Screening and Evaluation of Neurodevelopmental Impairments in Infants Under 6 Months of Age with Congenital Heart Disease.
Clinical evaluation of neurodevelopmental impairments before 6 months of age is needed in congenital heart disease (CHD) to promote early referral to developmental interventions. The objective was to identify the risk of cerebral palsy (CP) and to compare neurodevelopment outcomes in infants with and without CHD. In a longitudinal study, 30 infants with CHD and 15 infants without CHD were assessed at 1 month, 3 months, and 6 months of age. Included measures were General Movement Assessment (GMA), Test of Infant Motor Performance (TIMP) and the Bayley Scale of Infant Development, third edition (Bayley-III), selected to identify the risk of CP, document neurodevelopmental impairments and infants' eligibility for early intervention services. Abnormal GMA categories were found in the CHD group where 48% had poor repertoire and 15% were at high risk of CP. At 3 months of age, CHD group had significantly lower TIMP scores compared to infants without CHD [t(41) = 6.57, p = 0.01]. All infants in the study had higher Bayley-III scores at 6 months than at 3 months of age. Infants with CHD had lower gross motor, fine motor and cognitive Bayley-III scores compared to their peers without CHD. Over time infants without CHD outperformed the CHD group in the gross motor skills [F(1,41) = 11.76, p = .001]. Higher prevalence of abnormal GMs, lower TIMP and Bayley-III were found in infants with single ventricle physiology compared to two-ventricle physiology. The risk of CP exists in infants with CHD, and these infants have worse outcomes compared to their peers without CHD. These differences are intensified in the single ventricle population.Clinical Trial Registration National Institute of Health, Unique identifier: NCT03104751; Date of registration-April 7, 2017.


Sarcoidosis presenting as progressive ascending lower extremity weakness and asymptomatic meningitis with hypoglycorrhachia.
A 26-year-old man developed progressive weakness over a two-month period. His chest radiograph showed diffuse interstitial infiltrates, and transbronchial lung biopsies demonstrated noncaseating granulomas consistent with sarcoidosis. Sarcoid neuropathy should be considered in the differential diagnosis of the patient presenting with an atypical Landry-Guillain-Barré syndrome.


The prevalence of high-grade prostatic intraepithelial neoplasia in surgical resection specimens: an Indian experience.
To the authors' knowledge there is a paucity of literature regarding the prevalence of high-grade prostatic intraepithelial neoplasia (HGPIN) in the Indian subcontinent. The objective of the current study was to document the prevalence of HGPIN in a low-risk Indian population. SA total of 110 prostate specimens (61 taken from the test group and 49 taken from the control group) were studied to document the prevalence of HGPIN in a low-risk Indian population. None of the benign prostate samples were found to harbor HGPIN, whereas 85.24% of the samples from malignant prostates did so. SA strong correlation between HGPIN and invasive carcinoma was observed, a finding that reinforces the view that HGPIN is a strong indicator of concurrent invasive prostate carcinoma.


Low UVA doses activate the transcription factor NFAT in human fibroblasts by a calcium-calcineurin pathway.
UVA radiation induces an inflammatory response as observed in erythema, and the cytokine genes involved in this response are under the control of the transcription factor NFAT (nuclear factor of activated T lymphocytes). The effects of UVA on NFAT DNA binding activity were investigated in cultured human fibroblasts. A dose-dependent increase was observed within the range of 0.6-4.5 J/cm2 UVA. Beyond this value, the activity decreased and a value of 60% of control was found at 13.5 J/cm2. The enhancement of NFAT activity was transient and peaked 45 min after irradiation. Furthermore, immunoblot analysis demonstrated a nuclear translocation of NFAT under low UVA doses. Concomitantly, as assessed by the fluorescent probe Fluo3, UVA induced an increase in intracellular free calcium, with a maximum increase found at 9 J/cm2. The UVA-induced activation of NFAT was prevented by the intracellular calcium trapping drug BAPTA, whereas the extracellular calcium chelator EGTA had no significant effect. In addition, the calcineurin inhibitors cyclosporin A and FK506 both prevented the UVA-induced NFAT activation. Furthermore, the antioxidant vitamin E prevented the UVA-induced increase in both intracellular free calcium and NFAT binding activity. Finally, the cytotoxicity of UVA was enhanced in the presence of the inhibitors cyclosporin and FK506, suggesting that the activation of NFAT might play a protective role after the UVA-induced oxidative stress. These results demonstrate that UVA activates the calcium-calcineurin signaling pathway of NFAT activation, that the calcium ions are mainly released from intracellular stores, and that the increase in calcium is, at least partially, due to the oxidative stress generated under UVA. Because NFAT regulates several genes implicated in the inflammatory response, the enhancement of NFAT activity by low UVA doses might be interpreted in view of the proinflammatory action of solar radiation.


