 0.1107). The overall conversion rate of cases performed by high-volume surgeons (≥ 50 total cases) in comparison to low-volume surgeons (10-49 total cases) was higher (4.86% versus 3.30%, P < 0.39). Conversion rates were lower among surgeons who completed residency training after 1990 (3.72% versus 4.35%, P < 0.82) and those with fellowship training (1.42% versus 5.18%, P < 0.034). Laparoscopic conversion continues to gain popularity and remains the gold standard procedure for appendectomy. Older patients have a higher likelihood of conversion with severe acute inflammation being the most common reason for conversion. Additional minimally invasive fellowship training was the only surgeon-specific factor that significantly impacted conversion rate.


Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome.
Previous studies have revealed that hormonal disturbances may accompany the chronic fatigue syndrome (CFS). Changes in the secretion of the pituitary-adrenal axis have been demonstrated, as well as abnormalities in the GH-IGF-I axis. However, data have not always been well characterized and were sometimes conflicting. The small number of CFS patients investigated in earlier studies may have played a role in the interpretation of the results. Hormonal testing was performed in 73 nonobese CFS patients and nonobese 21 age-and gender-matched healthy controls. We investigated GH, ACTH and cortisol responses to insulin-induced hypoglycaemia. In a subgroup of patients arginine and clonidine stimulation for GH was also performed. Nocturnal secretion of GH, ACTH and cortisol were determined. Serum levels of IGF-I, prolactin, TSH, and free thyroxine were also measured. Visceral fat mass was assessed by CT scanning. GH response to insulin induced hypoglycaemia assessed by peak value (17.0 +/- 13.1 microg/l vs. 22. 1 +/- 9.8 microg/l; P = 0.01) and by AUC (450.0 +/- 361.3 microg/l vs. 672.3 +/- 393.0 microg/l; P = 0.002) was significantly decreased in CFS patients vs. controls. Nocturnal GH secretion assessed by GH peak value (5.4 +/- 3.7 vs. 9.0 +/- 5.1 microg/l; P = 0.44) and by AUC (34.4 +/- 20.2 vs. 67.4 +/- 43.1; P = 0.045) was also significantly impaired in CFS patients. Arginine and clonidine administration showed no differences in GH secretion between CFS patients and controls. In the CFS group, GH peak values were significantly higher after ITT than after arginine (P = 0.017) or clonidine (P = 0.001). No differences in serum IGF-I levels were found between CFS patients and controls. Except for a significantly lower nocturnal cortisol peak value, no differences were found in ACTH and cortisol secretion between CFS patients and controls. Significantly higher serum prolactin levels (7.4 +/- 4.7 microg/l vs. 4.4 +/- 1.3 microg/l; P = 0.004) and significantly higher serum TSH levels (1.6 +/- 1.0 mU/l vs. 1.0 +/- 0.4 mU/l; P = 0.011) were found in CFS patients. Serum free thyroxine was comparable in both groups. Visceral fat mass was significantly higher in CFS patients (86.6 +/- 34.9 cm2 vs. 51.5 +/- 15.7 cm2; P < 0.001). We observed a significant impairment of GH response during insulin-induced hypoglycaemia and a low nocturnal GH secretion in CFS patients. These changes did, however, not lead to different concentrations in serum IGF-I. The clinical expression of this inadequate GH secretion can thus be questioned, although the alteration in body composition may be related to this relative GH deficiency. Significantly increased prolactin and TSH levels were found when compared to controls. These findings give support to the hypothesis of a decreased dopaminergic tone in CFS. Further investigations are required in order to identify specific adaptations within the neurotransmitter system in CFS and to determine the clinical importance of the impaired GH homeostasis.


Pyrolidium dithiocarbamate prevents shockwave lithotripsy-induced renal injury through inhibition of nuclear factor-kappa B and inducible nitric oxide synthase activity in rats.
Extracorporeal shockwave lithotripsy (SWL) is commonly used for treatment of renal stones. Free oxygen radicals are involved in the pathophysiology of renal injury due to SWL. We investigated the protective effect of pyrolidium dithiocarbamate (PDTC), an antioxidant and nuclear factor kappa-B (NFkappa-B) inhibitor, against renal injury. Forty-eight rats were divided into three groups: group 1, controls; group 2, SWL (15 kW, 1500 pulses); and group 3, SWL + pyrolidium dithiocarbamate (PDTC) (100 mg/kg/day given intraperitoneally 1 day before and 5 days after SWL). The rats were sacrificed and their kidneys were removed on days 7 and 35 after SWL. Samples were fixed in formaldehyde solution, and renal tissues were examined for proximal tubular injury under light microscopy. iNOS activity and active subunit of NFkappa-B, p65, were evaluated immunohistochemically using rat monoclonal antibodies interpreting results semiquantitatively. There were significant differences between SWL and control groups on days 7 and 35, considering histological changes under light microscope (p < 0.02). There was significant decrease in necrosis and fibrosis in PDTC group compared to SWL group. Expression of inducible nitric oxide synthase (iNOS) and p65 on days 7 and 35 were at basal levels as seen with immunohistochemical staining. There were high concentrations of iNOS and p65 in the SWL group (P < 0.02). No significant difference in concentrations was seen between the control and the PDTC groups (P > 0.02). We found that curcumin decreased the expression of iNOS, p65, and serum nitric oxide levels, and helped prevent interstitial, glomerular, tubular epithelial, and endothelial cellular injury. We believe that PDTC could be used, particularly in high-risk patients, as a protective agent against renal injury due to SWL.


Cognitive abilities are associated with specific conjunctions of structural and functional neural subnetworks.
Cognitive neuroscience assumes that different mental abilities correspond to at least partly separable brain subnetworks and strives to understand their relationships. However, single-task approaches typically revealed multiple brain subnetworks to be involved in performance. Here, we chose a bottom-up approach of investigating the association between structural and functional brain subnetworks, on the one hand, and domain-specific cognitive abilities, on the other. Structural network was identified using machine-learning graph neural network by clustering anatomical brain properties measured in 838 individuals enroled in the WU-Minn Young Adult Human Connectome Project. Functional network was adapted from seven Resting State Networks (7-RSN). We then analyzed the results of 15 cognitive tasks and estimated five latent abilities: fluid reasoning (Gf), crystallized intelligence (Gc), memory (Mem), executive functions (EF), and processing speed (Gs). In a final step we determined linear associations between these independently identified ability and brain entities. We found no one-to-one mapping between latent abilities and brain subnetworks. Analyses revealed that abilities are associated with properties of particular combinations of brain subnetworks. While some abilities are more strongly associated to within-subnetwork connections, others are related with connections between multiple subnetworks. Importantly, domain-specific abilities commonly rely on node(s) as hub(s) to connect with other subnetworks. To test the robustness of our findings, we ran the analyses through several defensible analytical decisions. Together, the present findings allow a novel perspective on the distinct nature of domain-specific cognitive abilities building upon unique combinations of associated brain subnetworks.


Thrombosis of the mesencephalic artery. A clinico-pathological study of two cases and its correlation with the arterial vascularisation.
Two cases of thrombosis of the mesencephalic artery are described : the location of the occlusion and of the infarcted area in the upper mesencephalon is correlated to the clinical syndrome, in particular to the existence or the absence of an oculomotor paralysis. In addition 27 normal brains are examined by means of the translucidation and the radiographic techniques after filling of the arterial system with a colloidal barium sulphate solution. This study supports the subdivision of the upper mesencephalon into five vascular territories and justifies the denomination of mesencephalic artery, which supplies a transitional region between the diencephalon and the brainstem.


