Altered gray matter density and disrupted functional connectivity of the amygdala in adults with Internet gaming disorder.
The aim of this study was to evaluate the altered brain structure and functional connectivity (FC) among subjects with Internet gaming disorder (IGD). We recruited 30 males with IGD and 30 controls and evaluated their gray matter density (GMD) and FC using resting fMRI. The severities of IGD, gaming urge, and impulsivity were also assessed. The results demonstrated that the subjects with IGD had a higher impulsivity and a greater severity of IGD. The subjects with IGD had a lower GMD over the bilateral amygdala than the controls. Further, the subjects with IGD had lower FC with the left amygdala over the left dorsolateral prefrontal lobe (DLPFC) and with the right amygdala over the left DLPFC and orbital frontal lobe (OFL). They also had higher FC with the bilateral amygdala over the contralateral insula than the controls. The FC between the left amygdala and DLPFC was negatively correlated with impulsivity. The FC of the right amygdala to the left DLPFC and orbital frontal lobe was also negatively correlated with impulsivity. Our results indicated that the altered GMD over the amygdala might represent vulnerability to IGD, such as impulsivity. Further analysis of the amygdala demonstrated impaired FC to the frontal lobe, which represents impulsivity. The results of this study suggested that the amygdala plays a very influential role in the mechanism of IGD. Its detailed role should be further evaluated in future study and should be considered in the treatment of IGD.


Hepatitis C virus treatment in people who inject drugs (PWID) in Bangladesh.
Given the considerable social marginalization experienced by people who inject drugs (PWID), treatment of hepatitis C virus (HCV) in this population presents unique challenges. This study assessed the feasibility of treating HCV infection with direct-acting antiviral (DAA) medications among PWID receiving harm reduction services from a Drop-in-Center in Dhaka, Bangladesh. In this prospective study conducted between December 2016 and May 2018, 200 PWID with either recent injecting drug use (i.e., within the previous two months) or a history of injecting drug use and are currently receiving opioid substitution therapy were recruited. Blood was collected to conduct relevant laboratory tests. Eligible PWID who tested positive for HCV RNA (n = 55), were provided daily daclatasvir (60 mg) and sofosbuvir (400 mg) for 12 weeks after which adherence level, sustained virologic response (SVR), and reinfection were assessed. At baseline, 40% (n = 79) of the 200 participants recruited to the study tested positive for antibodies to HCV and 34% (n = 68) had detectable HCV RNA in their blood. Of 55 eligible PWID who initiated treatment, 93% (n = 51) completed treatment while 87% (n = 48) were available for follow-up SVR assessment, all of whom achieved SVR. Thus, intent-to-treat SVR was 87% and the modified intent-to-treat SVR was 100% with one reinfection (4•2 cases per 100 person-years). Further, 75% (i.e., 41 out of the 55 participants) were at least 90% adherent to therapy. Our findings strongly suggest that HCV treatment using sofosbuvir+daclatasvir for PWID enrolled in existing harm reduction programs in Bangladesh is feasible but may require additional interventions such as Opioid Substitution Therapy, intense follow up by outreach workers, and services and counselling provided by full time clinicians.


The zinc finger transcription factor ATF1 regulates aluminum tolerance in barley.
Aluminum (Al) toxicity is a major abiotic stress that restricts crop production in acid soils. Plants have evolved internal and external mechanisms of tolerance, and among them it is well known that AtSTOP1 and OsART1 are key transcription factors involved in tolerance through regulation of multiple downstream genes. Here, we identified the closest homolog of these two proteins in barley, namely HvATF1, Al-tolerance Transcription Factor 1, and determined its potential function in Al stress. HvATF1 is expressed in the nucleus, and functions in transcriptional activation. The transcription of HvATF1 was found to be constitutive in different tissues, and was little affected by Al stress. Knockdown of HvATF1 by RNAi resulted in increased Al sensitivity. Transcriptomics analysis identified 64 differently expressed genes in the RNAi lines compared to the wild-type, and these were considered as candidate downstream genes regulated by HvATF1. This study provides insights into the different molecular mechanisms of Al tolerance in barley and other plants.


[A method for control over the training of student physicians in a department of skin and venereal diseases].
The authors emphasize the significance of independent work of physicians, trained at the Chair, for the improvement of their continuous education. The role of the teacher in this process is discussed, the methods of training are presented, and various forms of independent work of the physicians in hospitals and outside the classrooms are described.


Deciphering Biomarkers for Leptomeningeal Metastasis in Malignant Hemopathies (Lymphoma/Leukemia) Patients by Comprehensive Multipronged Proteomics Characterization of Cerebrospinal Fluid.
In the present work, leptomeningeal disease, a very destructive form of systemic cancer, was characterized from several proteomics points of view. This pathology involves the invasion of the leptomeninges by malignant tumor cells. The tumor spreads to the central nervous system through the cerebrospinal fluid (CSF) and has a very grim prognosis; the average life expectancy of patients who suffer it does not exceed 3 months. The early diagnosis of leptomeningeal disease is a challenge because, in most of the cases, it is an asymptomatic pathology. When the symptoms are clear, the disease is already in the very advanced stages and life expectancy is low. Consequently, there is a pressing need to determine useful CSF proteins to help in the diagnosis and/or prognosis of this disease. For this purpose, a systematic and exhaustive proteomics characterization of CSF by multipronged proteomics approaches was performed to determine different protein profiles as potential biomarkers. Proteins such as PTPRC, SERPINC1, sCD44, sCD14, ANPEP, SPP1, FCGR1A, C9, sCD19, and sCD34, among others, and their functional analysis, reveals that most of them are linked to the pathology and are not detected on normal CSF. Finally, a panel of biomarkers was verified by a prediction model for leptomeningeal disease, showing new insights into the research for potential biomarkers that are easy to translate into the clinic for the diagnosis of this devastating disease.


Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer's disease.
Cholinergic neurons were studied by immunohistochemistry, with an antiserum against choline acetyltransferase (ChAT), in the basal forebrain (Ch1 to Ch4) of four patients with Alzheimer's disease (AD) and four control subjects. ChAT-positive cell bodies were mapped and counted in Ch1 (medial septal nucleus), Ch2 (vertical nucleus of the diagonal band), Ch3 (horizontal nucleus of the diagonal band) and Ch4 (nucleus basalis of Meynert). Compared to controls, the number of cholinergic neurons in AD patients was reduced by 50% on average. The interindividual variations in cholinergic cell loss were high, neuronal loss ranging from moderate (27%) to severe (63%). Despite the small number of brains studied, a significant correlation was found between the cholinergic cell loss and the degree of intellectual impairment. To determine the selectivity of cholinergic neuronal loss in the basal forebrain of AD patients, NPY-immunoreactive neurons were also investigated. The number of NPY-positive cell bodies was the same in controls and AD patients. The results (1) confirm cholinergic neuron degeneration in the basal forebrain in AD and the relative sparing of these neurons in some patients, (2) indicate that degeneration of cholinergic neurons in the basal forebrain contributes to intellectual decline, and (3) show that, in AD, such cholinergic cell loss is selective, since NPY-positive neurons are preserved in the basal forebrain.


Surgical treatment of endomyocardial fibrosis.
Forty-six patients with endomyocardial fibrosis underwent endocardiectomy and replacement of tricuspid, mitral, or both atrioventricular valves between April, 1981, and October, 1984, at the Sree Chitra Tirunal Institute, Kerala State, India, which has a high incidence of the disease. Six patients were in New York Heart Association Functional Class III and 40 patients in Class IV. The operative mortality within 30 days of the procedure and late mortality during the first two years postoperation were 21.7% and 13%, respectively. Age under 15 years was a significant correlate of operative mortality (p = .05). Non-fatal thromboembolic episodes occurred in 6 patients during the two years of postoperative observation. The life table estimate of survival inclusive of operative mortality at two years was 67%. Despite high operative mortality, endocardiectomy with atrioventricular valve replacement is advisable for functionally disabled patients with endomyocardial fibrosis whose prognosis otherwise is dismal.


[New method for calculating the dissipation parameters in ultrafast biochemical reactions from protein crystal structure data].
A new method of calculating the spectral function of system-bath interaction during elementary biochemical reaction is proposed. This method was applied to the primary electron transfer in the photosynthetic reaction center of purple bacteria Rh. Sphaeroides. The calculated spectral functions differ significantly from the commonly used ohmic function. It is shown that the unidirectionality of the electron transfer along the A-branch in the reaction center of Rh. Sphaeroides can be caused by the asymmetry or reaction system interaction with the protein environment.


Harvard Community Health Plan's Mental Health Redesign Project: a managerial and clinical partnership.
Harvard Community Health Plan, founded in 1969 as a staff model HMO, is currently a staff and group model HMO with 521,000 members, 19 health centers and 12 independently owned group practices with 26 locations. In 1987, the Plan initiated a review of its mental health benefit and program because its costs were rising, member and clinician dissatisfaction was increasing and many believed the problem was the nature and scope of the benefit. After two years of study, surveys, interviews, cost and utilization analysis, the Plan identified its professional staff as its key asset but recognized many problem areas, including problems with access, variation from site to site, inconsistent service delivery, lack of consistent utilization management and the need for greater diversity along the spectrum of care available to members. From 1989 to 1990, more than 200 clinicians and support staff were engaged in the process of developing a variety of components to the "mental health redesign program." Three simultaneous efforts included developing a method of categorizing patients, restructuring the delivery system and redesigning the benefit. A Mental Health Patient Assessment Tool was created which assists clinicians in performing comprehensive evaluations, administers the benefit, measures progress and supports outcomes research. Delivery system changes included the implementation of self-referral, access standards, intake triage functions by non-clinical staff, program development and an outpatient utilization management function.


Acute effects of low doses of methyl parathion on human EEG.
Biological monitoring of workers exposed to organophosphates consists mainly of measuring serum or erythrocyte cholinesterase activity. However, animal experiments and a field study suggest that quantitative analysis of EEG may be more sensitive. In a parallel group design, 25 farmers were investigated, spraying methyl parathion or water for 50min. EEG was recorded before and after spraying. Serum and erythrocyte cholinesterase activity was compared with intraindividual pre-exposure values. Plasma methyl parathion concentrations ranged up to 12.1μg/l, methyl paraoxon was not detectable. Based on plasma concentrations, two exposed subgroups were defined. In EEG recorded with closed eyes, α(1)-power increased insignificantly (Kruskal-Wallis test) in both subgroups. β(1)-power was enhanced in both exposed subgroups, reaching significance (p≤0.05) at five of 17 electrodes. Spearman's rank correlation showed a significant association between methyl parathion plasma concentration and the median of β(1)-band power of the 17 electrodes (rho=0.48, p=0.015). Cholinesterase activity did not decrease. On a group basis, EEG is possibly more sensitive than cholinesterase. EEG changes suggest brain cholinesterase inhibition following low exposure to methyl parathion.