What turns CREB on? And off? And why does it matter?
Altered expression and function of the transcription factor cyclic AMP response-binding protein (CREB) has been identified to play an important role in cancer and is associated with the overall survival and therapy response of tumor patients. This review focuses on the expression and activation of CREB under physiologic conditions and in tumors of distinct origin as well as the underlying mechanisms of CREB regulation by diverse stimuli and inhibitors. In addition, the clinical relevance of CREB is summarized, including its use as a prognostic and/or predictive marker as well as a therapeutic target.


BE-FLARE: a fluorescent reporter of base editing activity reveals editing characteristics of APOBEC3A and APOBEC3B.
Base Editing is a precise genome editing method that uses a deaminase-Cas9 fusion protein to mutate cytidine to thymidine in target DNA in situ without the generation of a double-strand break. However, the efficient enrichment of genetically modified cells using this technique is limited by the ability to detect such events. We have developed a Base Editing FLuorescent Activity REporter (BE-FLARE), which allows for the enrichment of cells that have undergone editing of target loci based on a fluorescence shift from BFP to GFP. We used BE-FLARE to evaluate the editing efficiency of APOBEC3A and APOBEC3B family members as alternatives deaminase domains to the rat APOBEC1 domain used in base editor 3 (BE3). We identified human APOBEC3A and APOBEC3B as highly efficient cytidine deaminases for base editing applications with unique properties. Using BE-FLARE to report on the efficiency and precision of editing events, we outline workflows for the accelerated generation of genetically engineered cell models and the discovery of alternative base editors.


Complications of Diagnostic TMJ Arthroscopy: An Institutional Study.
The prevalence of using arthroscopy for the diagnosis of the TMJ disorders is increasing due to its superiority to conventional methods of imaging. Although considered to be safe, complications do occur. A single operator single-institution retrospective study consisting of 50 patients taken up for diagnostic arthroscopy was analysed for complications. Lacerations of external acoustic meatus was found in 03 patients (6%); immediate partial hearing loss was seen in 01 patient (2%); transient facial nerve palsy was found in 05 patients (10%); sensory disturbances over the distribution of auriculotemporal nerve was evident in 01 patient (2%); haemorrhage as visualised by excessive bleeding through trocar skin puncture wound was seen in 05 patients (5%). Post-operative pain more than the pre-operative pain on assessment by visual analogue scale was noted in 05 patients (10%) on the immediate post-operative day. Reduction in spontaneous mouth opening was noted in 15 patients (30%). Though the complication rate was found to be higher than most of the other studies, they were minor which resolved without any intervention. The cases with complications were clustered at the beginning of the series which suggests the steep learning curve and the importance of surgeons' experience and skill involved in this procedure.


Laboratory degradation studies of 14C-atrazine and -isoproturon in soil from sugarcane cultivated fields under Kenyan tropical conditions.
A study to compare the degradation rates of atrazine (6-chloro-N(2)-ethyl-N(4)-isopropyl-1,3,5-triazine-2,4-diammine) and isoproturon [3-(4-isopropylphenyl)-1,1-dimethylurea] in soils from sugarcane fields with different practices of herbicides application was carried out. (14)C-atrazine was poorly mineralized to (14)CO(2) (1.10% +/- 0.22%) after 139 days of incubation in soil without previous exposure to atrazine. In the same soil also with no previous isoproturon exposure isoproturon was mineralized to (14)CO(2) by 7.70% +/- 0.94%. Atrazine mineralization after 98 days was 13.4% +/- 0.30% in soil which discontinued the use of atrazine in 1997 while it was 89.9% +/- 1.23% in soil in which atrazine is currently being used. The isoproturon mineralization values were 7.24% +/- 0.85% and 22.97% +/- 0.96% in soil which discontinued atrazine and soil currently using atrazine, respectively.


Molecular epidemiology of a hepatitis C virus outbreak in a leprosy sanatorium in Japan.
The hepatitis C virus (HCV) outbreak that occurred between 1940 and 1999 in a closed leprosy sanatorium located on a small island in Japan was analyzed. The analysis of 318 nucleotides in the NS5B region of HCV allowed us to establish the existence of at least three different HCV strains in this sanatorium.