Anti-Apoptotic Effects of Dapsone After Spinal Cord Injury in Rats.
Spinal cord injury (SCI) is a condition producing irreversible damage to the neurological function. Among the leading mechanisms associated to cell death after SCI, excitotoxicity, oxidative stress, inflammatory response and apoptosis are considered potential targets to prevent tissue damage. We recently reported that dapsone an anti-inflammatory drug, decreases the activity of myeloperoxidase, lipid peroxidation, improve neurological function and increase the amount of spared tissue after SCI in rats. In this study, we characterized the anti-apoptotic effect of dapsone administered at 12.5 mg/kg/24 h dose, starting at 3 and 5 h after SCI. We monitored the activity of caspases-8, 9, and 3 and quantitated Annexin V and TUNEL positive cells in the core of the lesion. Results showed increased activities of caspase-8, 9 and 3 at 72 h by SCI to reach increments of 69, 143 and 293 %, respectively, as compared to sham group. Meanwhile, dapsone, administered at 3 and 5 after SCI, reduced caspase-8 activity by 36 and 44 % respectively, whereas the activity of caspase-9 was diminished by 37 %. Likewise, the activity of caspase-3 showed a decrease of 38 %. Finally, both Annexin V and TUNEL-positive cells were significantly reduced by DDS as compared to untreated SCI animals. Results showed that dapsone exerted anti-apoptotic effect after SCI.


The diagnosis of luteal phase deficiency: a critical review.
Luteal phase deficiency is an ovulatory dysfunction problem that is subtle but real. It may be the most common ovulatory problem in women. Luteal phase deficiency has been clearly demonstrated in the research setting (1) in spontaneous cycles, (2) when follicular maturation has been impeded, and (3) when luteotrophic influences have been suppressed. The diagnosis of LPD in the clinical setting remains problematic and controversial primarily because there is no practical diagnostic method that has been validated. This article has reviewed the methods that have been used to diagnose LPD. BBT charts are insensitive; these charts reliably diagnose LPD only when there are persistent short luteal phases. There is disagreement whether ovarian follicular size, as determined by ultrasonography, is decreased in LPD; however, ultrasonographic diagnosis of LPD would require daily scans through ovulation, which makes this approach impractical. Mild hyperprolactinemia is a probable cause of LPD in a minority of patients; a physician should obtain a PRL level in LPD women with the realization that there is considerable sampling variability. Determination of serum gonadotropin levels (LH or FSH or both) is not practical for the clinical diagnosis of LPD. Random serum P levels, whether single or multiple, are not helpful in the diagnosis of LPD in individual patients. The secretory pattern of P results in such wide confidence limits that P samples from individuals cannot be compared to normal in a useful manner. Most of the controversy about the diagnosis of LPD has centered around the use of individual serum P levels. The timed endometrial biopsy relies on the endometrium as a bioassay of P over time. The endometrial biopsy has not been carefully validated in terms of its sensitivity or accuracy for the diagnosis of LPD. However, it remains the best current method for the diagnosis of LPD when the standard guidelines for its use are followed. As opposed to the other tests for LPD, awareness of the usefulness of the biopsy has increased as we have learned more about CL physiology. No current research method for the diagnosis of LPD appears to be a practical method that could be applied in the clinical setting. Specific secretory proteins from the endometrium and methods to measure hormone secretion that circumvent the secretory pattern hold promise for improved methods to diagnose LPD in the future.


Case of neuro-Behçet's disease successfully maintained a remission using infliximab for 2 years.
Behçet's disease is a systemic inflammatory disorder with chronic remissions and relapses. Involvement of the central nervous system, called neuro-Behçet's disease (NBD), is a serious complication. Although corticosteroids and immunosuppressive agents are used, there is no definite standard of treatment with long term-effects for NBD. Here, we report a female case with NBD successfully treated by infliximab and corticosteroids for 2 years. Our report suggests treatment with infliximab may be effective for long-term remission of NBD.


Increase in resistance to fluconazole and itraconazole in Trichophyton rubrum clinical isolates by sequential passages in vitro under drug pressure.
Trichophyton rubrum, an anthropophilic dermatophyte fungus, is the predominant causative agent of superficial skin infections in human population. There are only scanty reports on drug susceptibility profiling of T. rubrum. Neither mechanisms for drug resistance development nor correlation between in vitro drug susceptibility and in vivo response to treatment is known for that species. In this study, changes in the in vitro susceptibilities to fluconazole (FLZ) and itraconazole (ITZ) among thirty T. rubrum clinical strains subjected to sequential passages in the presence or absence of the azoles were investigated. Each strain was passaged 12 times at 4-week intervals as three parallel cultures, maintained on a drug-free medium (1), and a medium containing FLZ (2) or ITZ (3) at subinhibitory concentrations. Susceptibility to FLZ and ITZ of the original strain and its 3 subcultures was determined by microdilution method. The MIC values of the two azoles remained unaltered for all T. rubrum strains tested, after 12 passages on a drug-free medium. Among the strains grown with FLZ, an increase in the MICs of FLZ and ITZ was noted in 17 (56.7 %) and 19 (63.3 %) strains, respectively. Increased MICs of ITZ and FLZ were demonstrated for 24 (80 %) and 20 (66.7 %) strains that were propagated with ITZ. The results indicate the capacity of T. rubrum to develop resistance toward the azoles after prolonged exposure to these drugs. Resistance of T. rubrum to azoles plays an important role in therapy failures and consequently contributes to persistence and chronicity of the infections.


Posttreatment itraconazole levels in the nail. New implications for treatment in onychomycosis.
A problem in the treatment of onychomycosis is the lengthy duration of therapy. The pharmacokinetics of itraconazole suggest a potential for briefer treatment. This study was designed to investigate itraconazole nail kinetics in 39 patients with onychomycosis in relation to their therapeutic outcome. All patients received itraconazole for 3 months at a dose of 100 or 200 mg daily. Itraconazole levels of distal nail clippings were determined during a 6-month posttherapy period. Therapeutic itraconazole concentrations were found in the nail plates of fingernails and toenails for up to 6 months after treatment. Cure of the toenails was observed in 79% of the patients treated with the 200 mg dosage and in 26% of those treated with 100 mg at 6 months after therapy. The data suggest that the drug reaches the nail via incorporation into the matrix and by diffusion from the nail bed and is eliminated with regrowth of the nail after discontinuation of treatment.


Increased epidermal growth factor receptor (EGFR) expression in malignant mammary phyllodes tumors.
Mammary phyllodes tumors are uncommon stromal-epithelial neoplasms, and are divided into benign, borderline malignant and frankly malignant groups on the basis of their histological features. Accumulating evidence shows that epidermal growth factor receptor (EGFR) is involved in the pathogenesis and progression of many malignancies. This study investigated 453 phyllodes tumors (296 benign, 98 borderline, 59 malignant) for EGFR expression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for gene amplification. The staining was correlated to tumor margin status, degree of malignancy, stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. Cases with strong positive IHC staining were selected for FISH. The overall positive rate for EGFR was 16.2% (48/296), 30.6% (30/98) and 56% (33/59) for benign, borderline malignant and frankly malignant phyllodes tumors, respectively. FISH demonstrated egfr gene amplification in 8% of immunohistochemically positive cases. The results of this study provide strong evidence that EGFR overexpression is involved in the pathogenesis of phyllodes tumors, although gene amplification may not be the major underlying mechanism for overexpression.


Enlarging the pupil for cataract extraction using flexible nylon iris retractors.
A technique using flexible iris retractors to manage small pupils during cataract extraction reduces iris trauma, allows adjustment of pupil size, and reduces intraoperative difficulty more than previously described techniques. This method is appropriate for extracapsular cataract extraction and phacoemulsification, as well as the posterior segment procedures for which it was originally described.


Clinical testing of propofol geriatic dose for sedation designed via in silico trial.
The geriatric population shows significant physiological changes due to aging and the multiple co-morbidities that they often present. Conventionally the propofol sedation dose for patients older than 65 years is 80% of the adult dose. We performed an in silico trial for elderly population and the results showed that the necessary simulated dose of propofol was lower than the conventional dose; therefore, a clinical trial was implemented to test three different propofol doses, two of them lower than the conventional dose, during a pacemaker implantation. The clinical trial showed that there was no clinical difference between the effects of the doses. A BIS monitor was used to measure the level of sedation, which proved to be adequate and well maintained by all patients. All the patients maintained an acceptable level of sedation, measured by a BIS monitor. Since propofol has some dose-dependent secondary effects, the use of lower doses, especially the ones designed for this age group, helps to avoid them.


