Development and Validation of a Novel Adult Spinal Deformity Surgical Invasiveness Score: Analysis of 464 Patients.
A surgical invasiveness index (SII) has been validated in general spine procedures but not adult spinal deformity (ASD). To assess the ability of the SII to determine the invasiveness of ASD surgery and to create and validate a novel ASD index incorporating deformity-specific factors, which could serve as a standardized metric to compare outcomes and risk stratification of different ASD procedures for a given deformity. Four hundred sixty-four patients who underwent ASD surgery between 2009 and 2012 were identified in 2 multicenter prospective registries. Multivariable models of estimated blood loss (EBL) and operative time were created using deformity-specific factors. Beta coefficients derived from these models were used to attribute points to each component. Scoring was iteratively refined to determine the R2 value of multivariate models of EBL and operative time using adult spinal deformity-surgical (ASD-S) as an independent variable. Similarly, we determined weighting of postoperative changes in radiographical parameters, which were incorporated into another index (adult spinal deformity-surgical and radiographical [ASD-SR]). The ability of these models to predict surgical invasiveness was assessed in a validation cohort. Each index was a significant, independent predictor of EBL and operative time (P < .001). On multivariate analysis, ASD-S and ASD-SR explained more variability in EBL and operative time than did the SII (P < .001). The ASD-SR explained 21% of the variation in EBL and 10% of the variation in operative time, whereas the SII explained 17% and 3.2%, respectively. The ASD-SR, which incorporates deformity-specific components, more accurately predicts the magnitude of ASD surgery than does the SII.


Gene expression analysis of zebrafish retinal ganglion cells during optic nerve regeneration identifies KLF6a and KLF7a as important regulators of axon regeneration.
Unlike mammals, teleost fish are able to mount an efficient and robust regenerative response following optic nerve injury. Although it is clear that changes in gene expression accompany axonal regeneration, the extent of this genomic response is not known. To identify genes involved in successful nerve regeneration, we analyzed gene expression in zebrafish retinal ganglion cells (RGCs) regenerating their axons following optic nerve injury. Microarray analysis of RNA isolated by laser capture microdissection from uninjured and 3-day post-optic nerve injured RGCs identified 347 up-regulated and 29 down-regulated genes. Quantitative RT-PCR and in situ hybridization were used to verify the change in expression of 19 genes in this set. Gene ontological analysis of the data set suggests regenerating neurons up-regulate genes associated with RGC development. However, not all regeneration-associated genes are expressed in differentiating RGCs indicating the regeneration is not simply a recapitulation of development. Knockdown of six highly induced regeneration-associated genes identified two, KLF6a and KLF7a, that together were necessary for robust RGC axon re-growth. These results implicate KLF6a and KLF7a as important mediators of optic nerve regeneration and suggest that not all induced genes are essential to mount a regenerative response.


Numerical analysis of the impact of anthropogenic emissions on the urban environment of Singapore.
Increased urbanization and anthropogenic activities in tropical cities lead to the temperature gradient between the urban and rural environments, causing the urban heat island (UHI) phenomenon. This study is a pioneering attempt that examines the changes in the temporal evolution of the surface energy budget induced by urbanization known as the Anthropogenic Influence (AI) in modifying the urban climate of a tropical city using Weather Research and Forecasting (WRF) numerical modeling system. The AI from buildings, traffic and power plants is determined in five different scenarios and the model is validated with high temporal resolution in-situ data. These increased AIs provide improved WRF capability with root mean square error (RMSE) less than 2 °C and mean bias error (MBE) less than 0.5 °C between different performance indicators. Building envelopes (without indoor activity/equipment) are found to be a major contributor in exacerbating the island wide urban heat ∆TaAI, max to 3.7 °C compared to baseline all green scenario. This is followed by the air-conditioner (AC) systems that contribute up to 1.4 °C. The maximum local contribution of traffic and power plants to urban heat is 0.9 °C and 0.4 °C, respectively.


[Expressions of fibronectin and bone morphogenetic protein-2, 4 during development of mouse tooth germ].
The purpose of this study was to investigate the distribution and relationship of fibronectin (FN), bone morphogenetic protein (BMP) 2, 4 during development of mouse tooth germ. Rat embryonic first molars were collected from E14 (bud stage) and E18 (bell stage). The expressions of FN and BMP-2, 4 were analyzed with immunohistochemistry. FN was located in the epithelium and dental mesenchyme on bud stage, but on bell stage, the FN was found at the region of differentiating odontoblasts and in the inner enamel epithelium, and also BMP-2, 4 were abundant mainly at the brisk region of differentiating odontoblasts. The results demonstrate that BMP-2, 4 and FN play the important roles during bud stage and bell stage, and there may be synergy between BMP-2, 4 and FN in regulating differentiation and maturity of odontoblasts.


[Benign monoclonal gammopathies. General clinical considerations on 30 cases].
With reference to a previously published series, an electronic computer is used to analyse clinical data and some criteria for diagnosing benign monoclonal gammopathies are set out.


Reciprocal change of sagittal profile in unfused spinal segments and lower extremities after complex adult spinal deformity surgery including spinopelvic fixation: a full-body X-ray analysis.
Few studies have described reciprocal changes of pathologic compensatory mechanisms in the setting of spinopelvic fixation using full-body radiograph. To elucidate how sagittal alignment of unfused spinal segments and lower extremities change reciprocally following complex thoracolumbar realignment surgery including fusion to the sacrum in adult spinal deformity. Retrospective cohort. Thirty-four patients who underwent fusion from lower thoracic to the sacrum/pelvis and 49 patients with fusion from upper thoracic to the sacrum/pelvis. The postoperative sagittal alignment change, and the correlation between the instrumented spinopelvic alignment change and reciprocal changes in unfused spinal segments/lower extremities. This study included 34 patients who underwent fusion from lower thoracic to the sacrum/pelvis (LT-P group) and 49 patients with fusion from upper thoracic to the sacrum/pelvis (UT-P group). The postoperative sagittal alignment changes were evaluated after subdividing the two groups according to T1 pelvic angle (TPA) (aligned group: TPA<20 and malaligned group: TPA>20). The correlation between the instrumented spinopelvic alignment change (ΔTPA and ΔLL), reciprocal changes in unfused spinal segments and lower extremities, and the cranial sagittal vertical axis-hip/ankle change (ΔCrSVA-Hip/Ankle) were also analyzed. At the baseline in both LT-P and UT-P groups, the patients in the malaligned subgroups showed greater C2-7 lordosis (C2-7L), sacrofemoral angle (SFA), and knee flexion angle (KA) than those in the aligned subgroups. At average 7.1 months postoperatively, these compensatory mechanisms were restored in accordance with instrumented TPA/LL change, especially in the UT-P group. The mid-thoracic alignment changed significantly kyphotic in the LT-P group. ΔTPA and ΔLL linearly correlated with ΔC2-7L, ΔKA, and ΔAA in the malaligned patients. The multivariate regression analysis revealed that change in lower extremity parameters (ΔSFA, ΔKA, and ΔAA) independently impacted ΔCrSVA-Hip/Ankle. Adequate thoracolumbar realignment surgery results in restoration of the pathologic compensatory mechanisms in the unfused spinal segments and lower extremities, especially in patients fused from upper thoracic spine. A preoperative clinical evaluation of the lower limb joints, as well as a full-body radiographic evaluation, is paramount to achieve optimal global sagittal balance in thoracolumbar realignment surgery.


Neuromedin U signaling regulates retrieval of learned salt avoidance in a C. elegans gustatory circuit.
Learning and memory are regulated by neuromodulatory pathways, but the contribution and temporal requirement of most neuromodulators in a learning circuit are unknown. Here we identify the evolutionarily conserved neuromedin U (NMU) neuropeptide family as a regulator of C. elegans gustatory aversive learning. The NMU homolog CAPA-1 and its receptor NMUR-1 are required for the retrieval of learned salt avoidance. Gustatory aversive learning requires the release of CAPA-1 neuropeptides from sensory ASG neurons that respond to salt stimuli in an experience-dependent manner. Optogenetic silencing of CAPA-1 neurons blocks the expression, but not the acquisition, of learned salt avoidance. CAPA-1 signals through NMUR-1 in AFD sensory neurons to modulate two navigational strategies for salt chemotaxis. Aversive conditioning thus recruits NMU signaling to modulate locomotor programs for expressing learned avoidance behavior. Because NMU signaling is conserved across bilaterian animals, our findings incite further research into its function in other learning circuits.


Naltrexone-induced hypothermia in the rat.
Naltrexone, in relatively high doses, has been reported to cause a fall in body temperature in human ex-heroin addicts who had been abstinent for at least 6 weeks. The underlying mechanism of this hypothermic effect has been investigated in rats. The first consideration was that the temperature change was a reflection of delayed withdrawal but rats implanted with a morphine pellet 45 days earlier showed no significant change in temperature after a dose of naltrexone that caused marked withdrawal hypothermia in dependent rats implanted 3 days previously. A fall in core temperature was only induced in rats after doses of 80 and 160 mg/kg i.p. of naltrexone. Behavioral thermoregulatory studies revealed that the animals correct the falling body temperature by increased exposure to a radiant heat source indicating that the central thermostats had not been significantly affected by the drug. These data suggest that the major component in the hypothermic effect of naltrexone is activation of efferent heat loss pathways or peripheral heat loss mechanisms. Due to current suggestions that opiate receptors might represent the receptors for an endogenous transmitter the results are discussed in relation to this consideration. When compared to the sites and mechanism of action of opiates on thermoregulation the results with naltrexone lend little support to the hypothesis that the fall in temperature is due to displacement of an endogenous substance from central opiate receptors.


Congenital sensorineural deafness in Australian Cattle dogs in the UK: Prevalence and association with phenotype.
The Australian Cattle dog (ACD) is one of many breeds predisposed to congenital sensorineural deafness (CSD). The objective of this study was to estimate CSD prevalence and investigate any association with phenotype in the ACD in the UK. The database of the authors' institution was searched for ACD puppies undergoing brainstem auditory evoked response (BAER) testing for CSD screening (1999-2019). Inclusion criteria were BAER performed at 4-10 weeks of age, testing of complete litters and available phenotypic data. The age, sex, coat and iris colour, presence and location of face and body patches, hearing status and BAER- determined parental hearing status of each puppy were recorded. A multivariable mixed-effects logistic regression model was used to calculate odds ratios and 95% confidence intervals to determine whether any of these variables were significantly associated with CSD, while adjusting for clustering at litter level. Inclusion criteria were met for 524 puppies. Hearing was bilaterally normal in 464 puppies (88.6%). The prevalence of unilateral and bilateral CSD was 9.7% and 1.7%, respectively. On the basis of multivariable analysis, the presence of a pigmented face patch was the only phenotypic variable significantly associated with CSD, and was linked to a reduced risk of the condition. The prevalence was similar to that reported in an Australian population of ACDs. The key findings from this study were that overall CSD prevalence in the ACD population in the UK was 11.4%, and puppies with a face patch were at reduced risk of the condition.