BioPerine Encapsulated Nanoformulation for Overcoming Drug-Resistant Breast Cancers.
The evolving dynamics of drug resistance due to tumor heterogeneity often creates impediments to traditional therapies making it a challenging issue for cancer cure. Breast cancer often faces challenges of current therapeutic interventions owing to its multiple complexities and high drug resistivity, for example against drugs like trastuzumab and tamoxifen. Drug resistance in the majority of breast cancer is often aided by the overtly expressed P-glycoprotein (P-gp) that guides in the rapid drug efflux of chemotherapy drugs. Despite continuous endeavors and ground-breaking achievements in the pursuit of finding better cancer therapeutic avenues, drug resistance is still a menace to hold back. Among newer therapeutic approaches, the application of phytonutrients such as alkaloids to suppress P-gp activity in drug-resistant cancers has found an exciting niche in the arena of alternative cancer therapies. In this work, we would like to present a black pepper alkaloid derivative known as BioPerine-loaded chitosan (CS)-polyethylene glycol (PEG) coated polylactic acid (PLA) hybrid polymeric nanoparticle to improve the bioavailability of BioPerine and its therapeutic efficacy in suppressing P-gp expression in MDA-MB 453 breast cancer cell line. Our findings revealed that the CS-PEG-BioPerine-PLA nanoparticles demonstrated a smooth spherical morphology with an average size of 316 nm, with improved aqueous solubility, and provided sustained BioPerine release. The nanoparticles also enhanced in vitro cytotoxicity and downregulation of P-gp expression in MDA-MB 453 cells compared to the commercial inhibitor verapamil hydrochloride, thus promising a piece of exciting evidence for the development of BioPerine based nano-drug delivery system in combination with traditional therapies as a crucial approach to tackling multi-drug resistance in cancers.


Impact of targeted interventions on heterosexual transmission of HIV in India.
Targeted interventions (TIs) have been a major strategy for HIV prevention in India. We evaluated the impact of TIs on HIV prevalence in high HIV prevalence southern states (Tamil Nadu, Karnataka, Andhra Pradesh and Maharashtra). A quasi-experimental approach was used to retrospectively compare changes in HIV prevalence according to the intensity of targeted intervention implementation. Condom gap (number of condoms required minus condoms supplied by TIs) was used as an indicator of TI intensity. Annual average number of commercial sex acts per female sex worker (FSW) reported in Behavioral Surveillance Survey was multiplied by the estimated number of FSWs in each district to calculate annual requirement of condoms in the district. Data of condoms supplied by TIs from 1995 to 2008 was obtained from program records. Districts in each state were ranked into quartiles based on the TI intensity. Primary data of HIV Sentinel Surveillance was analyzed to calculate HIV prevalence reductions in each successive year taking 2001 as reference year according to the quartiles of TI intensity districts using generalized linear model with logit link and binomial distribution after adjusting for age, education, and place of residence (urban or rural). In the high HIV prevalence southern states, the number of TI projects for FSWs increased from 5 to 310 between 1995 and 2008. In high TI intensity quartile districts (n = 30), 186 condoms per FSW/year were distributed through TIs as compared to 45 condoms/FSW/year in the low TI intensity districts (n = 29). Behavioral surveillance indicated significant rise in condom use from 2001 to 2009. Among FSWs consistent condom use with last paying clients increased from 58.6% to 83.7% (p < 0.001), and among men of reproductive age, the condom use during sex with non-regular partner increased from 51.7% to 68.6% (p < 0.001). A significant decline in HIV and syphilis prevalence has occurred in high prevalence southern states among FSWs and young antenatal women. Among young (15-24 years) antenatal clinic attendees significant decline was observed in HIV prevalence from 2001 to 2008 (OR = 0.42, 95% CI 0.28-0.62) in high TI intensity districts whereas in low TI intensity districts the change was not significant (OR = 1.01, 95% CI 0.67-1.5). Targeted interventions are associated with HIV prevalence decline.