Use of the progestin challenge test in nonhuman primates (Macaca fascicularis).
To determine whether the progestin challenge test (PCT) would provide a reliable, noninvasive indicator of endometrial stimulation in nonhuman primates. DESIGN; Randomized, 2x2, crossover study. SETTING; Nonhuman primates (Macaca fascicularis) in an academic research environment. Adult, surgically postmenopausal, female cynomolgous macaques (n = 27) were studied. Females were randomly assigned to receive estradiol (n = 14; 0.028 mg/kg body weight) or vehicle (n = 13) daily. All animals were administered two PCTs in a crossover study design using two doses (0.28 mg/kg or 0.56 mg/kg body weight) of medroxyprogesterone acetate (MPA). Incidence and severity of withdrawal bleeding and serum estradiol (E(2)) and progesterone (P(4)) levels were evaluated. Estradiol treatment resulted in endometrial "withdrawal" bleeding in all but one instance. Females receiving daily doses of E(2) exhibited a significantly greater (P<.01) incidence, severity, and duration of withdrawal bleeding compared to control animals. Of the five positive responses observed in the control females, four occurred when the higher dose of MPA was administered. These results indicate that the PCT is a useful, noninvasive method for determining the presence of endometrial stimulation in nonhuman primates.


Mesenchymal stem cell-based therapy as a new therapeutic approach for acute inflammation.
Acute inflammatory diseases such as acute colitis, kidney injury, liver failure, lung injury, myocardial infarction, pancreatitis, septic shock, and spinal cord injury are significant causes of death worldwide. Despite advances in the understanding of its pathophysiology, there are many restrictions in the treatment of these diseases, and new therapeutic approaches are required. Mesenchymal stem cell-based therapy due to immunomodulatory and regenerative properties is a promising candidate for acute inflammatory disease management. Based on preclinical results, mesenchymal stem cells and their-derived secretome improved immunological and clinical parameters. Furthermore, many clinical trials of acute kidney, liver, lung, myocardial, and spinal cord injury have yielded promising results. In this review, we try to provide a comprehensive view of mesenchymal stem cell-based therapy in acute inflammatory diseases as a new treatment approach.


High-Performance n-Type Organic Thermoelectrics Enabled by Synergistically Achieving High Electron Mobility and Doping Efficiency.
n-Doped polymers with high electrical conductivity (σ) are still very scarce in organic thermoelectrics (OTEs), which limits the development of efficient organic thermoelectric generators. A series of fused bithiophene imide dimer-based polymers, PO8, PO12, and PO16, incorporating distinct oligo(ethylene glycol) side-chain to optimize σ is reported here. Three polymers show a monotonic electron mobility decrease as side-chain size increasing due to the gradually lowered film crystallinity and change of backbone orientation. Interestingly, polymer PO12 with a moderate side-chain size delivers a champion σ up to 92.0 S cm-1 and a power factor (PF) as high as 94.3 µW m-1 K-2 in the series when applied in OTE devices. The PF value is among the highest ones for the solution-processing n-doped polymers. In-depth morphology studies unravel that the moderate crystallinity and the formation of 3D conduction channel derived from bimodal orientation synergistically contribute to high doping efficiency and large charge carrier mobility, thus resulting in high performance for the PO12-based OTEs. The results demonstrate the great power of simple tuning of side chain in developing n-type polymers with substantial σ for improving organic thermoelectric performance.


Inflammation, immunity, and vaccines for Helicobacter infection.
Pro-inflammatory cytokines such as IL-18, IFN-gamma, and IL-1beta play a significant role in the inflammation induced by Helicobacter. During the recent years of H. pylori research, the main focus has been on development of vaccines for therapeutic or prophylactic use against the infection. Both bacterial components of H. pylori as well as engineered vaccines have been tested as well as different forms of administration including systemic and oral/intranasal pathways.


Depressive symptoms among reservation-based pregnant American Indian adolescents.
To examine rates and correlates of depressive symptoms among pregnant reservation-based American Indian (AI) adolescents from the Southwestern United States (N = 53). Data were derived from a study evaluating a home-visiting program designed to promote positive parenting among young families. Participants included a volunteer, convenience sample of expectant mothers who completed behavioral and mental health self-report questionnaires. Depressive symptoms were assessed using the Center for Epidemiological Studies-Depression scale (CES-D). Three risk domains were analyzed in relation to depressive symptoms: sociodemographics, family relations, and psychosocial functioning. Forty-seven percent of expectant mothers scored at or above the widely accepted clinical cutoff score of 16 on the CES-D; 30% scored at or above 20, a score more likely to reflect elevated depressive symptoms among adolescents; and almost 20% scored at or above 28 (one standard deviation above the mean), a score suggestive of clinical depression. Higher levels of depressive symptoms were associated with less use of public assistance, external locus of control, less social support, and lower self-esteem. Data suggest that a large proportion of pregnant AI adolescents reported elevated depressive symptoms, though rates are similar to non-pregnant AI adolescent samples.


Simultaneously Providing Iron Source toward Electro-Fenton Process and Enhancing Hydrogen Peroxide Production via a Fe3O4 Nanoparticles Embedded Graphite Felt Electrode.
Electro-reduction of O2 to generate H2O2 is an attractive alternative to the current anthraquinone process and quite necessary for chemical industries and environmental remediation. In general, sufficient porous structure contributes to expose more catalytic active sites and shorten diffusion paths for the heterogeneous catalysis of O2. In this work, initially the Fe3O4 nanoparticles embedded graphite felt (Fe3O4@GF) is prepared through a mild hydrothermal following with thermal reduction method. This special combination not only provides iron source for the electro-Fenton reaction but also supplies rich active sites from the Fe3O4 embedded structure with abundant cracks, which are beneficial to increase the reaction rate. Compared with raw graphite felt (RGF), fresh Fe3O4@GF exhibits superior pollutant degradation kinetics with more than 400% increase and approximately 37.8% improvement to the removal of total organic carbon. A 98% decolorization of rhodamine B (RhB) can be achieved in just 5 min and quickly completes 100% removal of RhB in the next few seconds. As the electro-Fenton reaction progresses, Fe3O4 dissolves in the electrolyte, leaving a porous structure on the surface of the GF to form a porous GF (PGF), and the rapid radical reaction activates the GF surface. Both the chemical etching of Fe3O4 and the electro-Fenton process can further increase the specific surface area, defects, and actives sites of the electrode. As expected, the active PGF exhibits favorable performance of H2O2 production in electrolytes of different pHs: 1 (320.0 ± 36.5 mg L-1), 3 (301.9 ± 13.2 mg L-1), and 7 (320.4 ± 21.2 mg L-1). The degradation performance of PGF does not significantly decay even after 20 cycles of repeated use, indicating the good structural stability and long-term durability. The superiority of the in situ Fe source and fast reaction kinetics for electro-Fenton of Fe3O4@GF is confirmed, and this holey engineered strategy also provides the possibility to achieve swift water purification and open up a new way for developing efficient carbon-based electrodes.


Supply of codeine combination analgesics from Australian pharmacies in the context of voluntary real-time recording and regulatory change: A simulated patient study.
In recent years there have been growing concerns regarding non-prescription codeine use in Australia. Efforts to mitigate risks associated with non-prescription codeine, such as addiction and toxicity, have been primarily through two initiatives; regulatory changes restricting their availability, and voluntary live-recording supply of non-prescription codeine combination analgesics (CCAs). This study sought to explore the supply of CCAs in the climate of regulatory change. Eighty University of Sydney pharmacy students mystery-shopped 34 community pharmacies across metropolitan Sydney, Australia from August 2016 to November 2017, with scripted symptom-based (SBR) or direct product requests (DPR) for a CCA. Questions asked, staff involvement, regulatory compliance, voluntary recording, and product(s) supplied were recorded. Of 158 total visits, a non-prescription CCA was supplied in 101 instances. Sixty-one (60%) of these supplies complied with the legislative requirement for a pharmacist to supply the medicine. Voluntary recording was surmised to have been utilised 13 times (13% CCA supplies). CCAs were supplied less frequently in 2017 DPR scenarios compared to 2016 DPR scenarios (64% vs 86%; p = 0.024), and a greater proportion of 2017 DPR supplies were compliant with the legislative requirement of pharmacist supply (72% vs 46%; p = 0.041). No difference in proportion of sales surmised to have been voluntarily recorded was observed between the years. Interactions involving pharmacists resulted in less frequent supply of codeine than those without (58% vs 82%; p = 0.012). Mandatory legislative regulation of pharmacist supply of non-prescription codeine was more likely to be complied with than voluntary recording. Compliance with pharmacist supply for DPRs appeared to improve following the announcement of regulatory change to prescription-only, whereas voluntary recording of supply did not appear to change.