The prevalence and risk factors of different degrees of stress urinary incontinence in Chinese women: A community-based cross-sectional study.
To investigate the prevalence of SUI and explore the factors that could influence the severity of SUI in adult females. A cross-sectional study. A total of 1178 subjects were assessed using a risk-factor questionnaires and International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) and then divided into no SUI group, mild SUI group and moderate-to-severe SUI group according to the ICIQ-SF score. Univariate analysis between adjacent groups and ordered logistic regression models in three groups were then performed to analysis the possible associated factor with the progressive of SUI. The prevalence of SUI among adult women was 22.2% of them; 16.2% and 6% had mild SUI and moderate-to-severe SUI, respectively. Moreover, logistic analysis revealed that age, BMI, smoking, position preference for urination, urinary tract infections, urinary leaks during pregnancy, gynaecological inflammation and poor sleep quality were independent risk for the severity of SUI. SUI symptoms were mostly mild among Chinese females, specific risk factors such as unhealthy living habits and urination behaviours increased the risk of SUI and the aggravation of symptoms. Therefore, targeted interventions should be formulated for women to delay disease progression.


Natural sources of melanogenic inhibitors: A systematic review.
Melanin gives some natural protection against the harmful effects of ultraviolet radiation; however, excessive production of melanin causes skin hyperpigmentation. Depigmenting cosmetics can be used to control this process; however, depigmenting agents commonly used have some disadvantages, such as low bioavailability, photosensitization, cellular toxicity, and insolubility. Natural sources of melanogenic inhibitors have become important alternatives to synthetic ones. The objective of this review was to summarize the results of studies on natural extracts that have been reported in the literature to inhibit the process of melanogenesis, giving a view on their suitability for potential use in new cosmetic formulations for skin-lightening. A systematic literature search was carried out using the descriptors: "melanogenesis", "tyrosinase", "tyrosinase inhibition", and "natural agents". Publications were selected based on our designated inclusion and exclusion criteria, and a total of 15 studies met these criteria. The following were used in the review of each paper which met the criteria: the name of the plant (all of the natural extracts turned out to be from plants), the method used to obtain the plant extract, the method for evaluating anti-tyrosinase activity, the main results, and the conclusions. All evaluated natural agents demonstrated anti-tyrosinase effect. The species Leathesia difformis, Morus alba, Orostachys japonicus, Heracleum moellendorffii, Coix lacryma-jobi (adlay), Inula brittanica, and Gailardia aristata stood out from the others due to their application as potential inhibitors of more than three proteins related to melanogenesis, including the cyclic adenosine monophosphate response element-binding protein, microphthalmia-associated transcription factor, tyrosinase, tyrosinase-related protein-1, tyrosinase-related protein-2, and dopachrome tautomerase. The plants present an anti-tyrosinase effect that must be better explored in the new cosmetic formulations. The anti-melanogenic effects of the plant are mainly related to the presence of phenolic and antioxidant compounds.


L-Glutamate decarboxylase.
Much progress has been made in recent years regarding enzymological aspects of mammalian brain GAD, such as its purification and characterization, but some uncertainty still remains concerning its molecular weight and forms, and its subunit structure. The availability of antibodies to this enzyme has allowed immunocytochemical studies which have provided important information on the intrinsic organization of GABA-ergic neurones in the CNS, particularly in the cerebellum and nigrostriatal pathway. With the increased understanding of the enzymology of GAD and the distribution of central GABA-ergic neurones, it is becoming feasible to study the regulatory biochemistry of GAD in terms of control and adaptive mechanisms at the cellular level. In our own laboratory, as well as in others, initial approaches have already begun. Obviously, cellular regulation of this phenotypic enzyme is an important issue for the understanding of GABA-ergic neurones and their functions.


The effect of rumen epithelial development on metabolic activities and ketogenesis by the tissue in vitro.
1. An investigation was made on oxygen consumption, glucose and lactate uptake and ketogenesis from butyrate by rumen epithelium in vitro from lambs at various stages of development. 2. Oxygen uptake was decreased by about 35% and glucose uptake by about 90% between 2 weeks and 1/2 year of age. 3. The uptake of L-lactate and the utilization of butyrate as a substrate for respiration were increased during epithelial development. 4. The production of D(-)-3-hydroxybutyrate and acetoacetate from butyrate by the epithelium was largely increased between 4 to 10 weeks of age, independently of rumen fermentation. 5. A synergistic effect of glucose on the production of D(-)-3-hydroxybutyrate and on total ketone bodies from butyrate by the epithelium was observed. It accounted to 40-80% over butyrate depending on the stage of epithelial development.


Marijuana use in opioid exposed pregnancy increases risk of preterm birth.
The prevalence of opioid use disorder has increased across the United States, but the rural population of Appalachia has been disproportionately impacted. Concurrently, the slow, but steady progress in the legalization of marijuana may be affecting perception of marijuana use in pregnancy. However, marijuana use in pregnancy has been associated with adverse perinatal outcomes. Concomitant use of opioids and marijuana in pregnancy has not been evaluated. The primary aim of the study was to evaluate the association between confirmed marijuana use in late pregnancy and preterm birth in opioid-exposed pregnancies. A retrospective chart review was conducted that included all births from July 2011 to June 2016 from 6 delivery hospitals in South-Central Appalachia. Out of 18,732 births, 2368 singleton pregnancies indicated opioid use and met remaining inclusion criteria, with 108 of these mothers testing positive for marijuana at delivery. Independent sample t-test and Chi-Square analyses compared marijuana and non-marijuana exposed groups on maternal and neonatal outcomes. Regression analyses controlled for confounding variables in predicting neonatal abstinence syndrome (NAS), NICU admission, preterm birth, small for gestational age, and low birth weight outcomes as shown in Table 1. Neonates born to marijuana-positive women in opioid-exposed pregnancy were more likely to be born preterm, small for gestational age, have low birth weight, and be admitted to NICU. After statistically controlling for parity, marital status, tobacco and benzodiazepine use, preterm birth and low birth weight remained statistically significant with aOR of 2.35 (1.30-4.24) and 2.01 (1.18-3.44), respectively. Maternal use of marijuana in any opioid-exposed pregnancy may increase risk of preterm birth and low-birth weight infants. Prospective studies need to examine the dose and timing of marijuana and opioid use in pregnancy to better delineate perinatal effects. Nonetheless, pregnant women using opioids, including recommended medication assisted treatment for opioid use disorder, should be educated about the risks of concurrent marijuana use during pregnancy and may need to be counseled to abstain from marijuana use during pregnancy for an optimal outcome.


Representation of Women in Randomized Trials in Cardiac Surgery: A Meta-Analysis.
Background Women have traditionally been underrepresented in randomized clinical trials (RCTs). We performed a systematic evaluation of the inclusion of women in cardiac surgery RCTs published in the past 2 decades. Methods and Results MEDLINE, EMBASE, and the Cochrane Library were searched (2000 to July 2020) for RCTs written in English, comparing ≥2 adult cardiac surgical procedures. The percentage of women enrolled and its association with year of publication, sample size, mean age, funding source, geographic location, number of sites involved, and interventions tested were analyzed using a meta-analytic approach. Fifty-one trials were included. Of 25 425 total patients, 5029 were women (20.8%; 95% CI, 17.6-24.4; range, 0.5%-57.9%). The proportion of women dropped significantly during the study period (29.6% in 2000 versus 13.1% in 2019, P<0.001). Women were significantly more represented in European trials (26.2%; 95% CI, 21.2-31.9), and less represented in trials of coronary bypass surgery versus other interventions (16.8%; 95% CI, 12.3-22.7 versus 33.6%; 95% CI, 27.4-40.5; P=0.0002) and in trials enrolling younger patients (P=0.009); the percentage of women was higher in industry-sponsored versus non-industry sponsored trials (31.7%; 95% CI, 27.2-36.6 versus 15.5%; 95% CI, 10.0-23.2; P=0.0004) and was not associated with trial sample size (P=0.52) or study design (multicenter versus monocenter: P=0.22). After exclusion of trials conducted at Veteran Affairs centers, women representation was 24.4% (95% CI, 21.1-28.0; range, 10.4%-57.9%), with no significant changes during the study period. Conclusions The proportion of women in cardiac surgery trials is low and likely inadequate to provide meaningful estimates of the treatment effect.


A direct electron transfer formaldehyde dehydrogenase biosensor for the determination of formaldehyde in river water.
In this work, we report the construction of a direct electron transfer (DET) biosensor based on NAD-dependent formaldehyde dehydrogenase from Pseudomonas sp. (FDH) immobilized on the gold nanoparticle-modified gold electrode. To the best of our knowledge, a DET for FDH was achieved for the first time - the oxidation of formaldehyde started at a low electrode potential of -190 mV vs. Ag/AgCl and reached a maximum current density of 1100 nA cm-2 at 200 mV vs. Ag/AgCl. Also, the designed electrode was insensitive to substrate inhibition (in comparison to the free enzyme) and operated in solutions with formaldehyde concentrations up to 10 mM. The electrode was used and characterized as a mediatorless biosensor for the detection of formaldehyde. The biosensor demonstrated a limit of detection (0.05 mM), linear range from 0.25 to 2.0 mM, the sensitivity of 178.9 nA mM cm-2, high stability and selectivity. The biosensor has been successfully tested for the determination of added formaldehyde concentration in river water samples, thus the developed electrode could be applied for a fast, inexpensive and simple measurement of formaldehyde in various media.


Stimulation of an intracranial trigeminally-innervated structure selectively increases cerebral blood flow.
The cranial circulation, both extracerebral and cerebral, is innervated by fibers from the trigeminal nerve. This system is known as the trigeminovascular system. The large venous sinuses and dura mater are pain-sensitive and are innervated primarily by branches of the ophthalmic division of the trigeminal nerve. Studies were conducted in the alpha-chloralose anaesthetised cat to examine bulk carotid and cerebral blood flow responses to electrical stimulation of the trigeminal ganglion and superior sagittal sinus. Bulk carotid blood flow was measured using an ultrasonic flow probe and meter applied to the common carotid artery while cerebral blood flow was measured using laser Doppler flowmetry. Vascular resistance was calculated using simultaneously collected blood pressure data. Stimulation of the trigeminal ganglion resulted in a frequency-dependent reduction in both bulk carotid and cerebral vascular resistance. The mean maximal reduction was 39 +/- 5% at 20/s for the carotid bed and 37 +/- 6% at 20/s for the cerebral circulation. Stimulation of the superior sagittal sinus resulted in a frequency-dependent reduction in resistance that involved the cerebral circulation with little effect on bulk carotid resistance. The mean maximum reduction was 37 +/- 6% at 20/s for the cerebral circulation and 11 +/- 3% at 2/s for bulk carotid resistance. The more focused effects of superior sagittal sinus suggest a highly organised somatotopic arrangement of the trigeminal innervation of the cranial circulation. Such a physiological schema fits the known anatomy as reflected by the differential peptidergic innervation from the trigeminovascular system to cranial vessels and may be important in understanding the pathophysiology of migraine, cluster headache and subarachnoid haemorrhage.