Multi-view features integrated 2D\3D Net for glomerulopathy histologic types classification using ultrasound images.
Early diagnoses and rational therapeutics of glomerulopathy can control progression and improve prognosis. The gold standard for the diagnosis of glomerulopathy is pathology by renal biopsy, which is invasive and has many contraindications. We aim to use renal ultrasonography for histologic classification of glomerulopathy. Ultrasonography can present multi-view sections of kidney, thus we proposed a multi-view and cross-domain integration strategy (CD-ConcatNet) to obtain more effective features and improve diagnosis accuracy. We creatively apply 2D group convolution and 3D convolution to process multiple 2D ultrasound images and extract multi-view features of renal ultrasound images. Cross-domain concatenation in each spatial resolution of feature maps is applied for more informative feature learning. A total of 76 adult patients were collected and divided into training dataset (56 cases with 515 images) and validation dataset (20 cases with 180 images). We obtained the best mean accuracy of 0.83 and AUC of 0.8667 in the validation dataset. Comparison experiments demonstrate that our designed CD-ConcatNet achieves the best classification performance and has great superiority on histologic types diagnosis. Results also prove that the integration of multi-view ultrasound images is beneficial for histologic classification and ultrasound images can indeed provide discriminating information for histologic diagnosis.


New morphological and biochemical aspects of atherosclerosis.
According to morphological and biochemical findings, disturbances of metabolism (turnover) and function of smooth muscle cells and proteoglycans/GAG are decisive for the development of early and progressive atherosclerotic changes. The feedback dependencies between the smooth muscle cells and the components of the extracellular substance demonstrated, permit to call primary target points of atherogenic injuries of al constituents of this regulating circle system. If the increased turnovers of the arterial components do not return to a normal equilibrium, the result is hyperplasia of the cellular and intercellular constituents. The early atherosclerotic lesions can progress or relapse. In late and regressive lesions, the cell content as well as the anabolic and esp. the catabolic processes decrease. There result scars rich in collagen fibres and poorer in cells, ground substance, and elastin. The healing of atherosclerotic lesions can take place in any stage, the later the more difficult and insufficient. Disturbances of the fat metabolism, the own synthesis, and the intake of substances by smooth muscle and hematogenic cells are secondary sequels of the primary early atherosclerotic alterations and might be regarded as metabolic lesion of the smooth muscle cells. Other secondary and tertiary processes (calcification, fibrous degeneration, esp. of elastin) support the hypothesis that the early atherosclerotic lesions and their progress may finally start and perpetuate a metabolic insufficiency of the arterial wall.


Physical and chemical characterization of vitellogenin from the hemolymph and eggs of the tobacco hornworm, Manduca sexta.
1. Vitellogenin has been purified from mature eggs and the hemolymph of adult females of Manduca sexta by a combination of gel permeation chromatography and sodium bromide density gradient centrifugation. 2. It has a molecular weight of 2.6 x 10(5) and is a glycolipoprotein containing approx 11% lipids and 3% carbohydrates. 3. The carbohydrate moiety is comprised entirely of mannose and N-acetyl glucosamine. 4. Two polypeptide chains are present with molecular weights of 1.8 x 10(5) and 5.0 x 10(4). 5. Partial proteolytic hydrolysis of vitellogenin resulted in the degradation of the large polypeptide but did not affect the small one, suggesting that the small polypeptide is located in the interior of the particle. 6. The proteolytic hydrolysis products of the large polypeptide differed from one another by approx 12.5 x 10(3) daltons.


Pasteurella multocida enters polarized epithelial cells by interacting with host F-actin.
We investigated the interaction of an avian strain of Pasteurella multocida with the cytoskeleton of MDCK cells, which formed a polarized epithelium when grown on type I collagen coated filters. Bacteria were incubated with MDCK cells for 30 min. 2, 4 and 6 hours and their location and association with the cell cytoskeleton determined by double-label immunofluorescence confocal microscopy. Cells were stained with a polyclonal antiserum to the outer-membrane proteins of P. multocida and with rhodamine phalloidin which specifically binds filamentous (F) actin. Confocal microscopy revealed that bacteria entered the cells by 30 min, and that by 6 hours there was a marked alteration in the actin cytoskeleton in which long filaments were reorganized to discrete foci of short actin filaments, within which were one or more bacteria. Electron microscopy demonstrated that by 2 hours, each bacterium was associated with many short 5-6 nm filaments. Treatment of MDCK cells with cytochalasin D for either 30 minutes or 24 hours prior to infection disrupted the actin cytoskeleton and inhibited entry of P. multocida.


Gemella morbillorum endocarditis in a patient with a bicuspid aortic valve.
Gemella morbillorum is one of the rare causative microorganisms of endocarditis. We herein report a case of infective endocarditis in a patient with bicuspid aortic valve caused by G. morbillorum. Infective endocarditis diagnosis was established based on the Modified Duke's criteria. The patient was successfully treated with medical-surgical management.