Aqueous flare and cells in Fuchs syndrome.
To quantitatively evaluate aqueous flare and cells in patients with Fuchs syndrome. The medical records of 40 patients (47 eyes) diagnosed with Fuchs syndrome between February 2006 and January 2007 at the Uveitis Study Center of Sun Yat-sen University were retrospectively reviewed. Aqueous flare and cells were clinically evaluated and quantified with laser flare-cell meter. Statistical analysis was performed to investigate the relationship between flare values and cell counts, and clinical parameters including patients' age, sex, duration of disease, best-corrected visual acuity, keratic precipitate, iris depigmentation, intraocular pressure, and posterior subcapsular lens opacities. Aqueous flare values (photon counts/ms) were significantly higher in Fuchs syndrome (9.40+/-5.85) than in normal controls (5.77+/-1.89, P=0.000). Aqueous cell counts (cells/0.5 mm(3)) were also significantly higher in Fuchs syndrome (5.09+/-4.84) than in normal controls (1.14+/-1.03, P=0.000). The flare values were positively correlated with the cell counts (r=0.331, P=0.001). Both flare values and cell counts were higher in eyes with keratic precipitates scored 2+ or 3+ as compared to those with a 1+ score. Higher flare values and cell counts were also observed in eyes with a 2+ or 3+ iris depigmentation score as compared to those with a 1+ score. No difference was found between flare values and cell counts and other parameters. Breakdown of blood-aqueous barriers and increased cell counts are present in the affected eyes in patients with Fuchs syndrome. These changes are positively associated with the degree of keratic precipitates and iris depigmentation.


Social functioning in early psychosis: are all the domains predicted by the same variables?
The study aims to determine the predictive value of negative symptoms, depression, short-term verbal learning and gender on three areas of social functioning--social life, vocational functioning and independent living skills--in a sample of 88 individuals with early psychosis. Participants were recruited from early psychosis intervention programmes and community mental health clinics in British Columbia, Canada, and completed the following measures: client's assessment of strengths, interests, and goals, brief psychiatric rating scale, Beck depression inventory and California verbal learning task. Multiple linear regressions revealed that: more negative symptoms and higher depression predicted a less active social life; more negative symptoms and poorer short-term verbal learning ability predicted lower vocational functioning; and more negative symptoms and male gender predicted lower independent living skills. Results suggest that negative symptoms are predictive of all three areas of functioning but that specific variables add significant unique variance to individual areas of social functioning. Although a global social functioning score can be considered useful, greater precision can be gained by the use of domain-specific measures.


Partially de-epithelialized preputial flap (triangular soft tissue flap): an aid to prevent coronal urethrocutaneous fistulae.
A technique is described to fashion a partially de-epithelialized preputial flap, also called triangular soft tissue flap (TSTF), to cover the neourethra in the region of glans, corona and subcorona. This highly vascular TSTF acted as a mechanical barrier against coronal fistula formation in 16 subcoronal hypospadiacs aged 3-12 years who underwent Snodgrass tubularized incised plate urethroplasty. None had complications at 1-year of follow-up.


Effects of nitroglycerin at therapeutic doses on platelet aggregation in unstable angina pectoris and acute myocardial infarction.
The platelet aggregation response to adenosine diphosphate (ADP) and to thrombin was quantified in 10 patients, 5 with unstable angina pectoris and 5 with acute myocardial infarction, before, during and after a 45-minute infusion of nitroglycerin. An impedance aggregometer allowing rapid bedside studies in whole blood was used. The reproducibility of the methods was documented to be within 10%. Doses of nitroglycerin were titrated for a 10 mm Hg decrease in mean arterial blood pressure with mean doses being 1.2 +/- 0.2 (standard error of the mean) micrograms/kg/min. Nitroglycerin decreased the area under the aggregation curve induced by ADP from 43 +/- 3.6 to 30 +/- 6.3 cm2 (p = 0.007) and by thrombin from 8.9 +/- 1.7 to 4.1 +/- 0.9 cm2 (p = 0.003). Peak responses to ADP were decreased from 13.3 +/- 1 to 9.1 +/- 1.7 ohms (p = 0.005) and to thrombin from 9.3 +/- 2 to 5.0 +/- 1.2 ohms (p = 0.003). All patients had greater than or equal to 50% inhibition with 1 agent or the other and the inhibition was greater than 50% with each of the 2 aggregating agents in 6 patients. Analyses performed on blood withdrawn 15 minutes after the discontinuation of nitroglycerin showed a return to baseline before nitroglycerin results. When analyses were delayed and performed on blood preserved at room temperature for 30 minutes, no effect of nitroglycerin could be detected. Thus, bedside platelet aggregation studies document a significant and reversible effect of nitroglycerin at therapeutic doses on platelet function.


Characterization of maternal transfer of decabromodiphenyl ether (BDE-209) administered to pregnant Sprague-Dawley rats.
To evaluate maternal transfer of decabromodiphenyl ether (BDE-209), Sprague-Dawley rats were given daily oral doses of 5 μmol/kgb.w. BDE-209 in peanut oil from gestation day (GD) 7 to postpartum day (PD) 4. BDE-209 was increased temporally in maternal blood, placenta, fetuses and neonates. Furthermore, more BDE-209 was found in neonate whole-body samples obtained during lactational period (PD 4) than in that of fetal whole-body samples during pregnancy GD 15 and 21. Overall an increase was observed over time for nona-BDE levels in maternal blood and placenta, but these congeners were decreased in fetuses or neonates. Slight changes were observed for octa-BDEs in both maternal blood and placenta while a significant decrease was observed in the fetuses or neonates for BDE-196 and 198/203. These results demonstrated that BDE-209 and its metabolites can transport to the placenta and milk, and eventually enter the fetuses and/or the neonates.


Surgical treatment of pediatric trigeminal neuralgia: case series and review of the literature.
Pediatric trigeminal neuralgia (TN) is a rare entity. The purpose of this study was to retrospectively analyze a small series of pediatric patients diagnosed with TN and surgically treated with microvascular decompression (MVD) at a single center. Nine patients were identified who presented with TN symptoms that began before the age of 18. Four were excluded because of delayed surgical intervention or successful medical management. We retrospectively reviewed the charts of 5 patients with classical TN who underwent MVD at or before the age of 18. Patient ages ranged from 3 to 18 years (average, 11.7) at the time of procedure. All five patients were female. Four patients underwent a single procedure and one had bilateral MVDs. In all six cases, vascular compression of the trigeminal nerve was found during surgery. Compression was venous in three cases, arterial in two, and both in one. Pain relief was complete following the procedure in five of six cases. Pain relief was incomplete but substantial in one patient, allowing her to discontinue anticonvulsant medications. Follow-up duration ranges from 9.1 to 24.8 months with an average of 15.3 (± 6.1) and a median of 12.7 months follow-up. There were no complications such as CSF leak, infection, or cranial nerve deficits. Until now, there had been no reports on the effectiveness of MVD performed before the age of 18 to treat TN. These preliminary results suggest MVD may be performed with good pain relief and minimal side effects in the pediatric population.


Phenotyping apolipoprotein E*3-leiden transgenic mice by two-dimensional polyacrylamide gel electrophoresis and mass spectrometric identification.
Apolipoprotein E (ApoE) plays an important role in cholesterol and triglyceride metabolism, being one of the major structural components of chylomicrons and very low density lipoprotein (VLDL) remnants. ApoE functions as a ligand in the receptor-mediated uptake of these remnants from the blood by the liver. A variant form of ApoE, apolipoprotein E*3-Leiden, shows reduced affinity for the low density lipoprotein (LDL) receptor, and results in the dominant expression of type III hyperlipoproteinemia. Two-dimensional electrophoresis (2-DE) has been used to characterise protein expression in serum samples from control and transgenic mice expressing the human ApoE*3-Leiden mutation, fed a cholesterol-rich diet, and transgenic mice fed a normal diet. For the identification of proteins, single silver-stained spots were excised from the 2-DE gels and subjected to in-gel enzymatic digestion. Extracted peptides were analysed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). This proteomic approach has enabled the ApoE*3-Leiden variant to be positioned in a 2-DE separation of serum proteins, and has identified changes in the expression of haptoglobin, indicating that this protein may provide a marker for the potential onset of atherosclerosis.