Oxaliplatin rechallenge in metastatic colorectal cancer patients with clinically significant oxaliplatin-induced peripheral neurotoxicity.
We investigated whether rechallenge with oxaliplatin (OXA) can worsen the pre-existing oxaliplatin-induced peripheral neurotoxicity (OXAIPN) in metastatic colorectal cancer (mCRC) patients. Patients previously treated with OXA, having clinically significant grade 1 or 2 OXAIPN were assessed, after receiving rechallenge with OXA, using the clinical version of the Total Neuropathy Score (TNSc). Peripheral neuropathy was assessed at the end of first OXA exposure and at completion of OXA rechallenge. The first line OXA-based chemotherapy was completed at least 9 months earlier (OXA-free interval). We studied 25 mCRC patients, 14 males and 11 females, with a median age of 63 (35-77) years. After their first exposure to OXA-based chemotherapy, 9 (36%) patients developed grade 1 OXAIPN and 16 patients grade 2 (64%) neurotoxicity. OXA reintroduction with a median of 10 (8-14) cycles led to grade 1 OXAIPN in two patients (8%), grade 2 in 19 patients (76%), and grade 3 neuropathy in 4 (16%) patients Worsening of pre-existing OXAIPN was documented in seven (28%) patients and was significantly associated with higher OXA delivered cumulative dose (P < .001). Median TNSc scores following treatment (10; range 4-18) were significantly increased (P < .001), when compared to the scores recorded at the end of first line treatment (8; range 2-12). Rechallenging OXA appears to relatively worsen the severity of existing OXAIPN. However, the majority of rechallenged patients developed a clinically significant (grade 2) OXAIPN, rather than treatment-emergent grade 3. As such, OXA rechallenge might be a feasible option in patients previously having OXAIPN.


Astaxanthin exerts anti-inflammatory and antioxidant effects in macrophages in NRF2-dependent and independent manners.
Although anti-inflammatory effects of astaxanthin (ASTX) have been suggested, the underlying mechanisms have not been fully understood. Particularly, the modulatory action of ASTX in the interplay between nuclear factor E2-related factor 2 (NRF2) and nuclear factor κB (NFκB) to exert its anti-inflammatory effect in macrophages is unknown. The effect of ASTX on mRNA and protein expression of pro-inflammatory and antioxidant genes and/or cellular reactive oxygen species (ROS) accumulation were determined in RAW 264.7 macrophages, bone marrow-derived macrophages (BMDM) from wild-type (WT) and Nrf2-deficient mice, and/or splenocytes and peritoneal macrophages of obese mice fed ASTX. The effect of ASTX on M1 and M2 macrophage polarization was evaluated in BMDM. ASTX significantly decreased LPS-induced mRNA expression of interleukin 6 (Il-6) and Il-1β by inhibiting nuclear translocation of NFκB p65; and attenuated LPS-induced ROS with an increase in NRF2 nuclear translocation, concomitantly decreasing NADPH oxidase 2 expression in RAW 264.7 macrophages. In BMDM of WT and Nrf2-deficient mice, ASTX decreased basal and LPS-induced ROS accumulation. The induction of Il-6 mRNA by LPS was repressed by ASTX in both types of BMDM while Il-1β mRNA was decreased only in WT BMDM. Furthermore, ASTX consumption lowered LPS sensitivity of splenocytes in obese mice. ASTX decreased M1 polarization of BMDM while increasing M2 polarization. ASTX exerts its anti-inflammatory effect by inhibiting nuclear translocation of NFκB p65 and by preventing ROS accumulation in NRF2-dependent and -independent mechanisms. Thus, ASTX is an agent with anti-inflammatory and antioxidant properties that may be used for the prevention of inflammatory conditions.


The effectiveness of antimicrobial photodynamic therapy with prodigiosin against reference strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.
Prodigiosin (PG) is a secondary metabolite of bacterial origin that is able to absorb the visible light and plays a role as a photosensitizer in photodynamic therapy (PDT). This in vitro study aimed to investigate the cytotoxicity of PG-mediated PDT against the reference strains of Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and Pseudomonas aeruginosa (P. aeruginosa). The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of PG were determined. Each strain was then allocated into four groups as follows: G1: control (no treatment), G2: PG-treated groups that received different PG concentrations (1000-1.95 μM), G3: laser-treated group (wavelength: 520 nm, radiation dose: 187 J/cm2), and G4: PG-mediated PDT groups that were initially treated with different concentrations of PG and were then exposed to laser irradiation in the same way as the previous group. Finally, the number of colony-forming units per milliliter (CFU/mL) was calculated and analyzed using the SPSS software. PG had both bacteriostatic and bactericidal activities on the tested bacteria, with the maximum antibacterial effect being observed against S. aureus. In all bacterial strains, the maximum number of CFUs was observed in the control group followed by the laser-irradiated and PG-treated groups, but the differences were not statistically significant (p > 0.05). However, the utilization of PG-mediated PDT resulted in a significant decrease in the mean number of CFUs in all the tested bacteria (p < 0.0001). PG-mediated PDT had the potential to kill some bacterial strains in the laboratory. Yet, further studies are warranted to confirm its efficacy and safety to be applied in clinical settings.


Induction of apoptosis of peripheral blood mononuclear cells by antithymocyte globulin (ATG) in aplastic anemia: an in vivo and in vitro study.
Antithymocyte globulin (ATG) is the standard therapy for aplastic anemia (AA) patients who are not eligible for allogeneic bone marrow transplantation (BMT). The exact mechanism of action of ATG is still not known. Profound lymphopenia is observed throughout the treatment period with ATG and appears to contribute to its immunomodulatory effect. One of the possible mechanisms, which could account for ATG-mediated lymphopenia, is by induction of apoptosis of peripheral blood mononuclear cells (PBMCs). However, there is no conclusive evidence to support this mechanism. We investigated whether ATG could induce an in vivo apoptosis in PBMCs of 12 AA patients undergoing ATG therapy by terminal deoxynucleotidyltransferase (TdT)-mediated dUTP nick-end labeling (TUNEL) assay using flow cytometry. A significant increase in the percentage of apoptosis was observed in six patients. The median percentage prior to therapy was 3 percent (range: 1-10 percent), which increased to a peak median value of 27 percent (range 17-66 percent) with therapy. ATG also induced an in vitro apoptosis of normal PBMCs as demonstrated by Annexin V and TUNEL staining using flow cytometry. Induction of apoptosis was dose dependent: 52 percent of the PBMCs exhibited Annexin V positivity after incubation with ATG at a dose of 500 microg/ml for 6 h, and 37 percent of the PBMCs exhibited DNA fragmentation after incubation with ATG at a dose of 1000 microg/ml for 24 h as demonstrated by TUNEL assay. Thus, ATG induces in vivo apoptosis in PBMCs of AA patients undergoing therapy as well as an in vitro apoptosis in normal PBMCs, and apoptosis may be an important mechanism for ATG-induced lymphopenia.


Detecting the release of plastic particles in packaged drinking water under simulated light irradiation using surface-enhanced Raman spectroscopy.
Plastic cups and bottles used for mineral water packaging may release plastic particles during continuous exposure to heat, light, or unfavorable chemical environments during transportation and storage. Surface-enhanced Raman spectroscopy (SERS) can be used to detect and analyze these plastic particles in a highly sensitive and quantitative manner. In this study, we used copper oxide/silver nanoparticles (CuO/Ag NPs) as the SERS substrate to monitor the release of plastic particles in packaged mineral water samples under irradiation as a function of exposure time. The lower detection limit for plastic particles using this CuO/Ag NP SERS system was 1.6 ng/mL. Our results showed that both plastic cups and bottles released particles under irradiation, however, the plastic cup samples degraded much more readily, with the particle concentration increasing considerably from 5.37 ± 0.11 ng/mL to 3751 ± 0.19 ng/ml over the total exposure time period of 240 min. In this study, we have demonstrated that SERS can provide a highly sensitive, rapid, and economical method for detecting plastic particle contamination caused by degradation of the plastic materials used in mineral water packaging.


Cardiopulmonary bypass with cardioplegic arrest activates protein kinase C in the human myocardium.
The protein kinase C (PKC) family consists of 12 isoforms, 6 of which have been found in human myocardium (PKC alpha, beta I/beta II, delta, epsilon, eta, and lambda/iota). These kinases function in regulation of contractility, ion channels, and in cellular protection or damage during ischemia-reperfusion injury. This study investigated the effects of controlled ischemia-reperfusion injury through cardioplegic arrest on PKC activity in patients undergoing cardiac surgery. Myocardium and skeletal muscle were harvested from patients before and after cardiopulmonary bypass and cardioplegic arrest. Total PKC (n=12) was isolated and specifically, the PKC delta (n=8) and PKC epsilon (n=8) isoforms were immunoprecipitated for use in functional kinase assays. Cellular fractions (n=4) were separated by differential ultracentrifugation and analyzed by Western blotting for membrane translocation (an indirect indicator of increased activity). Immunofluorescent staining for PKC delta and PKC epsilon was performed on myocardial sections. An in vitro assay of hypoxic cardioplegic arrest followed by reoxygenation was performed using isolated cardiomyocytes, and apoptosis was assessed. Cardioplegic arrest was associated with a 24.4% +/- 4.6% increase (p < 0.05) in total PKC activity, a 26.7% +/- 4.9% increase (p < 0.05) in PKC delta activity, and a 35.3% +/- 14% increase (p < 0.05) in PKC epsilon activity in myocardium. Cardioplegic arrest induced migration of PKC delta and epsilon to the z-line of the cardiomyocyte. Inhibition of PKC delta in the in vitro studies demonstrated a considerable reduction in apoptotic cells. PKC delta and epsilon have previously been shown to mediate and protect, respectively, from ischemia-reperfusion injury after myocardial ischemia. Demonstration of increases in their activity after cardioplegic arrest provides support for their possible role in myocardial function after cardiac surgery. Isoform-specific modulators may be of potential therapeutic value in treating postoperative myocardial dysfunction.