Preparation of carbon molecular sieves by carbon deposition from methane.
To prepare carbon molecular sieves (CMSs), methane was pyrolyzed in an attempt to deposit fine carbon particles on the micropore mouths of the carbon substrates being heated; the carbon substrates included grain-based activated carbons and commercial activated carbons. To explore the effects of heat treatment alone, blank experiments were conducted by heating the samples in N2. The resultant products were characterized by N2-adsorption at 77K. Methane failed to deposit carbon at 800 degrees C. The porosity of activated carbons, however, was substantially influenced by heat treatment alone. The surface areas and micropore volumes of the activated carbons from grain sorghum decreased by 39.32% and 36.84%, respectively, upon heat treatment alone; this is attributable to the destruction of pore structure by sintering. In contrast, the corresponding values of the commercial activated carbons increased by 59.86% and 62.16%, respectively, upon heat treatment alone; this can be attributable to the development of microporosity.


Comparison of extracorporeal shockwave lithotripsy and retrograde intrarenal surgery in the treatment of renal pelvic and proximal ureteral stones ≤2 cm in children.
We aimed to compare extracorporeal shockwave lithotripsy (ESWL) and retrograde intrarenal surgery (RIRS) in pediatric patients with ≤2 cm renal pelvis and proximal ureteral stones. Medical records of 165 pediatric patients who underwent shockwave lithotripsy (SWL) or RIRS for upper urinary system stones up to 2 cm between January 2014 and December 2018 were retrospectively reviewed. After exclusions, the remaining 130 patients included 73 in the SWL group and 57 in the RIRS group. The groups were compared for demographic features, stone characteristics, operative data, success, and complications. The mean stone volume was 308 ± 85 (54-800) and 336 ± 96 (60-720) mm3 in SWL and RIRS groups, respectively (P = 0.46). There were no significant differences in success rates (60% vs. 70%, SWL and RIRS), auxiliary treatment rates (16.4% vs. 14%), and complication rates (26% vs. 24.5%). The number of active procedural sessions and number of anesthesia sessions was higher in the RIRS group (P < 0.001 and P < 0.001, respectively), while the procedural time and anesthesia time were higher in the SWL group (P < 0.001 and P < 0.001, respectively). Stone size was found to be an independent success predictive factor for both the treatment modalities. Both SWL and RIRS have similar success, complication, and auxiliary treatment rates. RIRS was superior in terms of total procedure and anesthesia durations, while SWL was superior in terms of numbers of anesthesia sessions and active procedure sessions. As both have similar success rates, the more minimally invasive SWL should be chosen for pediatric upper urinary system stones of less than 2 cm size.


Frequency flow dynamics of epileptic brain.
Epilepsy affects 1%-2% of the general population, almost 50% of whom are medically refractory and poses a huge burden. A device can possibly be designed for responsive brain stimulation of the epileptogenic focus for seizure control but optimal seizure detection patterns and stimulus parameters are not yet determined. To explore the possibility of identifying a signature prior to the seizure, we studied the dynamic evolution of frequency from electroencephalography (EEG) of three patients with partial epilepsy using the method of frequency flow. We found that prior to seizure, the frequency flow dynamics exhibit a buildup of 5-12 Hz activity which remains high during the initial stage of the seizure with a characteristic time constant and may be used for seizure detection and/or anticipation. We conclude that dynamics of frequency flow in the 5-12 Hz range can be a potential marker for the detection and/or the anticipation of the seizure in temporal lobe epilepsy.


Cross-cultural adaptation and psychometric evaluation of the French version of the Gilles de la Tourette Syndrome Quality of Life Scale (GTS-QOL).
The Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL) is a self-rated disease-specific questionnaire to assess health-related quality of life of subjects with GTS. Our aim was to perform the cross-cultural adaptation of the GTS-QOL into French and to assess its psychometric properties. The GTS-QOL was cross-culturally adapted by conducting forward and backward translations, following international guidelines. The psychometric properties of the GTS-QOL-French were assessed in 109 participants aged 16 years and above with regard to factor structure, internal consistency, reliability and convergent validity with the MOVES (Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey) and the WHOQOL-BREF (World Health Organization Quality of Life Brief). Exploratory factor analysis of the GTS-QOL-French resulted in a 6-factor solution and did not replicate the original structure in four subscales. The results showed good acceptability (missing values per subscale ranging from 0% to 0.9%), good internal consistency (Cronbach's alpha ranging from 0.68 to 0.94) and good test-retest reliability (intraclass correlation coefficients ranging from 0.70 to 0.81). Convergent validity with the MOVES and WHOQOL-BREF scales showed high correlations. Our study provides evidence of the good psychometric properties of the GTS-QOL-French. The cross-cultural adaptation and validation of this specific instrument will make it possible to assess health-related quality of life in French-speaking subjects with GTS. The GTS-QOL-French could be recommended for use in future research.


Supination torque following single- versus double-incision repair of acute distal biceps tendon ruptures.
Compared with single-incision (SI) distal biceps repair, double-incision (DI) repair has been described as permitting a more anatomic repair. We hypothesized that DI repair would result in greater terminal supination torque compared with SI repair for acute distal biceps ruptures. Patients were included if they sustained an isolated, acute distal biceps rupture repaired between January 2012 and December 2017. Isometric forearm supination torque in 4 positions was measured using a validated uniaxial torque-testing device. Testing took place at least 12 months from surgery. The primary outcome was supination torque in the 60° supinated position. Secondary outcomes included supination torque in other forearm positions and functional outcome scores. The study included 37 patients: 15 underwent repair with the DI technique and 22 with the SI technique. The mean age was 47.3 years, the median follow-up time was 28.1 months, and demographic data were similar between cohorts. Mean supination torque, relative to the unaffected side, was 61% (95% confidence interval, 45%-77%) for DI repair vs. 80% (95% confidence interval, 69%-92%) for SI repair in the 60° supinated position (P = .036). In a multivariable linear regression model controlling for arm dominance, age, follow-up time, and workers' compensation status; SI repair was associated with greater mean supination torque than DI repair by 20% (P = .015). Contrary to our hypothesis, we found a 20% mean improvement in terminal supination torque for acute distal biceps ruptures repaired with the SI technique compared with the DI technique. This finding may have clinical significance for the more discerning, high-demand patient.


Phase II study of intrabone single unit cord blood transplantation for hematological malignancies.
The outcomes of cord blood transplantation with non-irradiated reduced-intensity conditioning for hematological malignancies need to be improved because of graft failure and delayed engraftment. Intrabone infusion of cord blood cells has the potential to resolve the problems. In this phase II study, 21 adult patients with hematological malignancy received intrabone transplantation of serological HLA-A, B, and DR ≥4/6 matched single cord blood with a median number of cryopreserved total nucleated cells of 2.7 × 107 /kg (range, 2.0-4.9 × 107 /kg) following non-irradiated fludarabine-based reduced-intensity conditioning. Short-term methotrexate and tacrolimus were given as graft-versus-host disease prophylaxis, and granulocyte colony-stimulating factor was given after transplantation. No severe adverse events related to intrabone injection were observed. The cumulative incidences of neutrophils ≥0.5 × 109 /L, reticulocytes ≥1%, and platelets ≥20 × 109 /L recoveries were 76.2%, 71.4%, and 76.2%, respectively, with median time to recoveries of 17, 28, and 32 days after transplantation, respectively. The probability of survival with neutrophil engraftment on day 60 was 71.4%, and overall survival at 1 year after transplantation was 52.4%. The incidences of grade II-IV and III-IV acute graft-versus-host disease were 44% and 19%, respectively, with no cases of chronic graft-versus-host disease. The present study showed the safety of direct intrabone infusion of cord blood. Further analysis is required to confirm the efficacy of intrabone single cord blood transplantation with non-irradiated reduced-intensity conditioning for adult patients with hematological malignancy. This study was registered with UMIN-CTR, number 000000865.


Pretransplant islet culture: a comparison of four serum-free media using a murine model of islet transplantation.
Human islet transplant protocols frequently incorporate a brief period of islet culture before transplantation. The optimal medium for pretransplant islet culture is unknown. We compared four serum-free media formulated for human islets: Miami (MM1), Memphis (M-SFM), Edmonton (EDM), and hCell OCZEM-SF/AF (hCell). Islets isolated from a single human pancreas with purity >80% were cultured in 2500-islet-equivalent (IE) fractions using the media listed. After 7 days, each 2500-IE fraction was grafted under the kidney capsule of a streptozocin-diabetic rag1 mouse (n = 4 per group). Mice were evaluated with serum glucose monitoring, stimulated C-peptide release, and glucose tolerance tests. Islet fractions transplanted immediately after isolation (n = 4 mice) served as controls. In vitro islet function was assessed on days 0 and 3 and included insulin release (after static glucose stimulation), total cellular C-peptide content, cell count, and viability. Glucose control was improved in all cohorts of mice after transplant, but only islet grafts cultured in MM1 were statistically indistinguishable from fresh islets. MM1- and hCell-cultured islet grafts showed improved glucose tolerance compared with fresh islets; C-peptide release was similar among the four cohorts. In vitro, only islets cultured in MM1 had similar stimulation index to fresh islets, whereas only hCell- and MM1-cultured islets demonstrated recovery of C-peptide content and insulin release. Media choice before transplant can influence islet quality, even when culture periods are short. Miami MM1 and hCell media may provide better islet protection than alternative media.


Positive Promoting Effects of Smilax China Flower Absolute on the Wound Healing/Skin Barrier Repair-Related Responses of HaCaT Human Skin Keratinocytes.
Smilax china (SC) has pharmacological effects including anti-inflammatory activity, but its effects on skin wound healing and skin barrier function have not been investigated. Here, we investigated the effects of absolute extracted from SC flowers (SCF) on skin wound healing-linked responses and functional skin barrier proteins using human epidermal keratinocytes (HaCaT cells). SCF absolute contained 20 components and was non-toxic to HaCaT cells. The absolute increased the proliferation, migration, and sprout outgrowth of HaCaT cells, and enhanced the activations of serine/threonine-specific protein kinase and extracellular signal-regulated kinase1/2. In addition, it increased the syntheses of type I and IV collagens and the expressions of skin barrier proteins (filaggrin and loricrin). These results indicate SCF absolute may has positive effects on skin wound healing by accelerating keratinocyte migration and proliferation activities and collagen synthesis, and on skin barrier function by upregulating barrier proteins in keratinocytes. We suggest SCF absolute to be considered as a potential means of promoting skin wound and barrier repair.