The neuro-protective role of telomerase via TERT/TERF-2 in the acute phase of spinal cord injury.
To investigate the interaction of telomerase activity and telomere length on neuro-protection or neuro-degeneration effects after spinal cord injury (SCI). A contusive SCI model was developed using 56 Sprague-Dawley rats. Seven rats were allocated into acute injury phase groups (1, 3, 8, 24, and 48 h), and sub-acute and chronic injury phase groups (1, 2, and 4 weeks). Telomerase activity was assessed by telomerase reverse transcriptase (TERT) and telomeric repeat binding factor-2 (TERF-2). Differentiation of activated neural stem cells was investigated by co-expression of neuronal/glial cell markers. Apoptosis expression was also investigated by caspase-3, 8, and 9 using terminal deoxynucleotidyl transferase dUTP nick end labelling staining. Immunofluorescence staining and western blotting were performed for quantitative analyses. Expression of TERT increased gradually until 24 h post-injury, and was decreased following SCI (P < 0.05). TERF-2 also was increased following SCI until 24 h post-injury and then decreased with time (P < 0.05). Co-localization of TERT and TERF-2 was higher at 24 h post-injury. High expression of TERT was seen in neurons (Neu N Ab), however, expression of TERT was relatively lower in astrocytes and oligodendrocytes. Apoptosis analysis showed persistent high expression of caspases-3, -9, and -8 during the observation period. Increased TERT and TERF-2 activity were noted 24 h post-injury in the acute phase of SCI with TERF-2 maintaining telomeric-repeat length. Our results suggest that increased activity of telomere maintenance may be related to neuro-protective mechanisms against subsequent apoptosis resulting from DNA damage after acute SCI.


Streptozotocin-induced diabetes enhances protective effects of enalapril on nitric oxide-deficient stroke in stroke-prone rats.
Recently, we have shown that chronic administration of N-Nitro-L-Arginine Methyl Ester (L-NAME, an inhibitor of nitric oxide synthase) precipitates stroke in stroke-prone spontaneously hypertensive rats (SHRSP). Enalapril maleate, an angiotensin converting enzyme inhibitor was shown to delay the onset of such stroke. In the present study, five groups of 4-week-old SHRSP were used. Three groups of SHRSP were made diabetic using streptozotocin (100 mg/kg i.p.). One week later, the SHRSP from groups I (non-diabetic) and III (diabetic) chronically received L-NAME (0.5 g/L) in saline as drinking water. Two SHRSP groups, II (non-diabetic) and IV (diabetic) received L-NAME (0.5 g/L) and enalapril maleate (20 mg/L) in saline as drinking water. Control SHRSP (group C; diabetic) received only saline to drink. SHRSP groups I and III developed stroke in 10+/-2 and 11+/-2 days, respectively. The average stroke-free period in groups II and IV was 19+/-2 and 28+/-2 days, respectively. Protective effect of streptozotocin-induced diabetes disappeared when SHRSP drinking L-NAME and enalapril, concurrently received subcutaneous injections of insulin (2 units daily per 100 g rat). Present data suggest that experimental diabetes delays the onset of L-NAME-induced stroke in SHRSP only in the absence of angiotensin converting enzyme activity. In addition, diabetes-induced enhancement of stroke-protective effect of enalapril appears to be independent of reduction in mean and systolic blood pressures.


Garcinol modulates tyrosine phosphorylation of FAK and subsequently induces apoptosis through down-regulation of Src, ERK, and Akt survival signaling in human colon cancer cells.
Garcinol, from the fruit rind of Garcinia indica and other species, has been reported to suppress colonic aberrant crypt foci (ACF) formation in rats. In this study, we investigate the beneficial effects of tumor prevention by garcinol on the human colorectal cancer cell line, HT-29. Focal adhesion kinase (FAK) is the major signaling mediator of integrin-mediated cell-matrix contact-regulated cellular proliferation, migration, and apoptosis in adherent cells. Results of Matrigel analysis show that exposure of HT-29 cells to 10 microM garcinol inhibited cell invasion, and decreased the dose-dependent tyrosine phosphorylation of FAK. We further demonstrate by Western blot analysis that garcinol inhibited activation of the Src, MAPK/ERK, and PI3K/Akt signaling pathways. To investigate whether the loss of integrin-mediated cell-matrix contact can induce apoptosis, we demonstrate that garcinol induced it in HT-29 cells. The apoptotic dose of garcinol (20 microM) changed the ratio of the anti-apoptotic Bcl-2 and proapoptotic BAX proteins within 12 h, which correlated with a release of cytochrome c from the mitochondria to the cytosol, and with PARP cleavage. Additionally, we demonstrate that a decreasing MMP-7 protein level in HT-29 cells results in sensitization to garcinol. Garcinol also significantly inhibited the expression of MMP-7 in IL-1beta-induced HT-29 cells. These results suggest that garcinol reduces cell invasion and survival through the inhibition of FAK's downstream signaling.


Use of the avidin-biotin peroxidase system to detect rabies antigen in formalin-fixed paraffin-embedded tissues.
We stained rabies-infected nervous and salivary-gland tissues fixed in formalin or acetone and embedded in paraffin with the avidin-biotin peroxidase system. With this system, rabies-virus antigen was detected in neurons, glandular acinar cells, and vascular endothelial cells more effectively than by immunofluorescence, especially when tissues were enzyme-digested with pronase before immunoperoxidase staining. The avidin-biotin peroxidase system should be useful for routine diagnosis, retrospective studies of rabies, and identification of specific cells involved in the spread of virus in rabies-infected hosts.


Two dimensional echocardiographic quantification of infarct size alteration by pharmacologic agents.
In 27 closed chest dogs left ventricular wall motion abnormalities assessed quantitatively with two dimensional echocardiography were used as a measure of myocardial infarct size, and the change in extent of segmental wall motion abnormalities due to drug intervention early after infarction was evaluated. The extent of wall motion abnormalities was measured with echocardiography before and at 20 and 40 minutes and 5 1/2 hours after coronary occlusion. Three subgroups of dogs received, respectively, an infusion of nitroglycerin, phenylephrine or saline solution. Infarct size was measured with technetium pyrophosphate scintigraphy of the excised left ventricle. The infarct size correlated well with the extent of wall motion abnormalities before death. Wall motion was initially similar among the three groups but was significantly improved after treatment with nitroglycerin (P less than 0.025), remained stable with continued saline infusion and worsened significantly (P less than 0.05) after treatment with phenylephrine. Two dimensional echocardiography can be used to quantify experimental canine myocardial infarction and assess the effect of nitroglycerin.


Influence of common variants of TLR4 and TLR9 on clinical outcomes of Plasmodium falciparum malaria in Odisha, India.
In malaria, the toll-like receptors (TLRs) have recently emerged as major player of innate immunity. However, implication of TLR variants on clinical manifestations of malaria is conflicting. The present study aims to provide relevant information of growing interest in understanding the role of TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms on clinical outcomes of malaria. We genotyped TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms by PCR-RFLP methods and subsequently analyzed in 200 uncomplicated patients and 200 severe patients. Further, the severe malaria categorized into sub-clinical groups such as cerebral malaria (CM), non-cerebral severe malaria (NCSM), single organ dysfunction (SOD) and multi-organ dysfunctions (MODS) are analyzed. The TLR9-1237CC genotype was observed at significantly low frequency in MODS (p=0.0008), while in heterozygous state (TC) it was proportionately more frequent in SOD (p=0.087) as compared to mild malaria. The TLR9T-1486C heterozygote was more common in all categories of severe malaria. However, pair wise LD analysis revealed significant linkage between T-1237C and T-1486C, whereas haplotype analysis showed significantly low frequency of C-T haplotype in CM (p=0.005, pc=0.02) and high frequency of T-C haplotype in NCSM as compared to mild malaria. Although TLR9-1237C could be a risk factor for severe malaria in heterozygous state, negative association of CC genotype with MODS warrants caution of segregating severe malaria into its sub-clinical groups while interpreting data. Further, clinical outcome in malaria was observed to be apparently modulated by LD between TLR9 promoter variants.