Gly-345 plays an essential role in Pyrococcus furiosus chaperonin function.
Compared to the group I chaperonins, such as Escherichia coli GroEL, which facilitate protein folding, many aspects of the functional mechanism of archaeal group II chaperonins are unclear. Sequence homology between the chaperonin from Pyrococcus furiosus (PfCPN) and other group II chaperonins, together with the homo-oligomeric nature of PfCPN, suggest that PfCPN may serve as a model to clarify the role of the homologous position Gly-345 in the chaperonin-mediated protein folding. Here, we show that the purified chaperonin mutant in which the conserved residue Gly-345 is replaced by Asp (G345D) displays only about 25% ATP/ADP hydrolysis activities of the wild-type in the presence of Co(2+) and has a reduced capacity to promote folding of denatured malate dehydrogenase in vitro. This may be a reflection that Gly-345 plays an essential role in conformational change and protein refolding by archaeal group II chaperonins.


Paranasal mucoceles in children with cystic fibrosis: Management of a not so rare clinical condition.
Paranasal mucocele (PM) is reported as a complication in children with cystic fibrosis (CF) in up to 4% of patients. The objective of this study was to identify PMs in the personal large series of children with CF and to assess their diagnosis and treatment. Medical records of children with CF and PM who were admitted and treated by means of endoscopic nasal surgery between 2004 and 2020 were retrospectively reviewed. Thirty-four patients were included in the study (mean age 7.7 years). CT scan of sinuses showed a total of 53 PMs. Nasal endoscopic findings suggestive for PM were present in almost 80% of patients. PMs were located in the maxillary, ethmoid, and sphenoid sinuses in 29/34 (85.3%, bilateral in 17 cases), 4/34 (11.8%) and 1/34 (2.9%) patients, respectively. Marsupialization of PMs was performed in all patients using an endoscopic transnasal approach. No complications were observed. Resolution of symptoms and normalization of the endoscopic nasal picture was evident in all patients. After a mean follow-up of 85 months, no recurrences were observed. To the best of our knowledge, this is the largest series of CF patients with PMs. Even if not frequently reported in the literature, PMs should not be considered an uncommon finding in patients affected by CF. Routine nasal endoscopy is mandatory to favor early diagnosis. Endoscopic transnasal marsupialization represents the gold standard of care for patients with CF and PM(s).


Phenotypic and genetic correlations of pork myoglobin content with meat colour and other traits in an eight breed-crossed heterogeneous population.
Meat colour is one of the most important meat quality traits affecting consumption desire. Genetic improvement for meat colour traits is not so easy because pigs can be phenotyped only after slaughter. Besides the parameters from the optical instrument, other indexes that reflect the material basis of meat colour should be measured accurately and used in the genomic analysis. Myoglobin (Mb) is the main chemical component determining meat colour. However, to what extent the Mb content contributes to meat colour, and whether it can be used as a trait for pig breeding to improve meat colour, and the correlations of Mb content with complex porcine traits are largely unknown. To address these questions, we measured the muscle Mb content in 624 pigs from the 7th generation of a specially designed eight breed-crossed pig heterogeneous population, evaluated its phenotypic and genetic correlations with longissimus thoracis colour score at 24 h after slaughter. More than that, we also systematically phenotyped more than 100 traits on these animals to evaluate the potential correlations between muscle Mb content and economically important traits. Our results showed that the average muscle Mb content in the 624 pigs was 1.00 mg/g, ranging from 0.51 to 2.17 mg/g. We found that higher Mb content usually correlated with favourable meat colour, higher marbling score, less moisture content, and less drip loss. Genetic correlation analysis between muscle Mb content and 101 traits measured in this study shows that Mb content is also significantly correlated with 31 traits, including marbling, shear force, firmness, and juiciness. To our knowledge, this is one of the largest studies about the correlations of muscle Mb content with as many as 100 various traits in a large-scale genetically diversified population. Our results showed that the Mb content could be a selection parameter for the genetic improvement of meat colour. The selection for higher Mb content will also benefit marbling, shear force, firmness, and overall liking but might not affect the growth, carcass, and fat deposition traits.


[Sexuality in Forensic Psychiatry. Results of a Qualitative Study on Professionals' Perspectives and Recommendations for Clinical Practice].
Investigation of employees' perspectives on sexuality and sexual health of inpatients in two gender-separated forensic psychiatries in Bavaria. 19 semi-structured interviews were analyzed with qualitative content analysis. The results were discussed with employees and a recommendation for action was developed. Employees describe insufficient and non-systematic consideration of sexuality in forensic institutions. Regulations on permitted and non-permitted behavior either do not exist, are unknown or remain on an implicit level for many employees and patients. The consideration of sexuality and the sexual needs of patients should be comprehensible and transparent. An attached recommendation for dealing with sexuality can help institutions to give more consideration to sexuality in forensic institutions.


Association of mtDNA D-loop polymorphisms with risk of gastric cancer in Chinese population.
The aim of present study was to evaluate the association of common polymorphisms detected in mitochondrial DNA (mtDNA) D-loop region (mononucleotide repetitive D310, single nucleotide polymorphism (SNP) D16521) with susceptibility to gastric cancer (GC) in northwestern Chinese population. A total of 180 GC patients and 218 healthy controls were investigated by using PCR- denaturing high performance liquid chromatography (DHPLC) assay. Genotype and allele distributions and haplotype construction were analyzed in case-control study. We found D310 and D16521 heteroplasmy were significantly different between GC cases and controls (p < 0.05), and D16521 homoplasmy showed association with histological grade of GC (p < 0.05). Haplotype 7C/T, 8C/C and 9C/C had significant association with GC risk implied from analysis of D310 and D16521. Taken together, these findings suggested that mtDNA D-Loop polymorphisms and haplotypes may contribute to genetic susceptibility to GC in Chinese population.


Comparison of Phytochemical Profile and Bioproperties of Methanolic Extracts from Different Parts of Tunisian Rumex roseus.
The genus Rumex (Polygonaceae) is distributed worldwide and the different species belonging to it are used in traditional medicine. The present study aimed at the evaluation of the phytochemical profile and the biochemical properties of methanolic extracts from different parts (roots, stems, and leaves) of Rumex roseus, a wild local Tunisian plant traditionally used as food. The phytochemical analysis on the extracts was performed using standard colorimetric procedures, HPLC-DAD, and HPLC-DAD-ESI-MS; then, several in vitro cell-free assays have been used to estimate their antioxidant/free radical scavenging capability (TAC-PM, DPPH, TEAC, FRAP, ORAC, SOD-like activity, and HOCl-induced albumin degradation). Additionally, anti-inflammatory effect of these extracts was evaluated in an in vitro model of acute intestinal inflammation in differentiated Caco-2 cells. The results showed that the methanolic extracts from stems and, especially, leaves contain substantial amounts of flavones (apigenin and luteolin, together with their derivatives), while the extract from roots is characterized by the presence of tannins and quinic acid derivatives. All the extracts appeared endowed with excellent antioxidant/free radical scavenging properties. In particular, the extract from roots was characterized by a remarkable activity, probably due to its different and peculiar polyphenolic composition. Furthermore, both Rumex roseus roots and stems extracts demonstrated an anti-inflammatory effect in intestinal epithelial cells, reducing TNF-α-induced gene expression of IL-6 and IL-8. In conclusion, R. roseus methanolic extracts have shown to be potential sources of bioactive compounds to be used in the prevention and treatment of pathologies related to oxidative stress and inflammation.


The cochleovestibular nerve identified during auditory brainstem implantation in patients with narrow internal auditory canals: can preoperative evaluation predict cochleovestibular nerve deficiency?
To analyze the value of preoperative diagnostic tools in predicting the status of the cochleovestibular nerve (CVN) in patients with narrow internal auditory canals (IAC). Retrospective case series at a tertiary hospital. Eight profoundly deaf patients with narrow IACs who received auditory brainstem implantation were included in this study. The results of preoperative imaging, electrophysiologic, and auditory tests were correlated with the CVN status identified during auditory brainstem implantation. Temporal bone computed tomography (CT) findings, including the patency of the bony cochlear nerve canal and the diameter of the IAC, were limited in accurately reflecting the status of the CVN. Magnetic resonance imaging (MRI) and preoperative auditory responses to either pure tone or environmental sounds were more accurate markers for detecting the presence of a CVN than CT; however, there were limitations in cases with a very thin CVN or combined severe mental retardation. Absence of promontory or intracochlear electrically evoked auditory brainstem responses were not always indicative of an absent CVN. Visualization on MRI and detection of auditory responses suggested the presence of a CVN in patients with narrow IACs; however, the possibility of the presence of a CVN should be considered even when there is no clear evidence of a CVN on preoperative evaluations. Therefore, physicians should be prudent when determining candidacy for cochlear implantation or auditory brainstem implantation in patients with narrow IACs.


Application of microfluidic technology to pancreatic islet research: first decade of endeavor.
β-cells respond to blood glucose by secreting insulin to maintain glucose homeostasis. Perifusion enables manipulation of biological and chemical cues in elucidating the mechanisms of β-cell physiology. Recently, microfluidic devices made of polydimethylsiloxane and Borofloat glass have been developed as miniaturized perifusion setups and demonstrated distinct advantages over conventional techniques in resolving rapid secretory and metabolic waveforms intrinsic to β-cells. In order to enhance sensing and monitoring capabilities, these devices have been integrated with analytical tools to increase assay throughput. The spatio-temporal resolutions of these analyses have been improved through enhanced flow control, valves and compartmentalization. For the first time, this review provides an overview of current devices used in islet studies and analyzes their strengths and experimental suitability. To realize the potential of microfluidic islet applications, it is essential to bridge the gap in design and application between engineers and biologists through the creation of standardized bioassays and user-friendly interfaces.