Alpha-1-acid glycoprotein as potential biomarker for alpha-fetoprotein-low hepatocellular carcinoma.
The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of late diagnosis. We determined the performances of α -1-acid glycoprotein (AAG) and des-γ-carboxy prothrombin (DCP) for the diagnosis of HCC, especially for α-fetoprotein (AFP)-low HCC. Of the 220 patients included in this retrospective study, 124 had HCC, and 61 (49%) of these were AFP-low HCC (AFP ≤ 20 ng/mL). The remaining 96 patients, including 49 with chronic hepatitis B or C and 47 with cirrhosis, were considered as control. Plasma AAG was analyzed using high performance liquid chromatography (HPLC) and confirmed using Western blot technique. When all patients with HCC were evaluated, the area under receiver operating characteristic (ROC) curves for AAG (0.94, 95% CI: 0.91-0.97) and DCP (0.92, 95% CI: 0.88-0.95) were similar (P = 0.40). AAG had better area under ROC curve (0.96, 95% CI: 0.94-0.99) than DCP (0.87, 95% CI: 0.81-0.93) for AFP-low HCC (P < 0.05). At the specificity 95%, the sensitivity of AAG was higher in AFP-low HCC than in AFP-high HCC (82% and 62%, respectively). In contrast, higher sensitivity was obtained from DCP in discriminating HCC patients with low AFP than that in high AFP (57% and 90%, respectively). Our cross-sectional study showed that AAG was better performance in diagnosing HCC patients with low AFP, while DCP did better in those with high AFP.


Regulation of adipocyte differentiation of bone marrow stromal cells by transcription factor GATA-2.
GATA-2 is a transcription factor expressed in stem and progenitor cells of various cell lineages. In this study, we examined the role of GATA-2 in the differentiation of adipocytes, which are the main components of the microenvironment for hematopoiesis. Suppression of GATA-2 in TBR343, a preadipocytic stromal cell line, resulted in the acceleration of adipocyte differentiation. Conversely, overexpression of GATA-2 induced the resistance of adipocyte differentiation. In addition, regulatory elements of the GATA-2 gene in TBR343 are the same as those in hematopoietic cells. These results suggest that GATA-2 maintains a hematopoietic microenvironment by regulating the differentiation of adipocytes.


Antidepressant-like effect of n-3 PUFAs in CUMS rats: role of tPA/PAI-1 system.
BDNF is strongly implicated in the development of depression. Recent evidence has indicated that tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) are related to the cleavage of pro-brain-derived neurotrophic factor (BDNF) into its mature form. Chronic unpredicted mild stress (CUMS) is widely used to induce depressive behaviors in rodents. Therefore, we investigated the effects of PUFAs and sertraline on tPA/PAI-1 system in CUMS rats. After 5 weeks of CUMS procedures, the rats were induced to a depressive-like state. The expressions of PAI-1 and proBDNF were increased in the prefrontal cortex and hippocampus of CUMS rats. N-3 polyunsaturated fatty acids (PUFAs) or sertraline administration reversed the changes in behavioral test and induced the expression of tPA in certain brain areas, but failed to restore the CUMS-induced PAI-1 expression. Meanwhile, the antidepressant treatment also accelerated the extracellular conversion of proBDNF into mature BDNF in CUMS rats. Our results firstly showed the synchronously altered balance of tPA/PAI-1 system in the prefrontal cortex and hippocampus of CUMS rats, which was partly ameliorated by PUFAs and sertraline medication, providing new evidence for the involvement of tPA/PAI-1 system in the progression and treatment of depression.


Changes in the mechanical properties of the longitudinal and circular muscle tissues of the rat myometrium during gestation.
Changes in the mechanical properties of the longitudinal and circular muscle tissues of the rat myometrium during gestation were investigated. In isolated longitudinal and circular muscles of the rat myometrium, spontaneous contractions and contractions per unit cross-sectional area induced by 128 mM K+ and 1 X 10(-5) M acetylcholine (ACh) increased with the progress of gestation. These increases appeared in longitudinal muscles to a greater extent than in circular muscles. ACh induced the largest contraction for both intact muscle tissues, at all stages of gestation. In both muscle layers, the ACh-induced contraction reached the same amplitude as the 1 X 10(-5) M Ca-induced contraction of skinned muscles, except for the longitudinal muscle at the 22nd day of gestation. In Ca-free solution containing 2 mM EGTA, ACh produced contraction in both intact muscle tissues at all stages and the amplitude was increased during the progress of gestation, whereas the K-induced and spontaneous contractions ceased. In saponin-treated skinned muscles of both layers, the free Ca concentration required to produce contraction was lowered, the maximum amplitudes of the contraction were increased and the pCa-tension relationships shifted to the left during the progress of gestation. The results indicate that during the progress of gestation, Ca sensitivity of of the contractile proteins and mechanical responses to agonists increased and that the properties of the intracellular Ca store site were also altered in both muscle layers.


Land use effects on phosphorus sequestration in soil aggregates in western Iran.
Cultivating native lands may alter soil phosphorus (P) distribution and availability. The present study aimed to determine the distribution of P in soil aggregates for different long-term land management practices. The partitioned P in labile (L), Fe/Al-bound, Ca-bound, organic pools, and total P in four aggregate size fractions were determined for five land uses (forest, vineyard after 30 years, wetland, alfalfa, and wheat cultivated soil after 20 years). Both native land uses (forest and wetland) were distinguished by high and low amounts of large macro- and micro-aggregates, respectively, compared with disturbed soils (vineyard, alfalfa, and wheat soils). Labile P in large macro-aggregates were higher in native land use when compared with the other land uses, which led to increasing lability of P and accelerated water pollution. Soils under native conditions sequestered more Ca-bound P in large macro-aggregates than the soils in disturbed conditions. Conversion of native lands to agricultural land caused enhanced organic P storage in aggregates smaller than the 2 mm from 31.0 to 54.3%. Soils under forest had 30% total P more than the vineyard for the aggregates >2 mm after 30 years land use change. However, the amount of P in smaller (<2 mm) sized aggregates was increased by 29% for the vineyard when compared with the forest. The P storage as bound Ca particles for the large macro-aggregates had negative correlation with the micro-aggregates.


Preparation of monoclonal antibodies against poor immunogenic avian influenza virus proteins.
This study established a novel method of pre-screening peptides for monoclonal antibody (mAb) production. Whole virus particles were used as antigens to produce mAbs in the first stage. However, most mAbs obtained from this method were aimed toward hemagglutinin. For this reason, synthetic peptides were used as antigens for mAb production that aimed at the AIV proteins with low abundance or poor immunogenicity in the virus particle. The peptides that showed high immunogenicity were designed using bioinformatic tools for immunization. For high-throughput, a rabbit was used to screen the immunogenicities of the synthetic peptides. Those showed high immunity were used for mAb preparation in mice. Several new mAbs against PB2, PA, M1, M2, NS1 and NS2 proteins were successfully obtained in this study. Furthermore, the epitopes of M1 and NS1 mAbs were determined using competitive western blot assay and competitive ELISA. This study might simplify the mAb preparation and serves as the basis for developing mAb against poor immunogenic proteins.


Isolation and characterization of five new soluble placental tissue proteins (PP22, PP23, PP24, PP25, PP26).
Five new soluble placental tissue proteins (PP22, PP23, PP24, PP25, PP26) were isolated to purity from saline extracts of human term placentas and characterized by their physico-chemical properties. Specific antisera to the new proteins were obtained by immunizing animals with the corresponding purified proteins. They were used to detect and quantitate the new proteins in extracts of placentas and other human tissues by immunochemical methods such as gel diffusion tests. The immunohistochemical localization of the new proteins as well as measurement of their concentrations in body fluids by sensitive radioimmunoassays are presently under investigation.


Recessive LOXHD1 variants cause a prelingual down-sloping hearing loss: genotype-phenotype correlation and three additional children with novel variants.
Biallelic mutations in LOXHD1 have been identified as the cause of DFNB77 (deafness, autosomal recessive 77). It is a new progressive, severe-to-profound, and late-onset nonsyndromic sensorineural hearing loss (NSHL), and is highly heterogeneous genetically and phenotypically. This study aimed to provide an additional three cases of DFNB77. We presented three unrelated children diagnosed with prelingual mild-to-severe NSHL, and their audiograms showed mild hearing loss at 250 Hz before downsloping to a moderate-to-severe degree. Trio whole-exome sequencing (WES) was conducted to identify the pathogenic variants. Additionally, we reviewed the literature to further analyze the relationships between the genotype and audiology phenotype of LOXHD1. Six novel possible pathogenic LOXHD1 variants were identified, including three missense, one nonsense, and two splicing variants. The literature review showed that 68.5% of patients with DFNB77 onset before five years old; Most variants (62%) were associated with a down-sloping audiogram of mild-to-moderate hearing loss at low frequencies (200Hz, 500Hz), particularly variants in the protein domain of PLAT 9. We found that compared with homozygous LOXHD1 variants, individuals with heterozygous compound variants had a significantly milder phenotype, especially individuals carrying one missense and one splicing or bi-allelic missense variants (P < 0.05). Audiometric analysis at different ages showed that the hearing loss degree was aggravated at all frequencies by increasing age. We report three children with prelingual NSHL carrying six novel LOXHD1 variants. Furthermore, our work indicates that DFNB77 may be milder than previously reported and recommends considering the genotype combination and mutation location of LOXHD1 and race-specificity in DFNB77 molecular diagnoses and management.


Adenocarcinoma of the proximal small intestine. A marker for familial and multicentric cancer?
Adenocarcinoma of the small intestine is uncommon. The Hawaii Tumor Registry (HTR) has identified 49 of these tumors since 1960, and the Japan-Hawaii Cancer Study (JHCS) has identified only four of these tumors among a cohort of 8006 Hawaiian-Japanese men followed up for a period of 22 years. Each of the four men reported by the JHCS had multicentric gastrointestinal cancers. Newly diagnosed cancers are recorded separately by the HTR and JHCS, and linkage is maintained between the two files. Family histories are available from the JHCS, and these are supplemented by a state population file maintained by the Department of Genetics, University of Hawaii. Five men, all Japanese, were found to have carcinoma of the proximal small intestine. Each had multicentric carcinomas of the gastrointestinal tract. Carcinoma of the stomach and colon was found in the primary relatives of each of four men whose families lived in Hawaii. The familial clustering of uncommon neoplasms (small bowel carcinoma and multicentric large bowel carcinoma), and the concurrence of gastric and colonic carcinoma suggests that these subjects have a genetic trait that increases susceptibility to a broad range of carcinogens.