General and COVID-19-Related Mortality by Pre-Existing Chronic Conditions and Care Setting during 2020 in Emilia-Romagna Region, Italy.
In 2020, the number of deaths increased in Italy, mainly because of the COVID-19 pandemic; mortality was among the highest in Europe, with a clear heterogeneity among regions and socio-demographic strata. The present work aims to describe trends in mortality and to quantify excess mortality variability over time and in relation to demographics, pre-existent chronic conditions and care setting of the Emilia-Romagna region (Northern Italy). This is a registry-based cross-sectional study comparing the 2020 observed mortality with figures of the previous five years by age, sex, month, place of death, and chronicity. It includes 300,094 deaths in those 18 years of age and above resident in the Emilia-Romagna region. Excess deaths were higher during the first pandemic wave, particularly among men and in March. Age-adjusted risk was similar among both men and women (Mortality Rate Ratio 1.15; IC95% 1.14-1.16). It was higher among females aged 75+ years and varied between sub-periods. Excluding COVID-19 related deaths, differences in the risk of dying estimates tended to disappear. Metabolic and neuropsychiatric diseases were more prevalent among those that deceased in 2020 compared to the deaths that occurred in 2015-2019 and therefore can be confirmed as elements of increased frailty, such as being in long-term care facilities or private homes as the place of death. Understanding the impact of the pandemic on mortality considering frailties is relevant in a changing scenario.


Counseling for stress urinary incontinence in the era of adverse publicity around mesh usage: Results from a large-sample global survey.
To investigate doctors' opinions of the use of synthetic mesh for the treatment of stress urinary incontinence (SUI) and the effect on patient's attitude following recent adverse publicity and legal findings. Electronic survey approved by International Urogynecological Association (IUGA) and American Urogynecologic Society (AUGS), distributed to their members. A total of 593 respondents completed the survey. The preferred initial surgical treatment for SUI was retropubic midurethral sling (MUS) (62%), followed by trans-obturator MUS (19%), mini-slings (10%), and then bulking agents (5%). Despite prolongation of consultation, most respondents (87%) believed that clinicians should provide a patient information leaflet (PIL) for their patients. However, only 70% of respondents were doing this. Most participants would use either the IUGA PIL or their institution PIL (61%). Only 8% felt that patients have a positive preconception of synthetic mesh for SUI. Eighty-three per cent of respondents had not changed their recommendations for treatment and the consent process. A logistic regression model identified preferences of certain geographic areas as predictors of consenting practices. Despite the negative publicity and the current medicolegal litigation involving MUS for SUI treatment, the majority of respondents still prefer this as the initial surgical treatment. Most clinicians value PIL in the surgical consent process.


Thyroidectomy reduces stress-induced prolactin secretion in rats. Participation of brain serotonergic systems.
Plasma prolactin levels were measured in thyroidectomized and sham-operated rats under immobilization stress. Thyroidectomy significantly reduced prolactin secretion during stress. The pretreatment of thyroidectomized rats with 6-chloro-2-[1-piperazinyl]- pyrazine (MK 212), a serotonin agonist that easily penetrates the blood-brain barrier, reversed the reduction in stress-induced prolactin release in the thyroidectomized group.


Individualized HbA1c Goals, and Patient Awareness and Attainment of Goals in Type 2 Diabetes Mellitus: A Real-World Multinational Survey.
While glycemic control is key in effective type 2 diabetes mellitus management, many patients fail to reach their individualized glycemic goal. This analysis aimed to describe a real-world picture of diabetes management: individualized hemoglobin A1c (HbA1c) goals, rate of goal attainment, HbA1c at each line of therapy, and patient awareness of their glycemic goal. Secondly, we aimed to understand physician satisfaction with HbA1c amongst patients aware vs. those unaware of HbA1c goal. Analysis of physicians and the next ten consulting patients with type 2 diabetes mellitus conducted in Europe and the USA including medical record data abstraction/assessment by physicians, a patient-reported survey and a physician survey. Patients were diagnosed for 3 months or more with a known current and target HbA1c. For the sub-analysis assessment of patient awareness of HbA1c goal, in addition to the above, these patients had to have completed a patient-reported questionnaire and answer the question on awareness of HbA1c goal. A total of 730 physicians provided data on 8794 patients with type 2 diabetes mellitus; 5331 patients were eligible for this analysis. Overall, mean (standard deviation, SD) individualized HbA1c goal was 6.8% (0.68%). Of eligible patients, 39.1% met their HbA1c goal; of 60.9% of patients not reaching their HbA1c goal, the mean distance from individualized HbA1c goal was 0.9% (SD 1.0%). Physicians progressed patients' antihyperglycemic therapy when HbA1c was 8% or higher. Among 2560 patients who were included in the sub-analysis assessing the effect of patient awareness of their HbA1c goal on multiple parameters, 70.5% were aware of their HbA1c goal; mean HbA1c goal was 6.8% (0.7%) and current mean HbA1c value 7.1% (1.2%). A total of 949 patients in the sub-analysis (39.2%) achieved their goal; achieving HbA1c goal was not related to knowledge of goal. Patients aware of their HbA1c goal were slightly more adherent to their antihyperglycemic medication. They also were prescribed more antihyperglycemic agents, more often on a later therapy line receiving a GLP-1 receptor agonist, SGLT2i, or insulin, and more often tested their blood glucose levels than patients who were unaware. Physicians were not satisfied with the current blood glucose level of one third of their patients, believing that more of those who were aware of their HbA1c goal could achieve better glucose control (32.4% of aware vs. 28.2% of unaware patients; p = 0.003). Our results showed that the proportion of patients with type 2 diabetes mellitus achieving their goals for glycemic control was suboptimal when compared to current guideline criteria, with only about 40% of patients achieving their individualized HbA1c goal. Treatment intensification was often delayed until HbA1c was 8% and higher. Patients aware of their HbA1c goal were slightly more adherent to their antihyperglycemic medication; however, awareness of HbA1c goal did not enhance goal attainment. This highlights the need for a holistic approach to diabetes management, involving patient education, and patient-physician communication and partnership.


Penicillium caerulescens, sp. nov. isolated from soil.
One new species of Penicillium Link ex Gray nom. cons. prop. is described and illustrated. This species has been recovered from samples of sandy soil under pine trees. It differs from all species of the Genus described so far and is, therefore, considered and proposed as new taxon: Penicillium caerulescens n. sp.


The antiprogesterone RU486 stabilizes the heterooligomeric, non-DNA-binding, 8S-form of the rabbit uterus cytosol progesterone receptor.
The salt-induced (0.3 M KCl) transformation of the non-transformed, heterooligomeric 8S-form of the rabbit uterus cytosol progesterone receptor (PR) was analyzed by density gradient ultracentrifugation (8S----4S conversion) and DNA-cellulose chromatography (non-binding----binding forms). After 1 h treatment at 2 C, greater than 90% of agonist (R5020 or Org2058)-PR complexes were transformed, contrary to antagonist (RU486)-PR complexes, which did not undergo any transformation. Thus, there is stabilization of the non-transformed receptor form by RU486 as compared to the effect of agonist binding. The hydrodynamic parameters of both agonist- and antagonist-bound non-transformed receptors were similar and the calculated Mr were approximately 283,000 and approximately 293,000, respectively. In both cases, purification indicated the presence of a 90-kD non-hormone-binding protein associated with the hormone binding unit(s). Transformation of RU486-PR complexes occurred after exposure to high salt at increased temperature and was correlated to the dissociation of the 90-kD protein from the receptor. Both agonist- and antagonist-bound transformed forms of PR had apparent similar affinities for DNA-cellulose. Molybdate-stabilized and KCl-treated RU486-PR complexes were more stable, as assessed by steroid binding, than the corresponding R5020-PR complexes, arguing in favor of a stabilizing effect of both the 90-kD protein and RU486 against inactivation. These cell-free experiments support the concept that RU486 in the rabbit uterus system stabilizes the 8S non-DNA binding, non-transformed form of the receptor at low temperature. The possibility that impaired dissociation of the heterooligomeric receptor form is involved in the antiprogesterone activity of RU486 is discussed.