Natural language model for automatic identification of Intimate Partner Violence reports from Twitter.
Intimate partner violence (IPV) is a preventable public health problem that affects millions of people worldwide. Approximately one in four women are estimated to be or have been victims of severe violence at some point in their lives, irrespective of age, ethnicity, and economic status. Victims often report IPV experiences on social media, and automatic detection of such reports via machine learning may enable improved surveillance and targeted distribution of support and/or interventions for those in need. However, no artificial intelligence systems for automatic detection currently exists, and we attempted to address this research gap. We collected posts from Twitter using a list of IPV-related keywords, manually reviewed subsets of retrieved posts, and prepared annotation guidelines to categorize tweets into IPV-report or non-IPV-report. We annotated 6,348 tweets in total, with the inter-annotator agreement (IAA) of 0.86 (Cohen's kappa) among 1,834 double-annotated tweets. The class distribution in the annotated dataset was highly imbalanced, with only 668 posts (~11%) labeled as IPV-report. We then developed an effective natural language processing model to identify IPV-reporting tweets automatically. The developed model achieved classification F1-scores of 0.76 for the IPV-report class and 0.97 for the non-IPV-report class. We conducted post-classification analyses to determine the causes of system errors and to ensure that the system did not exhibit biases in its decision making, particularly with respect to race and gender. Our automatic model can be an essential component for a proactive social media-based intervention and support framework, while also aiding population-level surveillance and large-scale cohort studies.


Clinical efficacy and safety of cervical intralymphatic immunotherapy for house dust mite allergic rhinitis: A pilot study.
Previous studies have demonstrated that intralymphatic immunotherapy (ILIT), a less time-consuming alternative to conventional subcutaneous immunotherapy (SCIT), is safe and effective. However, because of the private location of inguinal lymph nodes, inguinal ILIT is relatively inconvenient. We proposed a novel form of ILIT that involves 3 injections of allergen into cervical lymph nodes. The aim of this study is to determine the clinical efficacy and safety of cervical ILIT on house dust mite induced allergic rhinitis (AR) in adults. In this study, we performed a prospective cohort study to determine the clinical efficacy and safety of cervical ILIT on house dust mite induced AR in adults, by comparing the symptom scores, quality-of-life scores (QOLS) and drug scores (use of rescue medication) before and after treatment. Meanwhile, side events were also recorded. Cervical ILIT elicited no moderate-severe adverse events. Patients receiving cervical ILIT experienced a significant improvement in nasal symptoms, eye symptoms and quality of life, as compared to baseline (P all <0.001). A reduction in the use of rescue medication was also demonstrated (P < 0.001). In this first-in-human clinical study, cervical ILIT was demonstrated safe and induced allergen tolerance after 3 injections.


The periaqueductal gray: a prerequisite for ACTH-induced excessive grooming.
The periaqueductal gray is known to be involved in the expression of a variety of behaviours such as aggression, beta-endorphin-induced immobility and peptide-induced excessive grooming. In order to establish whether the periaqueductal gray (PAG) is indispensible for peptide-induced excessive grooming, lesions were placed in the dorsal part of this structure. Subsequently, the grooming-inducing abilities of adrenocorticotropin (ACTH), beta-endorphin and bombesin were tested. The lesioned animals did not display excessive grooming after intracerebroventricular injection of ACTH. beta-Endorphin administration into the lesioned animals resulted in an extreme display of immobility. Local injection of bombesin into the PAG resulted in reduced scratching behaviour followed by immobility. It was hypothesized that excessive grooming (elicited by ACTH) may be mediated through a non-opioid primary target site-situated in the lesioned region of the PAG-while excessive scratching and immobility (elicited by bombesin or beta-endorphin, respectively) may be mediated through an opioid primary target site (situated in the remaining part of the PAG). Furthermore, the analysis of social behaviour of lesioned animals revealed that these animals reacted towards an unfamiliar partner predominantly with freezing behaviour. The increase of beta-endorphin-induced immobility and socially induced freezing (which is morphologically very similar to beta-endorphin-induced immobility) in lesioned animals supports the hypothesis that the release of opioid peptides such as beta-endorphin in the PAG plays a role in the regulation of social behaviour.


A linchpin approach to unsaturated fatty acids: 11,12-epoxyeicosatrienoic acid and 11S,12S-dihydroxyeicosatrienoic acid ethyl esters.
[Chemical reaction: See text] A "linchpin" coupling strategy is described for the construction of long-chain fatty acid metabolites. This strategy led to a short synthesis of the ethyl esters of both 11,12-epoxyeicosatrienoic acid (EET) and 11S,12S-dihydroxyeicosatrienoic acid (DHET).


Population ecology and the management of whale watching operations on a data-deficient dolphin population.
Whale watching is a popular commercial activity, producing socio-ecological benefits but also potential long-term effects on the targeted cetacean population. This industry is currently developing in data-deficient contexts in a largely unregulated fashion. Management schemes should adopt precaution and be informed by the relevant literature, but would be more effective if the assessment of the target population vulnerability, biological impacts, and management implications was drawn from site-specific data.This paper focuses on a reef-associated, data-deficient population of spinner dolphins in the Egyptian Red Sea. In Satayah Reef, new information on population size and dynamic parameters were documented using visual observation and photo-identification-based capture-recapture methods (Cormack-Jolly-Seber time-since-marking model).Dolphins occurred on 98% of the survey days. Average school size was 66 individuals (±42.1 SE), with most groups including calves. The population was equally divided into recurrent and transient individuals. An "emigration + mortality" model best described residence at the site. Five recurrent males (5% of the Satayah population) provided connectivity between this and the geographically close population of Samadai Reef.Average annual survival probability was 0.83 (±0.06 SE) in the year following first capture and 0.99 (±0.06 SE) for recurrent individuals. Mean yearly population sizes ranged 143-207 individuals.The study had the power to detect a 30% decline in the population, but not the rate of change in abundance estimated from the data (r = 0.018 ± 0.04), which would have required a 3- to 5-times longer study. Synthesis and application: These findings advance the assessment of the Satayah population's intrinsic vulnerability and have three major management applications: (a) the delineation of management units; (b) the identification of key indicators for future impact monitoring and assessment; and (c) realistic estimates of the statistical power for trend detection. Based on our results, we recommend supporting future research, devising site-specific time-area closure plans, and integrating them in a regional scheme. Approaches employed in this case study can inform the management of whale watching industries targeting other data-deficient populations.


Mid-term clinical and radiographic outcomes of porous tantalum modular acetabular components for hip dysplasia.
It is still challenging to perform successful cementless cup fixation during total hip arthroplasty for hip dysplasia. In this multicenter study we evaluated the clinical results of porous tantalum modular acetabular cups (TM cups) in 45 dysplastic hips with a mean follow-up period of 9.8 years. The mean Japanese Orthopaedic Association hip score improved from 48.2 preoperatively to 92.1 at the most recent follow-up. All of the cups were radiographically stable with no evidence of progressive radiolucencies or osteolysis regardless of bone grafting. Sixteen hips with bone grafts showed the integration of grafted bone without any radiolucencies. There were no revisions of TM cups. The use of TM cups for dysplastic hips provided satisfactory 10-year clinical and radiographic results.


Correlation of serum delta-like ligand-4 level with the severity of diabetic retinopathy.
Diabetic retinopathy (DR) is one of the most serious microvascular complications of type 2 diabetes mellitus (T2DM). Delta-like ligand-4 (DLL4) maintains the normal physiological microenvironment of the retina. However, the relationship between the level of DLL4 and the severity of DR remains unclear. We retrospectively analyzed serum DLL4 levels and other laboratory and clinical data in 94 T2DM patients (35 patients without DR [NDR], 32 with non-proliferative DR [NPDR], 27 with proliferative DR [PDR]), and 30 healthy controls. The serum DLL4 level was significantly greater in the NDR group (43.38 ± 16.23 pg/mL), NPDR group (56.57 ± 25.89 pg/mL), and PDR group (74.97 ± 25.28 pg/mL) than in the healthy controls (29.9 ± 8.92 pg/mL; all p < 0.05). Among T2DM patients, the level of DLL4 increased as the severity of DR increased (p < 0.05). Logistic regression analysis demonstrated that DR was positively associated with DLL4, glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), and duration of T2DM (all p < 0.05). Consistently, receiver operating characteristic (ROC) curve analysis also indicated that DLL4 was a potential candidate biomarker for identifying the severity of DR. T2DM patients, especially those with DR, have increased serum levels of DLL4. DLL4 may be used as a biomarker and an independent risk factor for DR, and targeting DLL4 may be a potential therapy in patients with DR.


Community Legal Systems: Targeting PrEP and HIV Education to Decrease Risk of HIV Transmission.
The southern U.S. has both high HIV and incarceration rates in comparison to its population. As in the rest of the country, HIV prevention is based on education, behavior change, and biomedical efforts, such as pre-exposure prophylaxis (PrEP). This study examined the implementation of an educational intervention and supportive services to obtain PrEP in a population of individuals (N = 218) involved in an Adult Drug Court (ADC) or on probation or parole (P-P). Nearly all ADC and P-P participants self-reported risk behaviors linked to HIV acquisition. Results supported the acceptance and usefulness of the intervention as rated by participants. Participants showed increased knowledge of HIV risks and testing post-education. In multivariate analysis, predictors of interest in using PrEP included low stigma beliefs, specifically their level of prejudice views, high depressive symptoms, and white race. The intervention shows promise. Given the high risk documented for ADC and P-P individuals, HIV prevention is a critical component for increased protective behaviors.


Glycosylation of eukaryotic peptide chain initiation factor 2 (eIF-2)-associated 67-kDa polypeptide (p67) and its possible role in the inhibition of eIF-2 kinase-catalyzed phosphorylation of the eIF-2 alpha-subunit.
We have reported previously that a 67-kDa polypeptide (p67) present in reticulocyte lysates protects the alpha-subunit of reticulocyte eukaryotic peptide chain initiation factor 2 (eIF-2) from phosphorylation by an eIF-2 kinase, heme-regulated protein synthesis inhibitor (Datta, B., Chakrabarti, D., Roy, A.L., and Gupta, N. K. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 3324-3328). We now present evidence that this p67 contains multiple O-linked N-acetylglucosamine (GlcNAc) residues, and these glycosyl residues may be required for p67 activity to protect the eIF-2 alpha-subunit from eIF-2 kinase phosphorylation. Our results are as follows. 1) p67 binds specifically to wheat germ agglutinin, and such binding is completely inhibited in the presence of 0.2 M GlcNAc. 2) The binding of p67 to wheat germ agglutinin leads to complete loss of p67 activity to protect the eIF-2 alpha-subunit from eIF-2 kinase phosphorylation. 3) p67 accepts 10-12 [3H]galactose molecules from UDP-[3H]galactose in the presence of galactosyltransferase. This radioactivity is resistant to endo-beta-N-acetylglucosamine F (+ peptide:N-glycosidase F) treatment but is completely lost when the 3H-labeled p67 is treated with sodium borohydride in mild alkali (beta-elimination reaction). These results suggest that p67 contains terminal GlcNAc moieties O-linked to the protein. 4) Upon hexosaminidase treatment, p67 reaction product migrated as a lower molecular mass (Mr approximately 65 kDa) protein in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. 5) A monoclonal antibody (D1) against p67 has been isolated. D1 apparently recognizes a specific GlcNAc-containing peptide epitope in p67 and does not react with hexosaminidase-treated p67. These results suggest that p67 activity in the cell may also be regulated post-transcriptionally by glycosylation of p67 protein.