Study on the transmission route of virus aerosol particles and control technology of air conditioning in the enclosed space.
The patient's breathing and air conditioning system in the enclosed space are the main factors that cause indoor cross-infection. However, the research on the influence and the control mechanism of different air conditioning systems on the transmission path of virus aerosol particles exhaled by patients is still limited. To evaluate the effects of different air conditioning systems on the spread of human exhaled pollutants, computational fluid dynamics (CFD) was used to study the movement and diffusion of exhaled air from two rows of 12 sitting adults in a hospital's closed transfusion room. In this paper, three different air conditioning systems are considered: Ceil-supply and Down-return (Ceil-to-Down), Up-supply and Down-return (Up-to-Down), Down-supply and Up-return (Down-to-Up). The distribution of exhaled air velocity, temperature, and virus particle concentration were studied, and it is found that the horizontal diffusion distance of exhaled pollutants is about 0.75 -1.1 m. When up to down systems are used, the air conditioning system shall be closed in time in case of respiratory infectious diseases, so as to avoid cross-infection in the enclosed space. A relatively clean air area with a height of about 1.1 m will be formed, which can inhibit the transmission of the virus to a certain extent when using the down-to-up system. But for those who are exposed to the enclosed space for a long time, the down-to-up system is not the most suitable air conditioning system.


The influence of visual experience and cognitive goals on the spatial representations of nociceptive stimuli.
Localizing pain is crucial because it allows for detecting which part of the body is being hurt and identifying in its surrounding which stimulus is producing the damage. Nociceptive inputs should therefore be mapped according to somatotopic ("which limb is stimulated?") and spatiotopic representations ("where is the stimulated limb?"). Because the body posture constantly changes, the brain has to realign the different spatial representations, for instance when the arms are crossed with the left hand in the right space and vice versa, to adequately guide actions towards the threatening object. Such ability is thought to be dependent on past sensory experience and contextual factors. We compared performances of early blind and normally sighted participants during temporal order judgement tasks. Two nociceptive stimuli were applied, one on each hand, with the hands either uncrossed or crossed. Participants reported which stimulus they perceived as first presented, according to either its location on the body or the position of the stimulated hand, respectively, prioritizing anatomy or external space as task-relevant reference frame. Relative to the uncrossed posture, sighted participants' performances were decreased when the hands were crossed, whatever the instruction be. Early blind participants' performances were affected by crossing the hands during spatial instruction, but not during anatomical instruction. These results indicate that nociceptive stimuli are automatically coded according to both somatotopic and spatiotopic representations, but the integration of the different spatial reference frames depends on early visual experience and ongoing cognitive goals, illustrating the plasticity and the flexibility of the nociceptive system.


Resource-Efficient Sensor Data Management for Autonomous Systems Using Deep Reinforcement Learning.
Hyperconnectivity via modern Internet of Things (IoT) technologies has recently driven us to envision "digital twin", in which physical attributes are all embedded, and their latest updates are synchronized on digital spaces in a timely fashion. From the point of view of cyberphysical system (CPS) architectures, the goals of digital twin include providing common programming abstraction on the same level of databases, thereby facilitating seamless integration of real-world physical objects and digital assets at several different system layers. However, the inherent limitations of sampling and observing physical attributes often pose issues related to data uncertainty in practice. In this paper, we propose a learning-based data management scheme where the implementation is layered between sensors attached to physical attributes and domain-specific applications, thereby mitigating the data uncertainty between them. To do so, we present a sensor data management framework, namely D2WIN, which adopts reinforcement learning (RL) techniques to manage the data quality for CPS applications and autonomous systems. To deal with the scale issue incurred by many physical attributes and sensor streams when adopting RL, we propose an action embedding strategy that exploits their distance-based similarity in the physical space coordination. We introduce two embedding methods, i.e., a user-defined function and a generative model, for different conditions. Through experiments, we demonstrate that the D2WIN framework with the action embedding outperforms several known heuristics in terms of achievable data quality under certain resource restrictions. We also test the framework with an autonomous driving simulator, clearly showing its benefit. For example, with only 30% of updates selectively applied by the learned policy, the driving agent maintains its performance about 96.2%, as compared to the ideal condition with full updates.