Acceptability of compulsory powers in the community: the ethical considerations of mental health service users on Supervised Discharge and Guardianship.
To explore mental health service users' views of existing and proposed compulsory powers. A qualitative study employing in-depth interviews. Participants were asked to respond to hypothetical questions regarding the application of compulsory powers under the Mental Health Act 1983 for people other than themselves. Community setting in Southeast England. Mental health service users subject to Supervised Discharge/Guardianship. Participants considered that the use of compulsory powers was justified if there were some ultimate benefit, and if there was evidence of mental health problems, dangerousness, or a lack of insight. However, participants rejected intrusions into their autonomy and privacy. This paper's participants indicated that the proposed CTO may be unacceptable because it would threaten service users' autonomy. Service users' acceptance of proposed changes is conditional and they emphasised the importance of consent; there is no suggestion that consent will be required for the CTO. The findings also have implications for the exploration of mental health service users' views and how they might contribute to policy, service planning, and research.


Pilot study indicate role of preferentially transmitted monoamine oxidase gene variants in behavioral problems of male ADHD probands.
Attention deficit hyperactivity disorder (ADHD) is an etiologically complex childhood onset neurobehavioral disorder characterized by age-inappropriate inattention, hyperactivity, and impulsivity. Symptom severity varies widely and boys are diagnosed more frequently than girls. ADHD probands were reported to have abnormal transmissions of dopamine, serotonin, and/or noradrenaline. Monoamine oxidase A (MAOA) and B (MAOB), mitochondrial outer membrane bound two isoenzymes, mediate degradation of these neurotransmitters and thus regulating their circulating levels. Case-control analyses in different populations, including Indians, suggested involvement of MAOA and MAOB genes in the etiology of ADHD. Due to high heritability rate of ADHD, we tested familial transmission of MAOA and MAOB variants to ADHD probands in 190 nuclear families having ADHD probands from Indo-Caucasoid ethnicity. Subjects were recruited following the Diagnostic and Statistical Manual of Mental Disorders-4th edition (DSM-IV). Appropriate scales were used for measuring the behavioral traits in probands. Genotyping was performed through PCR-based amplification of target sites followed by DNA-sequencing and/or gel-electrophoresis. Data obtained were analyzed by family based statistical methods. Out of 58 variants present in the analyzed sites only 15 were found to be polymorphic (30 bp-uVNTR, rs5906883, rs1465107, rs1465108, rs5905809, rs5906957, rs6323, rs1137070 from MAOA and rs4824562, rs56220155, rs2283728, rs2283727, rs3027441, rs6324, rs3027440 from MAOB). Statistically significant maternal transmission of alleles to male probands was observed for MAOA rs5905809 'G' (p = 0.04), rs5906957 'A' (p = 0.04), rs6323 'G' (p = 0.0001) and MAOB rs56220155 'A' (p = 0.002), rs2283728 'C' (p = 0.0008), rs2283727 'C' (p = 0.0008), rs3027441 'T' (p = 0.003), rs6324 'C' (p = 0.003), rs3027440 'T' (p = 0.0002). Significantly preferential maternal transmissions of different haplotype combinations to male probands were also noticed (p < 0.05), while female probands did not reveal such transmission bias. Behavioral traits of male probands exhibited significant association with gene variants. Age of the mother at pregnancy also revealed association with risk variants of male probands. It may be inferred that the MAOA and MAOB variants may contribute to the etiology of ADHD in the Indo-Caucasoid population and could be responsible for higher occurrence of ADHD in the boys.


G6PD Viangchan (871G>A) is the most common G6PD-deficient variant in the Cambodian population.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common hereditary enzymopathy among Southeast Asians. We studied G6PD mutations in 108 migrant Cambodian laborers in Chanthaburi province and cord blood samples from 107 Cambodian newborns at Buriram Hospital. Thirty-one (26.1%) of 119 Cambodian males and three of 96 (3.1%) females were G6PD deficient and were assayed for G6PD mutations. G6PD Viangchan (871G>A) was identified in most G6PD-deficient Cambodians (28 of 34; 82.4%); G6PD Union (1360C>T) and G6PD Coimbra (592C>T) was found in one case each. We concluded that G6PD Viangchan (871G>A) was the most common mutation among Cambodians. This finding is similar to G6PD-deficient Thais and Laotians, suggesting a common ancestry of people from these three countries.


Factors associated with delays in seeking post abortion care among women in Kenya.
Delays in seeking quality post abortion care services remain a major contributor to high levels of mortality and morbidity among women who experience unsafe abortion. However, little is known about the causes of and factors associated with delays in seeking care among women who suffer complications of unsafe abortion. This study looks at factors that are associated with delays in seeking post-abortion care among women in Kenya. Data for this study were from a nationally representative sample of 350 healthcare facilities that participated in the 2012 Incidence and Magnitude of Unsafe Abortion study in Kenya. Data included socio-demographic characteristics, reproductive health and clinical histories from all women treated with PAC during a one-month data collection period. Delay in seeking care was associated with women's age, education level, contraceptive history, fertility intentions and referral status. There is need to improve women's access to quality sexual and reproductive health information and services, contraception and abortion care. Improving current PAC services at lower level facilities will also minimize delays resulting from long referral processes.


The development of tachyphylaxis to electrical stimulation in guinea-pig ileal longitudinal muscles and the possible participation of adenosine and adenine nucleotides.
1 Electrically (30 Hz) induced contractions of guinea-pig isolated ileal longitudinal muscles were reduced by tetrodotoxin (1 micron), adenosine (30 micron) and morphine (10 micron). 2 When stimulated with 10 or 30 Hz for 10 s at 1 min intervals, a progressive decline of amplitude of the contraction was seen (development of tachyphylaxis). At this time, the contractile response to 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) (10 micron) was also greatly reduced. 3 The smaller responses to electrical stimulation and DMPP during tachyphylaxis were restored to their initial amplitude by the addition of theophylline (10 micron). The appearance of tachyphylaxis was prevented by pretreatment with theophylline (1 to 10 micron) and was greatly accelerated by pretreatment with dipyridamole (0.1 1 micron). 4 In [14C]-choline or [3H]-adenosine preloaded muscle strips, electrical stimulation (30 Hz) increased the 14C- or 3H-output, the effect being sensitive to tetrodotoxin blockade. The tachyphylaxis to electrical stimulation was accompanied by a considerable and sustained increase in 3H-output, an effect that was accelerated by dipyridamole (1 micron). The 14C-output initially increased but fell off gradually with the development of tachyphylaxis at which time theophylline (30 micron) reversed the fall. 5 There was a marked increase in the proportion of released [3H]-adenosine to its derivatives during the development of tachyphylaxis. Approximately 60% of the released total radioactivity after tachyphylaxis was found to be [3H]-adenosine. 6 These results suggest that the development of tachyphylaxis may be closely associated with the release of endogenous adenosine derivatives (mostly adenosine) which have presynaptic inhibitory actions on the cholinergic elements in guinea-pig ileum.


"Chronic obstructive pulmonary disease and phenotypes: a state-of-the-art."
Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous and multisystemic disease with progressive increasing morbidity and mortality. COPD is now widely accepted as a heterogeneous condition with multiple phenotypes and endotypes. This review will discuss the old and new concepts for the different types of COPD phenotypes, as well as the inclusion of them in current guidelines. Phenotypical approach to COPD is having huge impact on everyday practice and changed nonpharmacological and pharmacological management of COPD in last decade. However, phenotypical approach is small step to precision medicine in COPD management in the absence of big, specific and well-designed COPD trials with exact identification of phenotypes for more personalization of the treatment of COPD.