[Severe poisoning by 4-aminopyridine in a body builder].
A 22-year-old man was admitted to hospital with severe, accidental intoxication with 4-aminopyridine, a medicine which increases the acetylcholine concentration in the synapses and has a limited application in the treatment of some neurological diseases. The patient acted on the assumption of body-building capacities of this 'amino'. Apart from the previously documented symptoms of intoxication such as an epileptic attack and confusion, he showed cardiac arrhythmias, conduction disorders and severe hypertension. The serum concentration of 4-aminopyridine was 335 mg/l, while the therapeutic level is 25-75 mg/l.


Clinical correlates of rapid eye movement sleep without atonia in Parkinson's disease.
The aim of the present study was to investigate the relationship between rapid eye movement (REM) sleep without atonia (RWA) and Parkinson's disease (PD) progression. We quantified tonic and phasic RWA by performing polysomnography in 198 PD patients. We then correlated the extent of RWA with clinical patient characteristics. PD patients were categorized into quartiles of tonic and phasic RWA. We found that patients with more RWA tended to be older and have longer PD duration, a greater likelihood of REM sleep behavior disorder (RBD), more advanced Hoehn & Yahr (H&Y) stage, a higher dose of parkinsonian medication, poorer cognitive performance, worse quality of life, and more severe sleep disturbance. After adjusting for age, sex, and PD duration, patients in the highest two RWA quartile were more likely to have severe PD (H&Y stage ⩾ 3.0) than those in the lowest RWA quartile. These findings provide evidence that RWA, especially with regard to tonic muscle activity, is associated with PD severity. Further studies are warranted to determine the importance and utility of assessing RWA to evaluate sleep in PD patients.


Association between BMI trajectories from childhood to early adulthood and the carotid intima-media thickness in early adulthood: Tehran lipid and glucose study.
Childhood and adolescence overweight/obesity is an important predictor of obesity and increased long-term cardiometabolic abnormalities in adulthood. In this study, we aimed to investigate the association of body mass index (BMI) and waist circumference (WC) trajectories among children and adolescents with adulthood carotid intima-media thickness (cIMT) as a determinant of subclinical atherosclerosis. In this prospective cohort study, 1265 participants aged 3 to 18 were followed up for 18 years. By using Latent Class Growth Analysis, three groups of BMI and WC trajectory were defined; low stable, moderate-increasing, and high-increasing. Linear and logistic regression analysis were used to investigate the association of each lifetime BMI and WC trajectory group with cIMT. Although the high-increasing BMI trajectory group was significantly associated with higher cIMT (ß=0.0464, P < 0.001), moderate-increase was not (ß=0.0096, P = 0.102); in reference to the low-stable BMI trajectory group. Among WC trajectory groups, both moderate- (ß=0.0177, P = 0.006) and high-increasing (ß=0.0533, P < 0.001), in reference to the low-stable group, were significantly associated with higher cIMT. The results did not change after adjustment for baseline BMI. The ORs of high-increasing BMI, moderate-increasing WC, and high-increasing WC trajectories were 3.24, 1.92, and 3.29, respectively for high cIMT. Our study resulted that a high-increasing trajectory of childhood BMI and moderate- and high-increasing trajectories of childhood WC are associated with higher cIMT and higher risk of high-cIMT. Regular monitoring and screening of BMI and WC trajectory from childhood may improve identifying individuals with high risks of cardiovascular disease, more accurately.


Late development of pelviureteric junction obstruction (PUJO) in a girl with previously normal pyelogram: a case report.
A case of ureteropelvic junction obstruction in a girl with previously normal pyelogram is presented. The aetiology of this development is unclear but this report emphasizes the need for a close follow-up of patients with persistent flank pain even if the initial pyelograms are normal.


Influence of COMT polymorphism in cognitive performance on dementia in community-dwelling elderly Mexican (SADEM study).
There is an inconsistent finding about the relationship of catechol-O-methyltransferase (COMT) with dementia susceptibility, as well as with cognitive impairment. To substantiate this, we examined COMT genotype effects in certain cognitive domains in dementia. To evaluate the effects of COMT Val158Met on cognitive performance, we used The Mini-Mental State Examination (MMSE), the cognitive subscale of the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) and the Syndrome Kurz Test (SKT). The results show COMT Val/Met, Val/Val genotype polymorphisms had a significant effect on cognition performance (OR = 1.75 (95 %CI 1.22-2.54) and (OR = 2.76 (95 %CI 1.78-4.26), p < 0.001), and with adjustment for all cognitive test scores together, Val/Val (OR = 4.98 (95 % CI 1.47-16.86) and Val/Met (OR = 3.62 (95 % CI 1.37-9.56) had effect. Our study allows us to understand the role of COMT in cognitive performance in dementia, as well as interaction with other known risk factors for this pathology. This data might help in developing new therapeutic targets for cognitive impairment, main symptom of dementia. Other risk genotypes or haplotypes should be evaluated to determine the association with cognitive decline in dementia.


Laparoscopic management for fibroepithelial polyp causing ureteropelvic junction obstruction in a child.
An 11-year-old boy with episodes of intermittent gross hematuria and recurrent left flank pain was referred to our institute with left ureteropelvic junction (UPJ) obstruction. (99m)Tc diethylenetriamine pentaacetic acid (DTPA) renography revealed an obstructive pattern in the left kidney, and the existence of a crossing vessel at the UPJ was suspected with excretory urography. Laparoscopic surgery was performed, and intraoperatively no aberrant vessels were found. Upon opening the ureter, a solitary round polyp was found. The segment of the UPJ area containing the polyp was completely removed, followed by laparoscopic dismembered pyeloplasty. Pathologic findings demonstrated a benign fibroepithelial polyp.


A quantitative assessment of patient barriers to insulin.
To assess diabetes treatment preferences with a focus on patient barriers to insulin treatment. A questionnaire using indirect and direct methods was administered as part of the International Diabetes Management Practices Study (IDMPS). Discrete choice modelling was used to assess how product attributes influence patients' preferences for diabetes treatment. A multinomial logit model was used to find the odds ratio for each parameter, representing the probability of selecting a chosen alternative given a choice set. This allowed for the derivation of relative attribute importance, an indication of how influential product attributes are in the respondents' choices. The IDMPS questionnaire was administered to 14,033 individuals with diabetes in 18 countries. The majority of respondents were women (53%) and had Type 2 diabetes mellitus (T2DM; 85%). Across subgroups, administration (i.e. oral vs. injection) was a driver of preference. Patient preferences varied according to diabetes type; individuals with T2DM assigned much higher relative importance to administration than those with Type 1 diabetes mellitus (T1DM; 30.86% vs. 4.99%; p<0.0001). Individuals with T2DM treated with insulin placed less importance on administration than insulin-naïve T2DM patients (3.09% vs. 47.48%; p<0.0001). Diabetes education also had a significant effect on the priority given to administration between T2DM patients who received diabetes training and those who did not (28.21% vs. 33.68%, respectively; p<0.0001). The insulin barriers perceived by patients with diabetes evolved with their disease experience. While administration was the primary preference driver for insulin-naïve patients, patients were increasingly concerned with more clinically relevant barriers as they gained experience with insulin. This finding suggests that patients using insulin understand the importance of achieving an optimal balance between safety and efficacy.


Long-term variability of trace gases over the Indian Western Himalayan Region.
The four-year continuous measurements of CO, NOx, NH3, SO2, and O3 were carried at a high altitude site (32.12°N, 76.56°E at 1347 m AMSL) of the Indian Western Himalayan area to study the mixing ratios of these gases for understanding the changing trends of these trace gases over the region. Each of these trace gases showed significant daily and monthly variabilities. The highest variability was recorded in the monthly mean values of O3 as it varied from 10 to 63 ppb during the study period. All the trace gases except CO showed maximum variability in the pre-monsoon seasons due to the strong advection and vertical circulation of air masses at the site. The seasonal mean maxima of CO were recorded during the monsoon season, while the mean maxima of NH3 were recorded during the post-monsoon seasons. The meteorological parameters have been found to influence the mixing ratios of trace gases. The least variability in the mean seasonal mixing ratios of SO2 during the study period indicated the constant point source of SO2 near the site. The trajectories analysis revealed that the area receives maximum air masses from the southeast to the west directions where a number of the coal-based thermal power plants, industries, cement plants, and agricultural fields are also located. The influence of valley-to-mountain circulations was also observed at the site, resulting in the transport of pollutant-rich air masses from local and distant sources to the site. A comparison of the mixing ratios of different trace gases obtained in the present study is also made with the values reported for other high altitude stations in the world.


BCL-2 Modulates IRE1α Activation to Attenuate ER Stress and Pulmonary Fibrosis.
BCL-2 family members are known to be pro-survival agents in numerous biological settings. Here we provide evidence that in injury and repair processes in lungs, BCL-2 mainly acts to attenuate endoplasmic reticulum (ER) stress and limit extracellular matrix (ECM) accumulation. Days after intratracheal bleomycin mice lose a fraction of their alveolar type II epithelium from terminal ER stress driven by activation of the critical ER sensor and stress effector IRE1-α. This fraction is dramatically increased by BCL-2 inhibition because IRE1-α activation is dependent on its physical association with the BCL-2-pro-apoptotic family member BAX and we found BCL-2 to disrupt this association in vitro. In vivo, Navitoclax (a BCL-2/BCL-xL inhibitor) given 15-21 days after bleomycin challenge evoked strong activation of IRE-1α in mesenchymal cells and markers of ER stress but not apoptosis. Remarkably, following BCL-2 inhibition, bleomycin-exposed mice demonstrated persistent collagen accumulation at day 42 compared to resolution in controls. Enhanced fibrosis proved to be due to the RNAase activity of IRE1a downregulating MRC2 mRNA and protein, a mediator of collagen turnover. The critical role of MRC2 was confirmed in PCLS cultures of day 42 lungs from bleomycin-exposed WT and MRC2 null mice. Soluble and tissue collagens accumulated in PCLS cultures from Navitoclax-treated, bleomycin challenged mice compared to controls, nearly identical to that of challenged but untreated MRC2 nulls. Thus, apart from mitochondrial-based anti-apoptosis, BCL-2 functions to attenuate ER stress responses, fostering tissue homeostasis and injury repair.


Diffuse neurofibroma obstructing the external auditory meatus.
A case is presented of a 36-year-old male with narrowing of the external meatus due to a diffuse neurofibroma. This unusual variety of neurofibroma spreads superficially and has many ecstatic blood vessels. The size, vascularity, uncertain edges and a tendency to recur makes surgical removal difficult. The treatment options are discussed.