A novel role of the sympatho-adrenergic system in regulating valve calcification.
Aortic valve calcification is a progressive process resembling ossification. Recent evidence indicates that the sympathetic nervous system plays an important role in regulating bone deposition and resorption through the beta2-adrenergic receptors (beta2-ARs). The aim of this study is to determine the level and pattern of expression of beta2-ARs in human valve interstitial cells (ICs) and assess their influence on differentiation of the cells into an osteoblast-like phenotype. Immunohistochemical analysis demonstrated a high expression of beta2-ARs, beta1-ARs, beta3-AR,s and receptor activator of nuclear factor-kappaB (RANK) in calcified aortic valves. The expression of beta2-ARs and beta1-ARs mRNA was assessed by real-time TaqMan PCR in cultures of human aortic valve ICs. Human valve ICs treated with the selective beta2-AR agonist, salmeterol, in the presence of osteogenic medium showed a significant 5-fold decrease in the alkaline phosphatase (ALP) activity in comparison to cells treated with osteogenic medium only (P<0.05). Immunocytochemical staining of the valve ICs showed a concomitant reduction in osteocalcin expression. In addition, other beta2-AR agonists caused a reduction in the protein expression of bone markers including ALP, Cbfa-1, and periostin. Human valve ICs treated with norepinephrine, in the presence of osteogenic medium, did not show a significant reduction in the ALP activity. These findings suggest an important role of the beta2-ARs in regulating valve calcification and may identify potential therapeutic targets.


Germline Testing of Patients With Non-small Cell Lung Cancers Demonstrating Incidentally Uncovered BRCA2 Apparent Pathogenic Germline Variants.
Tumor next generation sequencing (NGS) is used to interrogate nearly every non-small cell lung cancer (NSCLC) for the purpose of identifying actionable genetic alterations. Occasionally, tumor NGS also uncovers "incidental" apparent pathogenic germline variants (PGVs), with BRCA2 being among the most common of those. If germline testing confirms a BRCA2 PGV in a patient with NSCLC, therapies targeting that BRCA2 PGV might be considered, if the patient has exhausted standard NSCLC therapeutic options. Surveillance and preventive therapies for BRCA2-related cancers would be recommended or considered for that patient, as well as for family members found to carry that same BRCA2 PGV. Here, I offer my perspective related to the evidence supporting and against germline testing in patients with NSCLCs that show incidental BRCA2 apparent PGVs. I use an example to underscore how important it is to explain to patients, before tumor NGS, the possibility of uncovering an incidental PGV. I also review the myriad uncertainties related to identifying a BRCA2 PGV, when the sole indication for germline testing was the uncovering of the incidental BRCA2 apparent PGV.


The syndrome of renal tubular acidosis and nerve deafness. Discordant manifestations in dizygotic twin brothers.
The syndrome of renal tubular acidosis (RTA) and nerve deafness is a distinct nosological entity that is inherited as an autosomal recessive trait. We studied a pair of dizygotic twin brothers both with nerve deafness but only one with RTA. Distal RTA was diagnosed in twin A because of inappropriately high urinary pH (6.9) and low net acid excretion (40.0 muEq/min per 1.73 m2) in the presence of hyperchloraemic metablic acidosis, and fractional bicarbonate excretion of 1.6% at a normal serum bicarbonate concentration. The urine minus blood PCO2 differences (U-B PCO2) during a neutral sodium phosphate load and in alkaline urine induced by bicarbonate supplementation were: 11 and 0 mm Hg, respectively. Twin A developed nephrocalcinosis and, after a 9.5-year follow-up period, was 5.3 cm taller than his brother. Twin B remained asymptomatic. Periodic determinations of blood pH and serum bicarbonate were normal and urine pH decreased to 4.6 in the face of ammonium chloride-induced metabolic acidosis. The U-B PCO2 assessed in alkaline urine was 33.5 mm Hg. Audiograms demonstrated bilateral nerve deafness in both brothers. The presence of deafness without RTA has not been previously reported in this syndrome. This report also shows that a primary distal acidification defect is responsible for the RTA observed in this syndrome.


Neonatal lupus erythematosus: new serologic findings.
A child with neonatal lupus was evaluated and found to possess serum anti Ro(SSA) antibodies. The cutaneous lesions and anti Ro(SSA) antibodies disappeared during the next 5 mo. The infant's mother was asymptomatic but possessed anti Ro(SSA) and anti La(SSB) antibodies.


Neurologic complications after irradiation of the cervical spinal cord for malignant tumour of the head and neck.
A total of 165 patients with tumours of the head and neck were irradiated via fields including the entire cervical portion of the spinal cord. Eight patients (4.8 per cent) developed mild reversible signs of radiation myelitis. Only one of these cases was found among the 44 patients who received a dose to the spinal cord of over 5 000 rad via fields of less than 16 cm in length; 7 cases were patients with Hodgkin's disease who were given up to 3 700 rad via mantle fields. A survey of previous reports on transverse spinal lesions provoked by irradiation revealed a possibility of overdosage in several cases, and dose tolerance limits mentioned previously should accordingly be applied with caution.


Tenfold population increase in Western Europe at the Neandertal-to-modern human transition.
European Neandertals were replaced by modern human populations from Africa ~40,000 years ago. Archaeological evidence from the best-documented region of Europe shows that during this replacement human populations increased by one order of magnitude, suggesting that numerical supremacy alone may have been a critical factor in facilitating this replacement.


Pulmonary arteriovenous fistula: mechanical ventilation and hypoxemia.
Pulmonary arteriovenous malformation (PAVM) is an uncommon congenital anomaly. As PAVM is a direct communication between branches of the pulmonary artery and vein, major disturbances in gas exchange can result. We present a patient with an unsuspected PAVM who came to our institution for drainage of a brain abscess. Arterial blood gas analysis during and after surgery demonstrated a large alveolar-arterial gradient for oxygen in the absence of any obvious pulmonary pathology while the patient was receiving positive pressure ventilation (PPV). Oxygenation improved considerably upon resumption of spontaneous ventilation. A diagnosis of PAVM was made subsequently. We conclude that positive pressure ventilation can worsen right to left shunting in patients with PAVM.


Genome analysis of Spiroplasma citri strains from different host plants and its leafhopper vectors.
Spiroplasma citri comprises a bacterial complex that cause diseases in citrus, horseradish, carrot, sesame, and also infects a wide array of ornamental and weed species. S. citri is transmitted in a persistent propagative manner by the beet leafhopper, Neoaliturus tenellus in North America and Circulifer haematoceps in the Mediterranean region. Leafhopper transmission and the pathogen's wide host range serve as drivers of genetic diversity. This diversity was examined in silico by comparing the genome sequences of seven S. citri strains from the United States (BR12, CC-2, C5, C189, LB 319, BLH-13, and BLH-MB) collected from different hosts and times with other publicly available spiroplasmas. Phylogenetic analysis using 16S rRNA sequences from 39 spiroplasmas obtained from NCBI database showed that S. citri strains, along with S. kunkelii and S. phoeniceum, two other plant pathogenic spiroplasmas, formed a monophyletic group. To refine genetic relationships among S. citri strains, phylogenetic analyses with 863 core orthologous sequences were performed. Strains that clustered together were: CC-2 and C5; C189 and R8-A2; BR12, BLH-MB, BLH-13 and LB 319. Strain GII3-3X remained in a separate branch. Sequence rearrangements were observed among S. citri strains, predominantly in the center of the chromosome. One to nine plasmids were identified in the seven S. citri strains analyzed in this study. Plasmids were most abundant in strains isolated from the beet leafhopper, followed by strains from carrot, Chinese cabbage, horseradish, and citrus, respectively. All these S. citri strains contained one plasmid with high similarity to plasmid pSci6 from S. citri strain GII3-3X which is known to confer insect transmissibility. Additionally, 17 to 25 prophage-like elements were identified in these genomes, which may promote rearrangements and contribute to repetitive regions. The genome of seven S. citri strains were found to contain a single circularized chromosome, ranging from 1.58 Mbp to 1.74 Mbp and 1597-2232 protein-coding genes. These strains possessed a plasmid similar to pSci6 from the GII3-3X strain associated with leafhopper transmission. Prophage sequences found in the S. citri genomes may contribute to the extension of its host range. These findings increase our understanding of S. citri genetic diversity.


Small angle x-ray scattering from the inner and outer membranes from Escherichia coli.
Small angle X-ray data from purified forms of inner or cytoplasmic and outer membranes from Escherichia coli have been obtained and appear to be qualitatively similar. Transitory changes are apparent in the circularly averaged X-ray profiles from inner membranes. Such results could be due to the loss or denaturation of peripheral membrane proteins. Some partially dried forms of outer membrane are partly ordered and produce diffraction patterns which support an underlying bilayer structure. An extra light membrane fraction which results from membrane preparations utilizing a French pressure cell for spheroplast disruption has been characterized and shown to be similar to inner membrane. The purified membranes produce small angle X-ray diffraction patterns which are much different from those of lipid dispersions and the differences are attributable to the high protein content of the intact membranes. While the small angle X-ray region may be useful for characterizing the membrane preparations, the paucity of detail in the diffraction pattern suggest that it will be of little value in describing the complex underlying membrane structure.


Genome-scale metabolic modeling elucidates the role of proliferative adaptation in causing the Warburg effect.
The Warburg effect--a classical hallmark of cancer metabolism--is a counter-intuitive phenomenon in which rapidly proliferating cancer cells resort to inefficient ATP production via glycolysis leading to lactate secretion, instead of relying primarily on more efficient energy production through mitochondrial oxidative phosphorylation, as most normal cells do. The causes for the Warburg effect have remained a subject of considerable controversy since its discovery over 80 years ago, with several competing hypotheses. Here, utilizing a genome-scale human metabolic network model accounting for stoichiometric and enzyme solvent capacity considerations, we show that the Warburg effect is a direct consequence of the metabolic adaptation of cancer cells to increase biomass production rate. The analysis is shown to accurately capture a three phase metabolic behavior that is observed experimentally during oncogenic progression, as well as a prominent characteristic of cancer cells involving their preference for glutamine uptake over other amino acids.