Natural Language Processing for Imaging Protocol Assignment: Machine Learning for Multiclass Classification of Abdominal CT Protocols Using Indication Text Data.
A correct protocol assignment is critical to high-quality imaging examinations, and its automation can be amenable to natural language processing (NLP). Assigning protocols for abdominal imaging CT scans is particularly challenging given the multiple organ specific indications and parameters. We compared conventional machine learning, deep learning, and automated machine learning builder workflows for this multiclass text classification task. A total of 94,501 CT studies performed over 4 years and their assigned protocols were obtained. Text data associated with each study including the ordering provider generated free text study indication and ICD codes were used for NLP analysis and protocol class prediction. The data was classified into one of 11 abdominal CT protocol classes before and after augmentations used to account for imbalances in the class sample sizes. Four machine learning (ML) algorithms, one deep learning algorithm, and an automated machine learning (AutoML) builder were used for the multilabel classification task: Random Forest (RF), Tree Ensemble (TE), Gradient Boosted Tree (GBT), multi-layer perceptron (MLP), Universal Language Model Fine-tuning (ULMFiT), and Google's AutoML builder (Alphabet, Inc., Mountain View, CA), respectively. On the unbalanced dataset, the manually coded algorithms all performed similarly with F1 scores of 0.811 for RF, 0.813 for TE, 0.813 for GBT, 0.828 for MLP, and 0.847 for ULMFiT. The AutoML builder performed better with a F1 score of 0.854. On the balanced dataset, the tree ensemble machine learning algorithm performed the best with an F1 score of 0.803 and a Cohen's kappa of 0.612. AutoML methods took a longer time for completion of NLP model training and evaluation, 4 h and 45 min compared to an average of 51 min for manual methods. Machine learning and natural language processing can be used for the complex multiclass classification task of abdominal imaging CT scan protocol assignment.


Confirmation of the association of human papillomavirus with human colon cancer.
The human papillomavirus (HPV) has been shown to be associated with neoplasms of the human colon using immunohistochemistry and in situ hybridization. We now report our use of the polymerase chain reaction and Southern blotting to investigate that same association. We selected 38 carcinomas, 21 adenomas, and 24 normal mucosal samples for the current study. Tissue sections were prepared, and then DNA was extracted and subjected to 40 cycles of amplification using Thermus aquaticus DNA polymerase and a set of degenerate primers. Amplified products were analyzed by agarose gel electrophoresis and Southern blotting. The L1 region of the HPV genome was identified in 13 of 38 carcinomas (32%), 8 of 21 adenomas (38%), and 2 of 24 normal biopsy specimens (8%). These observations validate our previous results and confirm the presence of HPV in human colon mucosa and tumors of that mucosa.


Food label use and food label skills among immigrants from the former Soviet Union.
To assess food label use and skills and to identify their correlates among immigrants from the former Soviet Union (FSU). Cross-sectional survey of a convenience sample of 200 FSU immigrants residing in New York City. Food label use and skills; acculturation; and socioeconomic and psychosocial factors. Chi-square tests and multivariate logistic regression analysis assessed relationships among the outcomes and socioeconomic and other characteristics. Fifty-five percent reported using food labels always/often; only 32% had good label skills. FSU immigrants particularly had difficulty understanding servings per package and percent daily value. Food label use was significantly associated with factors such as positive attitude toward food labels, and importance of recommendations such as avoiding too much salt and saturated fat. However, these factors were not related to food label skills, which was positively associated with longer residency in the United States (> 7 y). There is a need for nutrition education among FSU immigrants to increase their food label use and skills to promote healthful food selection. Developers of new food labels should consider ways to present percent daily value and servings per package in a more consumer-friendly manner. Simplifying the presentation of this information could improve food label skills in FSU immigrants, among others.


Inverse correlation between fibrinogen and bone mineral density in women: Preliminary findings.
Hemostatic factors may be involved in bone health. The present preliminary study investigated the association between plasma fibrinogen and bone mineral density (BMD) in perimenopausal women. A significant inverse correlation between fibrinogen and BMD was observed (correlation coefficient = -0.42, p < 0.01). This correlation appeared to be more clearly observed in the subgroup with a high level of high-sensitivity C-reactive protein than in that with a low level of high-sensitivity C-reactive protein, and in the subgroup with a high level of diacron reactive oxygen metabolites (an oxidative stress marker) than in that with a low level of diacron reactive oxygen metabolites. Thus, fibrinogen may be a possible marker of BMD in this population. More studies on the associations among hemostasis, inflammation, oxidative stress, and bone metabolism are warranted in the clinical setting.


Integrating landfill bioreactors, partial nitritation and anammox process for methane recovery and nitrogen removal from leachate.
A new process consisting of a landfill bioreactor, partial-nitritation (PN) and the anammox process has been developed for landfill leachate treatment. In this study, the landfill bioreactor exhibited excellent performance in methane-rich biogas recovery, with a specific biogas yield of 0.47 L gas g(-1) COD and methane percentages of 53-76%. PN was achieved in the aerobic reactor by high free ammonia (101 ± 83 mg NH3 L(-1)) inhibition for nitrite-oxidizing bacteria, and the desired PN effluent composition (effluent nitrite: ammonium ratio of 1.1 ± 0.3) was controlled by adjusting the alkalinity concentration per unit of ammonium oxidized to approximately 14.3 mg CaCO3 mg(-1) N in the influent. The startup of anammox process was successfully achieved with a membrane bioreactor in 160 d, and a maximum nitrogen removal rate of 216 mg N L(-1) d(-1) was attained for real landfill leachate treatment. The quantitative polymerase chain reaction results confirmed that the cell-specific anammox activity was approximately 68-95 fmol N cell(-1) d(-1), which finally led to the stable operation of the system.


Neurocritical Care Aspects of Ischemic Stroke Management.
This article reviews the care of patients with ischemic stroke in the intensive care unit, including early general critical care interventions for airway control blood pressure goals according to the type of acute stroke treatment, poststroke cerebral edema management, hemorrhagic conversion in ischemic stroke, fibrinolytic reversal, and management of carotid endarterectomy and infective endocarditis. The importance of preventing common intensive care complications is discussed, including aspiration pneumonia, deep venous thrombosis, urinary tract infections, cardiac arrhythmias, and hyperglycemia.


TENS to the posterior aspect of the legs decreases postural sway during stance.
The purpose of this study was to examine the effect of Transcutaneous Electrical Nerve Stimulation (TENS) applied to the posterior aspect of the legs, on postural sway during stance. Thirty healthy subjects were tested while standing on a force platform under four stimulation conditions: no TENS, bilateral TENS, and unilateral left and right TENS. Thirty-second long tests, employing detection threshold amplitudes, were performed in three blocks. In each block, the four conditions were applied both with and without vision in a random order. The results indicate that the application of TENS brought about a decrease in postural sway as expressed by average sway velocity, in addition to a decrease in the absolute values of maximal and minimal medio-lateral and anterior-posterior velocity. Thus, similar to sub-threshold random electrical noise, it appears that the application of low-amplitude TENS to the lower limbs decreases postural sway during stance. Considering the ease of TENS application and the high prevalence of postural disorders, the potential clinical significance of this observation is to be determined by further studies.


Towards robust and effective shape modeling: sparse shape composition.
Organ shape plays an important role in various clinical practices, e.g., diagnosis, surgical planning and treatment evaluation. It is usually derived from low level appearance cues in medical images. However, due to diseases and imaging artifacts, low level appearance cues might be weak or misleading. In this situation, shape priors become critical to infer and refine the shape derived by image appearances. Effective modeling of shape priors is challenging because: (1) shape variation is complex and cannot always be modeled by a parametric probability distribution; (2) a shape instance derived from image appearance cues (input shape) may have gross errors; and (3) local details of the input shape are difficult to preserve if they are not statistically significant in the training data. In this paper we propose a novel Sparse Shape Composition model (SSC) to deal with these three challenges in a unified framework. In our method, a sparse set of shapes in the shape repository is selected and composed together to infer/refine an input shape. The a priori information is thus implicitly incorporated on-the-fly. Our model leverages two sparsity observations of the input shape instance: (1) the input shape can be approximately represented by a sparse linear combination of shapes in the shape repository; (2) parts of the input shape may contain gross errors but such errors are sparse. Our model is formulated as a sparse learning problem. Using L1 norm relaxation, it can be solved by an efficient expectation-maximization (EM) type of framework. Our method is extensively validated on two medical applications, 2D lung localization in X-ray images and 3D liver segmentation in low-dose CT scans. Compared to state-of-the-art methods, our model exhibits better performance in both studies.