Clinicopathological significance of RCAN2 production in gastric carcinoma.
Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Genes expressed only in cancer tissue may be useful biomarkers for cancer diagnosis and therapeutics. The aims of the present study were to analyse regulator of calcineurin 2 (RCAN2) in a large number of GCs, and to investigate how these expression patterns correlate with clinicopathological parameters and various markers. An immunohistochemical analysis of RCAN2 in 207 GC tissue samples showed that 110 (53%) GCs were positive for RCAN2. RCAN2-positive GCs were more advanced in terms of TNM classification and tumour stage than RCAN2-negative GCs. Furthermore, RCAN2 was an independent prognostic classifier for GC patients. The cell growth and invasiveness of RCAN2 small interfering RNA (siRNA)-transfected GC cell lines were less than those of the negative control siRNA-transfected cell lines, whereas those of RCAN2-transfected cells were significantly increased as compared with those of empty vector-transfected cells. RCAN2 siRNA inhibits the phosphorylation of AKT and p44/p42 (ERK1/2). RCAN2 was colocalised with EGFR, nuclear β-catenin, MMP7, laminin-γ2, VEGF-A, and VEGF-C. These results suggest that RCAN2 is involved in tumour progression and is an independent prognostic classifier in patients with GC.


Scanning laser ophthalmoscope-evoked multifocal-ERG (SLO-m-ERG) by using short m-sequences.
To demonstrate the possibility of topographic mapping of retinal function under simultaneous control of fixation in humans, by scanning laser ophthalmoscope evoked multifocal electroretinography (SLO-m-ERG). A confocal scanning laser ophthalmoscope was used as a stimulator and trigger unit to take m-ERGs. Short m-sequences based on a modified algorithm were used, with the advantage that each measurement cycle can be evaluated separately. We examined 78 normal subjects; in 62 a distortion factor of 1:1 was applied, and a factor of 1:4 in 16. The recorded amplitudes decreased with eccentricity, approximately following the decrease of retinal cone density. Amplitudes were higher in the central hexagonal element in the group with 1:4 distortion than in the group with the 1:1 distortion setting. SLO-m-ERG is a reliable technique for topographic mapping of retinal function under simultaneous control of fixation.


Types, trends, and patterns of the reported antimicrobial errors to the eastern region's medical centers in Saudi Arabia: A cross-sectional study.
Medication errors (MEs) are a huge burden on any healthcare system and have been associated with significant morbidity and mortality. The medical literature reported heavily on MEs but lacked focus on analyzing high-risk medications such as antimicrobials. This was a retrospective analysis of the MEs database reported by the eastern region's medical centers in Saudi Arabia from January 1, 2019 to December 31, 2019. We used descriptive analysis to identify most common antimicrobials with errors, the stage of antimicrobial errors, type of the errors, contributing factors to the errors, and categories of errors based on the National Coordinating Council for Medication Error Reporting and Prevention (NCC-MERP) classification of errors. A total of 1422 (22.1%) antimicrobial errors were identified out of 6412 MEs. Amoxicillin/Clavulanate (18%) was the most common antimicrobial reported in the database. Most errors occurred in the prescribing phase (87.6%) and included mainly incorrect doses (32.1%) and duplicate therapy (20.5%). In addition, most errors were identified as category B (72.5%). Finally, inexperienced personnel (57.9%) was the most cited contributing factor. This study revealed that antimicrobial errors occur primarily during prescription and that policy gaps and inexperienced staff were contributory factors. To improve, the focus should shift to physician education, clear dosing guidelines, efficient workload management, and implementing antimicrobial stewardship programs to promote appropriate antimicrobial use.


Improving suicide surveillance systems through the use of the Patient Health Questionnaire-9.
Suicide is a major public health problem worldwide and continues to be one of the main causes of death. Implementing surveillance strategies for suicidal thoughts and behaviours would make it possible to identify individuals at high risk of ending their lives by suicide. While a universal screening would be controversial, the increasing use of the 9-item version of the Patient Health Questionnaire (PHQ-9) in different healthcare settings, such as primary care or hospital emergency departments, offers an opportunity for testing its performance for suicide surveillance. Beyond being a screening of depression, the PHQ-9 has shown merit as a marker of suicidal thinking, thoughts of self-harm, and suicide. Implementing systematic surveillance strategies for suicide in different healthcare settings including data from the PHQ-9 might be an effective way to improve case detection. This could help to enhance the identification of highest risk population groups and, consequently, to avoid potentially preventable suicides.


Experimental studies on enteropathogenicity and pathogenesis of group 'F' vibrio infections.
Group 'F' vibrios are a recently recognised group of bacteria that have been isolated from cases of diarrhoea and a variety of sources in the environment. They have been shown to cause accumulation of fluid in rabbit gut loops. The enterotoxic factor was found to be heat-labile as evidenced by heat treatment, time course of fluid accumulation and negative suckling mouse assay. It was associated with cytotoxic factor(s). These organisms were seen to be lacking in invasive capacity. Prostaglandins and 5-hydroxytryptamine were found to play no role in causation of fluid outpouring into the loops but chlorpromazine was found to inhibit the fluid outpouring completely thereby indicating that the enterotoxin may act through mediation of cyclic AMP.


Cell cycle progression during gastric ulcer healing by ebrotidine and sucralfate.
1. The effect of antiulcer agents, ebrotidine and sucralfate, on the expression of gastric mucosal proliferating cell nuclear antigen (PCNA) and cyclin-dependent kinase (p34Cdk2) during chronic ulcer healing was examined. 2. Rats with experimentally induced gastric ulcers were treated twice daily for 14 days with either ebrotidine at 100 mg/kg, sucralfate at 100 mg/kg or vehicle, and at different stages of treatment their stomachs were used for quantitization of gastric mucosal PCNA and Cdk2 expression. 3. The assays revealed that the ulcer healing was accompanied by a marked elevation in mucosal expression of PCNA and Cdk2. The maximum increase in PCNA (4.7-fold) occurred by the second day of healing, and the expression of Cdk2 reached a maximum increase (2.3-fold) by the fourth day. 4. Accelerated ulcer healing with ebrotidine (7 days) and sucralfate (8 days) treatments was reflected in a significant enhancement of PCNA and Cdk2 expression. By the second day of treatment, ebrotidine evoked a 15-fold increase in PCNA expression, and sucralfate produced an 11.8-fold enhancement. The mucosal expression of Cdk2 attained a maximum of 4.3-fold increase over that of the controls by the sixth day of healing with ebrotidine, and a fivefold increase in Cdk2 expression occurred by the fourth day of ulcer treatment with sucralfate. 5. The findings implicate cell cycle regulatory proteins in the processes to leading to mucosal repair and suggest that the two drugs exert a similar effect on the expression of proteins that control cell cycle progression.


Maturation of human lactase-phlorizin hydrolase. Proteolytic cleavage of precursor occurs after passage through the Golgi complex.
Maturation of human intestinal lactase-phlorizin hydrolase (LPH) requires that a precursor (pro-LPH) be proteolytically processed to the mature microvillus membrane enzyme (m-LPH). The subcellular site of this processing is unknown. Using low-temperature experiments and brefeldin A (BFA), intracellular transport was blocked in intestinal epithelial cells. In Caco-2 cells incubated at 18 degrees C, pro-LPH was complex-glycosylated but not cleaved, while at 20 degrees C small amounts of proteolytically processed LPH were observed. These data exclude a pre-Golgi proteolytic event. BFA completely blocked proteolytic maturation of LPH and lead to an aberrant form of pro-LPH in both Caco-2 cells and intestinal explants. Therefore, proteolytic processing of LPH is a post-Golgi event, occurring either in the trans-Golgi network, transport vesicles, or after insertion of pro-LPH into the microvillus membrane.


Efforts to graduate more primary care physicians and physicians who will practice in rural areas: examining outcomes from the university of Minnesota-duluth and the rural physician associate program.
To compare practice choices (primary care or specialty) and practice locations (rural or metropolitan) of medical students at the Duluth and Twin Cities (Minneapolis and St. Paul; TC) campuses of the University of Minnesota (UMN). In the early 1970s, Minnesota created two medical education programs at UMN to increase the number of rural and primary care physicians: the first two years of medical school at UMN-Duluth, where the program focuses on recruiting students who will be rural family physicians, and the Rural Physician Associate Program (RPAP) elective, a nine-month, longitudinal immersion experience with a preceptor in a rural community. In 2008, the authors analyzed outcomes for four student groups: (1) UMN-Duluth and (2) UMN-TC medical students who participated in RPAP and (3) UMN-Duluth and (4) UMN-TC students who did not participate in RPAP. UMN medical students complete their first two years on either campus; they can apply to RPAP for their third year. Non-RPAP students spend most of their third- and fourth-year rotations in the Twin Cities metropolitan area. The UMN-Duluth and RPAP students were most likely to select a rural location and primary care practice. UMN-TC, non-RPAP students followed national trends, choosing predominantly metropolitan and specialty practices. RPAP and UMN-Duluth provide significant, complementary educational programs that lead more graduates to choose rural and primary care practices. Efforts across the nation to address the crisis in rural primary care should build on these successful efforts.


Systematic review and meta-analysis of 3D-printing in otolaryngology education.
Three-dimensional (3D) printing has received increased attention in recent years and has many applications. In the field of otolaryngology surgery, 3D-printed models have shown potential educational value and a high fidelity to actual tissues. This provides an opportunity for trainees to gain additional exposure, especially as conventional educational tools, such as cadavers, are expensive and in limited supply. The purpose of this study was to perform a meta-analysis of the uses of 3D-printing in otolaryngology education. The primary outcomes of investigation were surgical utility, anatomical similarity, and educational value of 3D-printed models. Secondary outcomes of interest included country of implementation, 3D-printer materials and costs, types of surgical simulators, and the levels of training of participants. MEDLINE, Embase, Web of Science, Google Scholar and previous reviews were searched from inception until June 2021 for eligible articles. Title, abstract, and data extraction were performed in duplicate. Data were analyzed using random-effects models. The National Institute of Health Quality Assessment Tool was used to rate the quality of the evidence. A total of 570 abstracts were identified and screened by 2 independent reviewers. Of the 274 articles reviewed in full text, 46 articles met the study criteria and were included in the meta-analysis. Surgical skill utility was reported in 42 studies (563 participants) and had a high degree of acceptance (84.8%, 95% CI: 81.1%-88.4%). The anatomical similarity was reported in 39 studies (484 participants) and was received positively at 80.6% (95% CI: 77.0%-84.2%). Educational value was described in 36 studies (93 participants) and had the highest approval rating by participants at 90.04% (87.20%-92.88%). A subgroup analysis by year of publication demonstrated that studies published after 2015 had higher ratings across all outcomes compared to those published prior to 2015. This study found that 3D-printing interventions in otolaryngology demonstrated surgical, anatomical, and educational value. In addition, the approval ratings of 3D-printed models indicate a positive trend over time. Future educational programs may consider implementing 3D-printing on a larger scale within the medical curriculum to enhance exposure to otolaryngology.