Exposure to Campus Messages about Dating and Sexual Violence: A Latent Class Analysis.
This study investigates college students' exposure to messages about campus dating and sexual violence (DSV) to discover classes of students based on the message source. Latent class analysis was performed with data assessing 5,284 students' exposure to 16 different sources of information regarding DSV, from having a professor discuss these topics to participating in related campus events. Several variables were included in the analysis to understand students' class membership in relation to pertinent student demographic factors. The best model indicated that there are five classes of students based on their exposure to messages, with some subgroups of students having high exposure to various sources of messages about DSV while others have low exposure. Still other subgroups are primarily exposed to messages through nonactive or noninstitutional sources of information. Subgroups of students, based on their exposure to DSV messaging, also differ regarding demographic makeup. The implications from these results include the need to tailor DSV programming on campus to subgroups of students based on their varying baseline levels of message exposure. As students are exposed to messaging through differing sources, including passive and noninstitutional, institutions can use this information when designing outreach efforts to better fit with the needs of various subgroups of students.


Nissen and Toupet fundoplications effectively inhibit gastroesophageal reflux irrespective of natural anatomy and function.
The physiology of Nissen fundoplication (NF) and Toupet fundoplication (TF) is controversial. The aim of this study was to determine the contribution of elevated intragastric pressure to the antireflux mechanism after surgically created fundoplication in explanted porcine stomachs. The stomachs and 6-8 cm of distal esophagus were removed from 15 pigs and placed in anatomic position. Five NF, 2 cm in length with three interrupted sutures, were performed, taking full-thickness bites of stomach and partial-thickness bites of esophagus around a 60 French dilator. Five 270 degree TF 2 cm in length with six interrupted sutures were performed taking full-thickness bites of stomach and partial-thickness bites of esophagus around a 60 French dilator. Each stomach served as its own control. The pylorus was tied off and the stomach was inflated with Ringer's lactate while the pressure was monitored. Before NF, reflux could be easily induced with a mean intragastric pressure of 5.5 +/- 3.7 mmHg. After NF reflux could not be induced but the sutures pulled out of the stomach at a mean pressure of 36.8 +/- 11.7 mmHg (p<0.01 vs control). Before TF, reflux could easily be induced with a mean intragastric pressure of 3.0 +/- 3.0 mmHg. After TF, reflux could not be induced and the sutures pulled out of the esophagus or stomach with a mean pressure of 30.8 +/- 9.0 mmHg (p<0.01 vs control). Porcine stomachs in vivo are resistant to reflux, but when explanted they reflux easily. NF and TF are so effective at interrupting reflux that the sutures tear out instead of allowing reflux. While not yet statistically significant, it appears that sutures tear out of the esophagus (TF) more readily than they tear out of the stomach (NF). TF and NF prevent reflux in the absence of anatomic or functional components of the lower esophageal sphincter.


Mapping the multi-step mechanism of a photoredox catalyzed atom-transfer radical polymerization reaction by direct observation of the reactive intermediates.
The rapid development of new applications of photoredox catalysis has so far outpaced the mechanistic studies important for rational design of new classes of catalysts. Here, we report the use of ultrafast transient absorption spectroscopic methods to reveal both mechanistic and kinetic details of multiple sequential steps involved in an organocatalyzed atom transfer radical polymerization reaction. The polymerization system studied involves a N,N-diaryl dihydrophenazine photocatalyst, a radical initiator (methyl 2-bromopropionate) and a monomer (isoprene). Time-resolved spectroscopic measurements spanning sub-picosecond to microseconds (i.e., almost 8 orders of magnitude of time) track the formation and loss of key reactive intermediates. These measurements identify both the excited state of the photocatalyst responsible for electron transfer and the radical intermediates participating in propagation reactions, as well as quantifying their lifetimes. The outcomes connect the properties of N,N-diaryl dihydrophenazine organic photocatalysts with the rates of sequential steps in the catalytic cycle.


Adenosine deaminase and adenosine kinase in rat hepatomas and kidney tumours.
Adenosine deaminase and adenosine kinase have been measured in rat liver, 12 transplantable hepatomas, regenerating, foetal and neonatal liver, adult and neonatal rat kidney and 2 transplantable kidney tumours. Adenosine, deaminase activity, relative to the normal liver value, was elevated 2-4 fold in hepatomas of rapid growth rate, was in the normal range in more slowly growing hepatomas and in regernerating liver, and was low in foetal and neonatal liver. Adenosine kinase activity was decreased, relative to rat liver values, in all the hepatomas; activity of this enzyme gave a negative correlation with tumour growth rate. Kinetic properties of the two enzymes were examined in partially purified preparations. Adenosine deaminases from both liver and rapidly growing hepatoma 3924A were subject to weak product inhibition by inosine. Adenosine kinase from liver and hepatoma 3924A was inhibited by the reaction products ADP and AMP, and the enzyme was also subject to excess substrate inhibition by concentrations of ATP in excess of 1 mM. In rat hepatoma cell lines growing in culture, the toxicity of adenosine correlated inversely with the ratio of adenosine deaminase activity to adenosine kinase activity. Chromatographic measurements showed that hepatoma cells incorporated less extracellular adenosine into their adenine nucleotide pools than did isolated liver cells. These results indicate that increased adenosine deaminase activity and decreased adenosine kinase activity may confer a selective advantage upon the cancer cell.


Community-Associated Methicillin-Resistant Staphylococcus aureus Infections in the Athlete.
Community-associated methicillin-resistant Staphlococcus aureus (CA-MRSA) has become of increasing concern in the athletic setting. Appropriate recognition, treatment, and prevention measures are all paramount to protect individual athletes and teamwide outbreaks. Relevant electronic databases (Medline or PubMed) through 2008 were searched. Articles and studies relevant to this topic were reviewed for pertinent clinical information. Clinical review. CA-MRSA is an increasing problem both in the community at large and in the athletic population. Early infections based on methicillin-resistant Staphlococcus aureus are often misidentified, leading to delay in appropriate treatment. A high level of suspicion, prompt recognition, and appropriate treatment can minimize morbidity associated with CA-MRSA. Careful selection of antibiotics in suspected cases is important, with more severe infections requiring hospitalization and intravenous antibiotics. Eradication of bacteria in colonized patients has not yet proven to be effective. Prevention of infections is multifaceted, and it includes education, proper personal hygiene, routine cleaning of equipment, and proper wound care.


Platelet alpha-adrenergic binding and biochemical responsiveness in depressed patients and controls.
In a study of platelet alpha 2-adrenergic receptor number in depressed patients, binding of tritiated dihydroergocriptine (3H-DHE) to platelet membranes was measured in 23 depressed patients and 51 controls. To examine the functional responsiveness of the platelet alpha 2-adrenergic receptor, basal cyclic adenosine 3',5'-monophosphate (cAMP) production, prostaglandin E1 (PGE1) stimulation of cAMP production, and norepinephrine (NE) inhibition of PGE1-stimulated cAMP production were measured in 23 depressed patients and 53 control subjects. Finally, plasma NE concentration was measured in 20 patients to explore the possible relationship between this endogenous agonist and platelet alpha 2-adrenergic receptor function. 3H-DHE binding to platelet membranes was significantly increased in the depressed patients compared to control subjects. Both the PGE1-stimulated cAMP response and the inhibition of this response by NE were significantly reduced in the depressed patients compared to the control subjects. Thus, an apparent dissociation between alpha 2-adrenergic receptor binding and functional responsiveness was observed. Plasma NE concentrations were neither significantly different in the depressed patients than in the controls nor correlated with any of the measures of cAMP responsiveness. They were, however, significantly negatively correlated with 3H-DHE binding in depressed patients with adequate PGE1 stimulation of cAMP production.


Elucidation of the RNA target of linezolid by using a linezolid-neomycin B heteroconjugate and genomic SELEX.
A covalently modified heteroconjugate between linezolid and neomycin B leads to an enhanced and more specific binding affinity to hairpin RNA targets in comparison to neomycin B itself. This heteroconjugate was used as a lure to select linezolid-specific hairpin RNA from an Escherichia coli genome RNA. The selected RNA obtained after eight cycles not only has typical stem-loop structures but also includes known sequences of the linezolid binding site. The results of RNA footprinting show that the binding site of the heteroconjugate encompasses both stem and loop regions, suggesting that the possible binding site for linezolid is in the terminal loop. In addition, findings from application of a surface plasmon resonance assay clearly demonstrate that linezolid binds to selected hairpin RNA in a highly specific manner with a low millimolar affinity. The results suggest that heteroconjugates might represent a generally useful approach in studies aimed at uncovering loop-specific RNA binding ligands that would be otherwise difficult to identify owing to their weak affinities.


Cortical and subcortical contributions to state- and strength-based perceptual judgments.
Perceptual judgments can be made on the basis of different kinds of information: state-based access to specific details that differentiate two similar images, or strength-based assessments of relational match/mismatch. We explored state- and strength-based perception in eleven right-hemisphere stroke patients, and examined lesion overlap images to gain insight into the neural underpinnings of these different kinds of perceptual judgments. Patients and healthy controls were presented with pairs of scenes that were either identical or differed in that one scene was slightly expanded or contracted relative to the other. Same/different confidence judgments were used to plot receiver-operating characteristics and estimate the contributions of state- and strength-based perception. The patient group showed a significant and selective impairment of strength-based, but not state-based, perception. This finding was not an artifact of reduced levels of overall performance, because matching perceptual discriminability levels between controls and patients revealed a double dissociation, with higher state-based, and lower strength-based, perception in patients vs. We then conducted exploratory follow-up analyses on the patient group, based on the observation of substantial individual differences in state-based perception - differences that were masked in analyses based on the group mean. Patients who were relatively spared in state-based perception (but impaired in strength-based perception) had damage that was primarily in temporo-parietal cortical regions. Patients who were relatively impaired in both state- and strength-based perception had overlapping damage in the thalamus, putamen, and adjacent white matter. These patient groups were not different in any other measure, e.g., presence of spatial neglect symptoms, age, education, lesion volume, or time since stroke. These findings shed light on the different roles of right hemisphere regions in high-level perception, suggesting that the thalamus and basal ganglia play a critical role in state- and strength-based perception, whereas temporo-parietal cortical regions are important for intact strength-based perception.


Evolution of Staphylococcus aureus under vancomycin selective pressure: the role of the small-colony variant phenotype.
Staphylococcus aureus small-colony variants (SCVs) often persist despite antibiotic therapy. Against a 10(8)-CFU/ml methicillin-resistant S. aureus (MRSA) (strain COL) population of which 0%, 1%, 10%, 50%, or 100% was an isogenic hemB knockout (Ia48) subpopulation displaying the SCV phenotype, vancomycin achieved maximal reductions of 4.99, 5.39, 4.50, 3.28, and 1.66 log10 CFU/ml over 48 h. Vancomycin at ≥16 mg/liter shifted a population from 50% SCV cells at 0 h to 100% SCV cells at 48 h, which was well characterized by a Hill-type model (R2>0.90).