Effects of Puberty on Blood Pressure Trajectories - Underlying Processes.
Puberty is a complex process leading to physical, sexual, and psychosocial maturation. The changes in morphology and organ function during puberty also affect blood pressure (BP) regulation, and as a consequence (BP) values change noticeably, reaching values often higher than after reaching full maturity. In children entering puberty, BP, especially systolic, increases and then reaches adult values by the end of puberty. The mechanisms responsible for this process are complex and not fully understood. Sex hormones, growth hormone, insulin-like growth factor-1, and insulin, whose production increases during puberty, significantly regulate BP through complex and overlapping mechanisms. During puberty, the incidence of arterial hypertension also increases, especially in children with excess body weight. The present paper presents the current state of knowledge regarding the influence of processes occurring during puberty on blood pressure.


Motor evoked potential latency and duration from tibialis anterior in individuals with chronic stroke.
Ipsilateral motor pathways from the contralesional hemisphere to the paretic limbs may be upregulated to compensate for impaired function after stroke. Onset latency and duration of motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS) provide insight into compensatory pathways but have been understudied in the lower limb. This study assessed MEP onset latency and duration in the lower limb after stroke, and compared ipsilateral and contralateral MEPs in the paretic and non-paretic limb. We hypothesized that: (1) onset latency would be longer for ipsilateral than contralateral MEPs and longer for the paretic than the non-paretic limb, and (2) duration would be shorter for ipsilateral than contralateral MEPs and longer for the paretic than the non-paretic limb. Data were collected as a part of a pre-test of a randomized controlled trial. TMS was applied to the ipsilateral and contralateral hemisphere of the paretic and non-paretic limb. MEP onset latency and duration were calculated from the tibialis anterior. Thirty-five participants with chronic stroke were included in the final analysis. Onset latency was longer in the paretic than the non-paretic limb (~ 6.0 ms) and longer after ipsilateral than contralateral stimulation (~ 1.8 ms). Duration was longer in the paretic than the non-paretic limb (~ 9.2 ms) and longer after contralateral than ipsilateral stimulation (~ 5.2 ms). Ipsilateral MEPs may be elicited through ipsilateral pathways with fewer fibers with a higher activation threshold and/or greater spinal branching. MEPs from the paretic limb may reflect slower central motor conduction, peripheral changes, or changes in motor pathway.


Cytogenetic comparison between clear cell sarcoma and a case of acral clear cell melanoma.
Clear cell melanoma is a recently described variant of melanoma characterized by prominent clear cell features similar to clear cell sarcoma. The present report describes a deeply invasive case of clear cell melanoma clinically, histologically, immunohistochemically, ultrastructurally and with the FISH technique and compares these findings with those in clear cell sarcoma. A 68-year-old male presented with an ulcerated, deeply invasive melanoma on the heel, corresponding to Clark level V, with a maximum tumour thickness of more than 14 mm; follow-up revealed inguinal lymph-node and lung metastases. Apart from characteristic histological features of melanoma with intraepidermal involvement, the lesion was immunohistochemically positive for 5100 protein, with HMB45 and A103 (anti-human Melan-A/MART-1), and ultrastructurally showed melanosomes. In deeply invasive parts, the lesion was indistinguishable from clear cell sarcoma, exhibiting nests, fascicles and sheets of pale-staining epithelioid to spindle-shaped cells ('clear cells') with scattered Touton-like multinucleated giant cells. Cytogenetic analysis using the FISH technique revealed a 12q13 chromosomal break in the vicinity of the ATFI gene but without ATF1 disruption. These findings may indicate the possible involvement of the ATF1 gene in clear cell melanoma tumorigenesis, similar to clear cell sarcoma with classical t(12;22) translocation.


Amygdala physiology in pain.
The amygdala has emerged as an important brain area for the emotional-affective dimension of pain and pain modulation. The amygdala receives nociceptive information through direct and indirect routes. These excitatory inputs converge on the amygdala output region (central nucleus) and can be modulated by inhibitory elements that are the target of (prefrontal) cortical modulation. For example, inhibitory neurons in the intercalated cell mass in the amygdala project to the central nucleus to serve gating functions, and so do inhibitory (PKCdelta) interneurons within the central nucleus. In pain conditions, synaptic plasticity develops in output neurons because of an excitation-inhibition imbalance and drives pain-like behaviors and pain persistence. Mechanisms of pain related neuroplasticity in the amygdala include classical transmitters, neuropeptides, biogenic amines, and various signaling pathways. An emerging concept is that differences in amygdala activity are associated with phenotypic differences in pain vulnerability and resilience and may be predetermining factors of the complexity and persistence of pain.


Gluconeogenic-glycolytic capacities and metabolic zonation in liver of rats with streptozotocin, non-ketotic as compared to alloxan, ketotic diabetes.
Activities (mumol X min-1 X g liver) and zonal distributions of key enzymes of carbohydrate metabolism were studied in livers of streptozotocin-diabetic rats and compared to the values in alloxan-diabetes. Streptozotocin led to a non-ketotic diabetes with blood glucose being increased by more than fivefold but ketone bodies being in the normal range, while alloxan produced a ketotic diabetes with blood glucose, acetoacetate and beta-hydroxybutyrate being elevated by more than fivefold. Portal insulin was decreased to about 20% in streptozotocin- and more drastically to about 7% in alloxan-diabetes. Conversely, portal glucagon was increased in the two states to about 250% and 180%, respectively. The glucogenic key enzyme phosphoenolpyruvate carboxykinase (PEPCK) was enhanced in streptozotocin- and alloxan-diabetes to over 300%, while the glycolytic pyruvate kinase L (PKL) was lowered to 65% and 80%, respectively. The normal periportal to perivenous gradient of PEPCK of about 3:1, as measured in microdissected tissue samples, was maintained with elevated activities in the two zones. The normal periportal to perivenous gradient of PKL of 1:1.7 was diminished with lowered activities in the two zones. The glucogenic glucose-6-phosphatase (G6Pase) was increased in streptozotocin- and alloxan-diabetes to 130% and 140%, respectively, while the glucose utilizing glucokinase (GK) was decreased to 60% and 50%, respectively. The normal periportal to perivenous gradient of G6Pase, demonstrated histochemically, remained unaffected. Carnitine palmitoyltransferase (CPT) was increased to over 190% and acetyl-CoA carboxylase (ACC) was decreased to 60% in streptozotocin, non-ketotic diabetes, while the two enzymes were altered more drastically to 400% and 50%, respectively, in alloxan, ketotic diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)


Genetic instability associated with the aroC321 allele in Salmonella typhimurium involves genetic duplication.
Strains of Salmonella typhimurium that contain the aroC321 allele require phenylalanine, tyrosine, and tryptophan for growth but revert to tryptophan-prototrophy at high frequencies (about 10(-4) per cell plated). The Trp+ derivatives remain auxotrophic for phenylalanine and tyrosine and are genetically unstable, in that they readily give rise to cells that require all three aromatic amino acids. On the basis of growth characteristics and genetic instability, it has been proposed that reversion to tryptophan-prototrophy in aroC321 strains occurs by genetic duplication. This paper provides genetic evidence in support of that hypothesis. The data indicate, moreover, that the tryptophan prototrophs contain a duplication that extends at least from glpT to xyl, a region of greater than 30% of the Salmonella chromosome. The aroC locus is found within the duplicated region, and aroC321/aroC321 merodiploids apparently grow as tryptophan prototrophs because of a gene-dosage effect.


Mitochondrial microRNAs: A Putative Role in Tissue Regeneration.
The most famous role of mitochondria is to generate ATP through oxidative phosphorylation, a metabolic pathway that involves a chain of four protein complexes (the electron transport chain, ETC) that generates a proton-motive force that in turn drives the ATP synthesis by the Complex V (ATP synthase). An impressive number of more than 1000 mitochondrial proteins have been discovered. Since mitochondrial proteins have a dual genetic origin, it is predicted that ~99% of these proteins are nuclear-encoded and are synthesized in the cytoplasmatic compartment, being further imported through mitochondrial membrane transporters. The lasting 1% of mitochondrial proteins are encoded by the mitochondrial genome and synthesized by the mitochondrial ribosome (mitoribosome). As a result, an appropriate regulation of mitochondrial protein synthesis is absolutely required to achieve and maintain normal mitochondrial function. Regarding miRNAs in mitochondria, it is well-recognized nowadays that several cellular mechanisms involving mitochondria are regulated by many genetic players that originate from either nuclear- or mitochondrial-encoded small noncoding RNAs (sncRNAs). Growing evidence collected from whole genome and transcriptome sequencing highlight the role of distinct members of this class, from short interfering RNAs (siRNAs) to miRNAs and long noncoding RNAs (lncRNAs). Some of the mechanisms that have been shown to be modulated are the expression of mitochondrial proteins itself, as well as the more complex coordination of mitochondrial structure and dynamics with its function. We devote particular attention to the role of mitochondrial miRNAs and to their role in the modulation of several molecular processes that could ultimately contribute to tissue regeneration accomplishment.


Appendectomies in patients with nephritis.
A retrospective study of 150 records of patients attending a renal clinic revealed a high (10 per cent) incidence of history of appendectomy. The possibility that an acute exacerbation of pyelonephritis, especially on the right side, might be misdiagnosed in some cases as appendicitis is discussed. Acute renal failure following unnecessary appendectomy in a patient with previously unrecognized and asymptomatic chronic renal disease may occur if this possibility is not borne in mind before operating on an atypical case of appendicitis.


Mask-R[Formula: see text]CNN: a distance-field regression version of Mask-RCNN for fetal-head delineation in ultrasound images.
Fetal head-circumference (HC) measurement from ultrasound (US) images provides useful hints for assessing fetal growth. Such measurement is performed manually during the actual clinical practice, posing issues relevant to intra- and inter-clinician variability. This work presents a fully automatic, deep-learning-based approach to HC delineation, which we named Mask-R[Formula: see text]CNN. It advances our previous work in the field and performs HC distance-field regression in an end-to-end fashion, without requiring a priori HC localization nor any postprocessing for outlier removal. Mask-R[Formula: see text]CNN follows the Mask-RCNN architecture, with a backbone inspired by feature-pyramid networks, a region-proposal network and the ROI align. The Mask-RCNN segmentation head is here modified to regress the HC distance field. Mask-R[Formula: see text]CNN was tested on the HC18 Challenge dataset, which consists of 999 training and 335 testing images. With a comprehensive ablation study, we showed that Mask-R[Formula: see text]CNN achieved a mean absolute difference of 1.95 mm (standard deviation [Formula: see text] mm), outperforming other approaches in the literature. With this work, we proposed an end-to-end model for HC distance-field regression. With our experimental results, we showed that Mask-R[Formula: see text]CNN may be an effective support for clinicians for assessing fetal growth.


Promoting Oxygen Reduction Reaction by Inducing Out-of-Plane Polarization in a Metal Phthalocyanine Catalyst.
Metal phthalocyanine (MPc) material with a well-defined MN4 moiety offers a platform for catalyzing the oxygen reduction reaction (ORR), while the practical performance is often limited by the insufficient O2 adsorption due to the planar MN4 configuration. Here, a design (called Gr-MG -O-MP Pc) is proposed, where the metal of MPc (MP ) is axially coordinated to a single metal atom in graphene (Gr-MG ) through a bridge-bonded oxygen atom (O), introducing effective out-of-plane polarization to promote O2 adsorption on MPc. Manipulating the out-of-plane polarization charge by varying types of MP and MG (MP = Fe/Co/Ni, MG = Ti/V/Cr/Mn/Fe/Co/Ni) in the axial coordination zone of -MG -O-MP - are examined by density functional theory simulations. Among them, the catalyst of Gr-V-O-FePc stands out with the highest calculated O2 adsorption energy, which is synthesized successfully and verified by systemic X-ray absorption spectroscopy measurements. Importantly, it delivers a remarkable ORR performance with half-wave potential of 0.925 V (versus reversible hydrogen electrode) and kinetic current density of 26.7 mA cm-2 . This thus demonstrates a new and simple way to pursue high catalytic performance by inducing out-of-plane polarization in catalysts.


Behavioral and neurobiological changes in a novel mouse model of schizophrenia induced by the combination of cuprizone and MK-801.
Schizophrenia is a mental illness characterized by episodes of psychosis, apathy, social withdrawal, and cognitive impairment. White matter lesions and glutamatergic hypofunction are reported to be the key pathogeneses underlying the multiple clinical symptoms of schizophrenia. Cuprizone (CPZ) is a copper chelator that selectively injures oligodendrocytes, and MK-801 is an antagonist of the N-methyl d-aspartate (NMDA) receptor. To better mimic the psychosis and complicated pathogenesis of schizophrenia, a novel possible mouse model was established by the combination of CPZ and MK-801. After exposure to CPZ for 5 weeks, the mice received a daily intraperitoneal injection of MK-801 for 2-weeks. Behavioral changes in the mouse model were evaluated using Y-maze, object recognition, and open field tests. Pathological changes were observed by transmission electron microscopy, oil red O staining, immunohistochemistry, and western blotting. The results showed that the novel mouse model induced by CPZ plus MK-801 exhibited severe spatial and recognition memory deficits, hyperactivity, and anxiety disorder. Moreover, the mice showed obvious demyelination and white matter damage and decreased expression levels of myelin basic protein (MBP) and 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) in the corpus callosum. Furthermore, the phosphorylation levels of Fyn and NMDA receptor 2B in the corpus callosum and NMDA receptor 1 in the cerebral cortex were noticeably decreased. Taken together, the novel mouse model induced by the combination of cuprizone and MK-801 showed comprehensive behavioral and neurobiological changes, which might make it a suitable animal model for schizophrenia.


Pseudomonas aeruginosa in public swimming pools and bathroom water of patients with cystic fibrosis.
Acquisition of Pseudomonas aeruginosa (PA) in the lungs of patients with cystic fibrosis (CF) is a marker of poor survival. PA is a ubiquitous pathogen prevalent in humid conditions. This study aimed to identify the prevalence of PA in public swimming pools, as well as from water taps. Water was collected from public indoor and outdoor pools in the area of St. Gallen, Switzerland. In addition, standing and running water was sampled from bathroom water taps of 50 patients with CF. Outdoor pools: In 2002, none of the 72 specimens from 28 pools revealed PA. In 2003, three specimens from 46 pools (7%) revealed PA, each were from a different paddling pool. Indoor pools: two of 128 specimens from 56 pools (4%) identified PA, both were from non-public hydrotherapy pools. Water taps: in winter, none of the 102 specimens was colonized with PA. in summer, only two out of 50 specimens of the standing water were positive for PA but none of the running water revealed PA. The prevalence of PA in public swimming pools and bathroom water taps in the eastern part of Switzerland is very low. On hot summer days, outdoor paddling pools and standing tap water can contain PA. This study does not support recommendations to avoid public swimming pools or running tap water if the water is maintained according to hygiene guidelines.


Amelioration of Auditory Response by DA9801 in Diabetic Mouse.
Diabetes mellitus (DM) is a metabolic disease that involves disorders such as diabetic retinopathy, diabetic neuropathy, and diabetic hearing loss. Recently, neurotrophin has become a treatment target that has shown to be an attractive alternative in recovering auditory function altered by DM. The aim of this study was to evaluate the effect of DA9801, a mixture of Dioscorea nipponica and Dioscorea japonica extracts, in the auditory function damage produced in a STZ-induced diabetic model and to provide evidence of the mechanisms involved in enhancing these protective effects. We found a potential application of DA9801 on hearing impairment in the STZ-induced diabetic model, demonstrated by reducing the deterioration produced by DM in ABR threshold in response to clicks and normalizing wave I-IV latencies and Pa latencies in AMLR. We also show evidence that these effects might be elicited by inducing NGF related through Nr3c1 and Akt. Therefore, this result suggests that the neuroprotective effects of DA9801 on the auditory damage produced by DM may be affected by NGF increase resulting from Nr3c1 via Akt transformation.


Menstrual blood-derived endometrial stem cell, a unique and promising alternative in the stem cell-based therapy for chemotherapy-induced premature ovarian insufficiency.
Chemotherapy can cause ovarian dysfunction and infertility since the ovary is extremely sensitive to chemotherapeutic drugs. Apart from the indispensable role of the ovary in the overall hormonal milieu, ovarian dysfunction also affects many other organ systems and functions including sexuality, bones, the cardiovascular system, and neurocognitive function. Although conventional hormone replacement therapy can partly relieve the adverse symptoms of premature ovarian insufficiency (POI), the treatment cannot fundamentally prevent deterioration of POI. Therefore, effective treatments to improve chemotherapy-induced POI are urgently needed, especially for patients desiring fertility preservation. Recently, mesenchymal stem cell (MSC)-based therapies have resulted in promising improvements in chemotherapy-induced ovary dysfunction by enhancing the anti-apoptotic capacity of ovarian cells, preventing ovarian follicular atresia, promoting angiogenesis and improving injured ovarian structure and the pregnancy rate. These improvements are mainly attributed to MSC-derived biological factors, functional RNAs, and even mitochondria, which are directly secreted or indirectly translocated with extracellular vesicles (microvesicles and exosomes) to repair ovarian dysfunction. Additionally, as a novel source of MSCs, menstrual blood-derived endometrial stem cells (MenSCs) have exhibited promising therapeutic effects in various diseases due to their comprehensive advantages, such as periodic and non-invasive sample collection, abundant sources, regular donation and autologous transplantation. Therefore, this review summarizes the efficacy of MSCs transplantation in improving chemotherapy-induced POI and analyzes the underlying mechanism, and further discusses the benefit and existing challenges in promoting the clinical application of MenSCs in chemotherapy-induced POI.


Human forniceal region is the stem cell-rich zone of the conjunctival epithelium.
The anterior surface of the eye is covered by several physically contiguous but histologically distinguishable epithelia overlying the cornea, limbus, bulbar conjunctiva, fornix conjunctiva, and palpebral conjunctiva. The self-renewing nature of the conjunctival epithelia makes their long-term survival ultimately dependent on small populations of stem cells. Hence, the objective of this study was to investigate the expression of the stem cell genes Sox2, OCT4, NANOG, Rex1, NES, and ABCG2 in cultured human conjunctival epithelium from different conjunctival zones, namely, the bulbar, palpebral and fornix zones. Three samples were taken from patients with primary pterygium and cataract (age range 56-66 years) who presented to our eye clinic at the UKM Medical Centre. The eye was examined with slit lamp to ensure there was no underlying ocular surface diseases and glaucoma. Conjunctival tissue was taken from patients who underwent a standard cataract or pterygium operation as a primary procedure. Tissues were digested, cultured, and propagated until an adequate number of cells was obtained. Total RNA was extracted and subjected to expression analysis of conjunctival epithelium genes (KRT4, KRT13, KRT19) and stem cell genes (Sox2, OCT4, NANOG, Rex1, NES, ABCG2) by reverse transcriptase-PCR and 2% agarose gel electrophoresis. The expression of Sox2, OCT4, and NANOG genes were detected in the fornical cells, while bulbar cells only expressed Sox2 and palpebral cells only expressed OCT4. Based on these results, the human forniceal region expresses a higher number of stem cell genes than the palpebral and bulbar conjunctiva.


A risk scoring system to determine recurrence in early-stage type 1 endometrial cancer: a French multicentre study.
To develop a risk scoring system (RSS) to determine recurrence in women with early-stage type 1 endometrial cancer (EC). Data of 396 women with early-stage type 1 EC who received primary surgical treatment between January 2001 and December 2012 were abstracted from multicentre database (training set). A risk model for predicting recurrence was developed and internally validated with the bootstrap technique. The RSS was externally validated using data from an independent population. Overall, the recurrence rate was 12.1 %. The median follow-up and initial time to recurrence were 34 (range 1-152) and 26 (range 1-151) months, respectively. Recurrence was associated with five variables: age ≥60 years, histological grade III, primary tumor diameter >2 cm, depth of myometrial invasion ≥50 %, and the positive lymphovascular space involvement status. These variables were included in the RSS and assigned scores. A total score of 6.5 points corresponded to the optimal threshold of the RSS. For women with a score <6.5 or ≥6.5, the recurrence rates were 8.4 % (30/357) and 48.7 % (19/39) in the training set, respectively. At this threshold, the diagnostic accuracy of the RSS was 87 %. Areas under the curve of the receiver-operating characteristics for predicting recurrence at internal and external validation were 0.74 [95 % confidence interval (CI) 0.71-0.77] and 0.82 (95 % CI 79-85), respectively. This RSS identified two subsets of women with low and high risk of recurrence among women with early-stage type 1 EC. It could be helpful to better define indications for nodal staging and adjuvant therapy.