Long-term survival in giant cell arteritis including temporal arteritis and polymyalgia rheumatica. A follow-up study of 90 patients treated with corticosteroids.
Ninety patients with giant cell arteritis (GCA) were followed for 9-16 years after diagnosis. Corticosteroids were given to all but one patient. Forty-two patients died during the observation period (27 women and 15 men). The survival was compared with that in the general population and found not to be reduced among the GCA patients. In fact, we found a lower mortality than expected after five years from diagnosis (p less than 0.05). We did not see any increase in deaths due to vascular or malignant diseases in our patients.


Glomerular deposition of complement-control proteins in acute and chronic glomerulonephritis.
Acute poststreptococcal glomerulonephritis (AGN) differed from membranoproliferative glomerulonephritis (MPGN) and lupus nephritis (SLE) in that two of the proteins that control the C3b-dependent convertase, beta 1H and the C3bC4b-inactivator cofactor (C3bC4bICo), were frequently absent from the glomerular deposits. In addition, factor B was distributed with C3 in the capillary walls in hypocomplementemic AGN patients. From this, it can be assumed that C3bBb is in the deposits, uninhibited by control proteins as would be predicted for alternative pathway activation. Factor B could not be found in normocomplementemic AGN, was rarely present in MPGN, but was usually present in SLE, most often in the mesangium. In MPGN and SLE, the control proteins were nearly always present in the glomeruli in a distribution like that of C3; IN MPGN they were particularly abundant. Complement profiles indicated an occasional transient reduction in serum C4 level early in AGN. Thus, although there is occasional evidence of early classical activation in AGN, more characteristic is a long period of alternative activation. Serum levels of control proteins did not deviate greatly from normal except for reduced serum beta 1H levels in MPGN type I.


Impact of glucagon response on early postprandial glucose excursions irrespective of residual β-cell function in type 1 diabetes: A cross-sectional study using a mixed meal tolerance test.
Controlling postprandial glucose levels in patients with type 1 diabetes is challenging even under the adequate treatment of insulin injection. Recent studies showed that dysregulated glucagon secretion exacerbates hyperglycemia in type 2 diabetes patients, but little is known in type 1 diabetes patients. We investigated whether the glucagon response to a meal ingestion could influence the postprandial glucose excursion in patients with type 1 diabetes. We enrolled 34 patients with type 1 diabetes and 23 patients with type 2 diabetes as controls. All patients underwent a liquid mixed meal tolerance test. We measured levels of plasma glucose, C-peptide and glucagon at fasting (0 min), and 30, 60 and 120 min after meal ingestion. All type 1 diabetes patients received their usual basal insulin and two-thirds of the necessary dose of the premeal bolus insulin. The levels of plasma glucagon were elevated and peaked 30 min after the mixed meal ingestion in both type 1 diabetes and type 2 diabetes patients. The glucagon increments from fasting to each time point (30, 60 and 120 min) in type 1 diabetes patients were comparable to those in type 2 diabetes patients. Among the type 1 diabetes patients, the glucagon response showed no differences between the subgroups based on diabetes duration (<5 vs ≥5 years) and fasting C-peptide levels (<0.10 vs ≥0.10 nmol/L). The changes in plasma glucose from fasting to 30 min were positively correlated with those in glucagon, but not C-peptide, irrespective of diabetes duration and fasting C-peptide levels in patients with type 1 diabetes. The dysregulated glucagon likely contributes to postprandial hyperglycemia independent of the residual β-cell functions during the progression of type 1 diabetes.


Differential gene expression in HaCaT cells may account for the various clinical presentation caused by anthropophilic and geophilic dermatophytes infections.
Despite the worldwide prevalence of dermatophyte infections, only a few genes are reported to be related to dermatophyte infections. In addition, the mechanism by which different ecological dermatophytes infection leads to varying intensity of inflammation remains unclear. To investigate the mechanism of varying intensity of skin inflammation caused by different ecological dermatophytes infection. We infected HaCaT cells with anthropophilic and geophilic dermatophytes to mimic various ecological dermatophyte infections. RNA-sequencing (RNA-seq) was employed to identify the change in the gene expression of HaCaT cells. To verify the expression of differentially expressed genes (DEGs), we selected 18 HaCaT cells genes to conduct qPCR experiments. In addition, immunoblotting was conducted to validate key genes from the MAPK signalling pathway. After HaCaT cells were infected with the anthropophilic Trichophyton rubrum (T rubrum) and the geophilic Microsporum gypseum (M gypseum), 118 and 619 differentially expressed genes were identified in HaCaT cells, respectively. These genes may provide a clue as to how keratinocytes respond to anthropophilic and geophilic dermatophytes. We also found that JUN may play a critical role in keratinocytes infected with M gypseum. Differential gene expression in HaCaT cells may account for the various clinical presentation caused by anthropophilic and geophilic dermatophytes infections. In addition, the intense inflammatory reaction of M gypseum infection may be triggered by activating the JNK-JUN signalling pathway.


Clinical response of alopecia, trichorrhexis nodosa, and dry, scaly skin to zinc supplementation.
Two unrelated patients had dry brittle hair, alopecia, trichorrhexis nodosa, dry scaly skin, pigment dyschromia, short stature, and neurosecretory growth hormone deficiency. By means of the zinc tolerance test, patient 1 was shown to have zinc deficiency, whereas no clear zinc deficiency could be demonstrated in patient 2. In both patients, hair and the skin abnormalities responded to oral zinc therapy.


Adverse treatment effects in the trial of the European Working Party on High Blood Pressure in the Elderly.
Adverse treatment effects were assessed in 840 elderly hypertensive patients randomly assigned to active treatment (a combination of triamterene and hydrochlorothiazide) or placebo; methyldopa was added to the regimen in one third of the treated patients. Symptoms of dry mouth, nasal stuffiness, and diarrhea were reported by significantly more treated patients than placebo control subjects. More patients receiving diuretics plus methyldopa than diuretics alone reported dry mouth and diarrhea. Significantly more treated patients than control subjects showed evidence of a high serum creatinine level, mild hypokalemia, and gout. More treated patients tended to have diabetes. The benefits of treatment outweighed these adverse treatment effects.


Real-time optical oximetry during FLASH radiotherapy using a phosphorescent nanoprobe.
The rapid depletion of oxygen during irradiation at ultra-high dose rate calls for tissue oximeters capable of high temporal resolution. This study demonstrates a water-soluble phosphorescent nanoprobe and fiber-coupled instrument, which together are used to measure the kinetics of oxygen depletion at 200 Hz during irradiation of in vitro solutions.


Synergy of fosfomycin with carbapenems, colistin, netilmicin, and tigecycline against multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa clinical isolates.
Fosfomycin represents a potential last-resort treatment option for infections with certain multidrug-resistant (MDR) Gram-negative pathogens. We evaluated double-drug combinations of fosfomycin with imipenem, meropenem, doripenem, colistin, netilmicin, and tigecycline for in vitro synergy against 100 MDR Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa clinical isolates, using the Etest method. Synergy was defined as a fractional inhibitory concentration index ≤ 0.5. The isolates were consecutively collected at a university hospital in Greece from various clinical specimens. Against 50 serine carbapenemase-producing K. pneumoniae isolates, synergy of fosfomycin with imipenem, meropenem, doripenem, colistin, netilmicin, and tigecycline was observed for 74.0%, 70.0%, 74.0%, 36.0%, 42.0%, and 30.0% of the isolates, respectively. Against 14 extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae isolates, synergy of fosfomycin with imipenem, meropenem, doripenem, colistin, netilmicin, and tigecycline was observed for 78.6%, 42.9%, 42.9%, 7.1%, 42.9%, and 21.4%, respectively; for 20 ESBL-producing E. coli isolates, the corresponding values were 55.0%, 25.0%, 30.0%, 15.0%, 25.0%, and 25.0%; and for 15 MDR P. aeruginosa isolates, the corresponding values were 46.7%, 53.3%, 73.3%, 13.3% , 13.3%, and 13.3%. Antagonism was not observed for any of the combinations tested. Further studies are needed in order to confirm the clinical relevance of the above findings.


Biological Implant for Complex Abdominal Wall Reconstruction: A Single Institution Experience and Review of Literature.
To present our single institution and surgeon's complex abdominal wall reconstructions (CAWR) experience with Permacol™ mesh through a non-randomized study. Data of 51 consecutive patients were prospectively collected between 2003 and 2015. Patients had a median of 3 comorbidities (range 0-10) and 68% were Center for Disease Control class II-IV. The mean previous repair was 1.3 (range, 0-12), and 25 (44%) had a mesh in situ. The median defect size was 625 cm2. Among the 56 CAWR procedures, in 16 (29%) bowel resection/anastomosis was performed. The overall post-operative complication rate was 45%, and it was wound-related except from 1 patient dead for myocardial infarction. One was lost at follow-up. Five were re-operated for recurrence with a second Permacol mesh, leading to 14 (26%) overall recurrences at a mean follow-up of 44 months (range, 4-123). In 33 (59%) cases, fascial closure was achieved. The mesh placement was intraperitoneal in 89%, retro-muscular in 9% and supra-fascial in 1% of cases. A multivariate analysis showed that predictor risk for recurrence was more than 3 previous repairs, wound class III-IV, whereas age, type of comorbidities, defect size and fascial closure did not influence the recurrence. Median post-operative performance status was 0 (range; 0-3). A satisfaction questionnaire was obtained in 43 patients, and 86% of them were satisfied with the outcome. Biological materials have the potential to reduce morbidity and improve outcome of definitive repair of CAWR.


Temperature dependence of the electrical and mechanical responses of the adductor pollicis muscle in humans.
Changes at low temperatures of the electrical and mechanical activity of the adductor pollicis muscle were studied in 10 volunteers. Decreasing temperatures resulted in increased amplitude and duration of the negative phase and peak-to-peak amplitude of the evoked muscle action potential. Distal latency, electromechanical latency, contraction time, and half-relaxation time were also increased while isometric force, contraction velocity, and relaxation velocity were decreased. The increase of contraction time is greater over the temperature range below 28 degrees C than above 29 degrees C. Skin temperature differs significantly from muscle temperature, showing about 3 degrees C lower values during cooling and up to 4 degrees C higher values during rewarming with radiant heat.