Electron probe x-ray analysis of siderosomes in the rabbit haemarthrotic synovial membrane.
Electron probe x-ray analysis of siderosomes produced in the rabbit synovial membrane by repeated injections of autologous blood revealed two kinds of siderosomes; (1) those containing a small amount of phosphorus and, (2) those in which no phosphorus was detectable. On the basis of these findings and past studies it is concluded that haemosiderin is an inorganic compound of iron, probably a hydrated ferric oxide and that a variable amount of organic material (proteins, lipids, phospholipids, etc.,) probably occurs in company with the haemosiderin in the siderosome, but these variable components which decrease in amount with the passage of time cannot be considered as an integral part of haemosiderin.


The 2013 American College of Cardiology/American Heart Association guidelines on treating blood cholesterol and assessing cardiovascular risk: a busy practitioner's guide.
The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults and Guideline on the Assessment of Cardiovascular Risk were released in mid-November 2013. This article explains the guidelines, the risk equations, and their derivations, and addresses criticisms so that practicing physicians may be more comfortable in using the guidelines and the risk equations to inform patients of their atherosclerotic cardiovascular risk and choices to reduce that risk. The article also addresses patient concerns about statin safety if lifestyle changes have been insufficient to reduce their risk.


Enantioselectivity and origin of enhanced efficiency in polyethylene terephthalate hydrolases catalyzed depolymerization.
Biotechnology is one of the most promising strategies to resolve the global crisis of plastic pollution. A clear understanding of the core enzyme mechanisms in the biotransformation process is critical for rational enzyme engineering and for practical, industrial-scale applications. Herein, we systematically examined and evidenced a largely unexplored piece in the depolymerization mechanism catalyzed by polyethylene terephthalate (PET) hydrolases: their enantioselectivity. We found that all the short-lived tetrahedron intermediates (IM3 and IM8) possess S-type chirality in six representative PET hydrolases. For instance, the binding percentage ratio of pro-S:pro-R is 57:21 in FAST-PETase, while pro-S binding leads to a much lower average energy barrier (5.2 kcal/mol) than pro-R binding (33.1 kcal/mol). Key structural features (e.g. the angle for Ser@H1-His@N1-PET@O2 and distance for His@N1-PET@O2) that significantly modulate the enantioselectivity were identified. The origin of the energy landscape variation between wild-type IsPETase and mutant FAST-PETase was also unveiled via analysis of key features, the distortion/interaction energy, and non-covalent bond interactions. This study supplies the missing piece in the mechanism for depolymerization catalyzed by PET hydrolases, and will aid in the rational design of enzymes for industrial recycling of PET plastic waste.


Impact of time-restricted feeding on kidney injury in male rats with experimental metabolic syndrome.
Disruptions to circadian rhythm may be implicated in the pathogenesis of metabolic syndrome (Met-S). For example, eating during an extended period of the day may negatively impact the circadian rhythms governing metabolic control, contributing, therefore, to Met-S and associated end-organ damage. Accordingly, time-restricted eating (TRE)/feeding (TRF) is gaining popularity as a dietary intervention for the treatment and prevention of Met-S. To date, no studies have specifically examined the impact of TRE/TRF on the renal consequences of Met-S. The proposed study seeks to use a model of experimental Met-S-associated kidney disease to address this knowledge gap, disambiguating therein the effects of calorie restriction from the timing of food intake. Spontaneously hypertensive rats will consume a high-fat diet (HFD) for 8 weeks and then be allocated by stratified randomisation according to albuminuria to one of three groups. Rats will have free 24-h access to HFD (Group A), access to HFD during the scheduled hours of darkness (Group B) or access to HFD provided in the form of two rations, one provided during the light phase and one provided during the dark phase, equivalent overall in quantity to that consumed by rats in Group B (Group C). The primary outcome measure will be a change in albuminuria. Changes in food intake, body weight, blood pressure, glucose tolerance, fasting plasma insulin, urinary excretion of C-peptide and renal injury biomarkers, liver and kidney histopathology and inflammation, and fibrosis-related renal gene expression will be assessed as secondary outcomes.


Identification of p26Xb and p24Xb of human T-cell leukemia virus type II.
Human T-cell leukemia virus type II (HTLV-II) isolated from a T-cell variant of hairy cell leukemia contains gag, pol and env genes as well as a fourth gene termed X, which can code three major open reading frames Xa, Xb and Xc. Proteins with molecular masses of 26 kDa (p26Xb) and 24 kDa (p24Xb) encoded by the Xb open reading frame were identified with antisera directed against synthetic peptides corresponding to the N-terminal and C-terminal amino acid sequences deduced from the structure of the Xb open reading frame. More than half the Xb products were found to be located in the nuclear fraction of HTLV-II-infected cells.


Deriving freshwater sediment quality guidelines of polycyclic aromatic hydrocarbons using method of species sensitivity distribution and application for risk assessment.
Contamination of polycyclic aromatic hydrocarbons (PAHs) in sediment has long been of great concern because of their toxic effects to benthic organisms. Sediment quality guidelines (SQGs) are the basis to evaluate the potential ecological risks of PAHs in sediments. Species sensitivity distribution (SSD) has been widely applied in deriving water quality criteria, but seldom employed in SQGs. In this study, SSD was used to derive the freshwater SQGs for four representative PAHs (naphthalene, phenanthrene, pyrene and benzo[a]pyrene) based on the sediment toxicity results. A linear relationship between the SQGs and octanol-water partition coefficient (log KOW) was developed, and applied to predict the SQGs of other twelve PAHs. The obtained SQGs were in the range of 0.46 - 1.79 mg/kg with a geometric mean of 0.97 mg/kg, which was proposed as the SQGs for total PAHs. Based on these SQGs, the risk quotients of PAHs in the sediments collected from Haihe River of China were calculated, and the toxic effects were also tested using three representative benthic organisms. As the risk quotients of the PAHs and heavy metals in the sediments were summed up, good correlations were found (p = 0.074 and 0.018) between them and the observed toxicities of the sediments. The SQGs developed for PAHs was promising in ecological risk assessment for contaminated freshwater sediments.


Effects of two contrasting potting media on the leaf development index, photosynthetic rate, and metabolite profile of camphor (Dryobalanops aromatica) seedlings.
Camphor (Dryobalanops aromatica C. F. Gaertn.) is a vulnerable tropical tree species that has been exploited for its timber as well as its resin, which is used for medicinal uses. The use of camphor in Indonesia is limited owing to the decreasing size of the species' population in its native habitat. Therefore, replanting programs have been encouraged for this species owing to its adaptability to mineral soils and shallow peatlands. However, experimental evidence of the effect of different growing media on morphology, physiology, and biochemistry is very limited, which is needed to evaluate the replanting program's success. Therefore, this study aimed to determine the responses of camphor (D. aromatica) seedlings grown in two different types of potting media i.e. mineral and peat, for 8 weeks of planting. In particular, the types of bioactive compounds produced in camphor leaves and their levels were assessed by analyzing their metabolite profiles. Leaf growth was evaluated morphologically using the plastochron index, while photosynthetic rates were measured with LI-6800 Portable Photosynthesis System. Metabolites were identified by using liquid chromatography-tandem mass spectrometry. The percentage of LPI of 5 or more was lower in the peat medium at 8% than in the mineral medium at 12%. The photosynthetic rate of camphor seedlings was 1-9 μmol CO2 m⁻2 s⁻1, with a higher rate in the peat medium than in the mineral medium, suggesting that the peat medium was better for growth. Lastly, the metabolomic analysis in the leaf extract revealed the presence of 21 metabolites, which were dominated by flavonoid compounds.


Pet hair as a potential sentinel of human exposure: Investigating partitioning and exposures from OPEs and PAHs in indoor dust, air, and pet hair from China.
We investigated the levels, compositions, and partitioning behaviors of organophosphate esters (OPEs) and polycyclic aromatic hydrocarbons (PAHs) in indoor air, dust, and pet hair from North China, as well as their potential exposures for humans and pets. The mean OPE concentrations in the indoor air (n = 19), dust (n = 26), and pet hair (n = 29) samples were 52.1 ng/m3, 3510 ng/g, and 1440 ng/g; while the mean PAH concentrations were 369 ng/m3, 6000 ng/g, and 22.6 ng/g, respectively. The matrix-air partitioning of OPEs and PAHs may reach equilibrium for compounds with octanol-air partition coefficients (logKoa) between 7 and 11 for dust and logKoa < 12 for pet hair. Correlation analysis suggested that pet hair could be used as a sentinel for the exposure to certain PAHs, e.g., phenanthrene (PHE) or fluoranthene (FLA), via exposure to indoor air. This work suggests that pet hair may be a better sentinel than air and dust for human exposure to OPEs and PAHs across different indoor microenvironments. Estimated daily intakes (EDIs) to OPEs and PAHs via air inhalation, dust ingestion, and dermal absorption were calculated for children, adults, and pets. The median ΣEDIs for children, adults, and pets were 26.7, 5.40, and 55.0 ng/kg/day for ΣOPEs, and 68.8, 19.1, and 130 ng/kg/day for ΣPAHs, respectively. Air inhalation was the main exposure route to PAHs and OPEs with logKoa < 10, whereas dust ingestion was the main exposure route to those with logKoa > 10.


Peer pressure induced punishment resolves social dilemma on interdependent networks.
Despite the fruitful evidence to support the emergence of cooperation, irrational decisions are still an essential part of promoting cooperation. Among the many factors that affect human rational decision-making, peer pressure is unique to social organisms and directly affects individual cooperative behaviors in the process of social interaction. This kind of pressure psychologically forces individuals to behave consistently with their partners, and partners with inconsistent behaviors may suffer psychological blows. As feedback, this psychological harm may in turn affect individual cooperative decisions. There is evidence that when peer pressure exists, partnerships can reduce free-riding in enterprise. Based on interdependent networks, this paper studies the impact of peer pressure on cooperation dynamics when the strategies of corresponding partners from different layers of the networks are inconsistent. We assume that when individuals are under peer pressure, their payoffs will be compromised. The simulation results show that the punishment effect will force the expulsion of partners with different strategies, which will further reduce the proportion of partners with inconsistent strategies in the system. However, in most cases, only moderate fines are most conductive to the evolution of cooperation, and the punishment mechanisms can effectively promote the interdependent network reciprocity. The results on the small world and random network prove the robustness of the result. In addition, under this mechanism, the greater the payoff dependence between partners, the better the effect of interdependent network reciprocity.