The role of diffusion-weighted magnetic resonance imaging in the treatment response evaluation of hepatocellular carcinoma patients treated with radiation therapy.
We investigated the role of diffusion-weighted magnetic resonance imaging (DW MRI) as a response evaluation indicator for hepatocellular carcinoma (HCC) treated with radiation therapy (RT). Inclusion criteria of this retrospective study were DW MRI acquisition within 1 month before and 3 to 5 months after RT. In total, 48 patients were enrolled. Two radiation oncologists measured the apparent diffusion coefficient (ADC). Possible predictive factors, including alteration of the ADC value before and 3 to 5 month after RT, in relation to local progression-free survival (LPFS) were analyzed and compared. Three months after RT, 6 patients (12.5%) showed a complete response, and 27 patients (56.3%) showed a partial response when evaluated using the modified response evaluation criteria in solid tumors (mRECIST). The average ADC ± SD values were 1.21 ± 0.27 ( × 10(-3) mm(2)/s) before and 1.41 ± 0.36 ( × 10(-3) mm(2)/s) after RT (P<.001). The most significant prognostic factor related to LPFS was mRECIST (P<.001). The increment of ADC value (≥ 20%) was also a significant factor (P=.02), but RECIST (version 1.1; P=.11) was not. When RECIST was combined with the increment of ADC value (≥ 20%), the LPFS rates were significantly different between the groups (P=.004), and the area under the curve value (0.745) was comparable with that of mRECIST (0.765). ADC value change before and after RT in HCC was closely related to LPFS. ADC value and RECIST may substitute for mRECIST in patients who cannot receive contrast agents.


Comparative genomics reveals evolutionary drivers of the dietary shift in Hemiptera.
Hemiptera insects exhibit a close relationship to plants and demonstrate a diverse range of dietary preferences, encompassing phytophagy as the predominant feeding habit while a minority engages in carnivorous or haematophagous behaviour. To counteract the challenges posed by phytophagous insects, plants have developed an array of toxic compounds, causing significant evolutionary selection pressure on these insects. In this study, we employed a comparative genomics approach to analyse the expansion and contraction of gene families specific to phytophagous insect lineages, along with their adaptive evolutionary traits, utilising representative species from the Hemiptera order. Our investigation revealed substantial expansions of gene families within the phytophagous lineages, especially in the Pentatomomorpha branch represented by Oncopeltus fasciatus and Riptortus pedestris. Notably, these expansions of gene families encoding enzymes are potentially involved in hemipteran-plant interactions. Moreover, the adaptive evolutionary analysis of these lineages revealed a higher prevalence of adaptively evolved genes in the Pentatomomorpha branch. The observed branch-specific gene expansions and adaptive evolution likely contribute significantly to the diversification of species within Hemiptera. These results help enhance our understanding of the genomic characteristics of the evolution of different feeding habits in hemipteran insects.


Evaluation of the content of bioactive compounds in cocoa beans during the fermentation process.
Cocoa (Theobroma cacao L.), one of the most important agricultural commodity products, is the key raw material for chocolate manufacturing. It is a source naturally occurring polyphenolic compounds and have been widely studied for their beneficial effects to human health. The objective of this study was to evaluate the fermentation time required to obtain more bioactive compounds and higher antioxidant activity in order to propose a mixture of unfermented and fermented cocoa beans in varying concentrations. Samples were collected every 12 h over a fermentation period of 144 h and evaluated according to their physico-chemical characteristics, as well as the content of bioactive compounds. It was verified that after 48 h of fermentation occurred a significant reduction in slate seeds, the appearance of partially fermented beans and the elevation of acidity and temperature. Until this period, a higher content of bioactive compounds with antioxidant activity was also observed. Thus, it is possible to propose a blend of cocoa beans fermented for 48 h and completely fermented beans to elaborate functional chocolates.


Kallikrein-Mediated Cytokeratin 10 Degradation Is Required for Varicella Zoster Virus Propagation in Skin.
Varicella zoster virus (VZV) is a skin-tropic virus that infects epidermal keratinocytes and causes chickenpox. Although common, VZV infection can be life-threatening, particularly in the immunocompromized. Therefore, understanding VZV-keratinocyte interactions is important to find new treatments beyond vaccination and antiviral drugs. In VZV-infected skin, kallikrein 6 and the ubiquitin ligase MDM2 are upregulated concomitant with keratin 10 (KRT10) downregulation. MDM2 binds to KRT10, targeting it for degradation via the ubiquitin-proteasome pathway. Preventing KRT10 degradation reduced VZV propagation in culture and prevented epidermal disruption in skin explants. KRT10 knockdown induced expression of NR4A1 and enhanced viral propagation in culture. NR4A1 knockdown prevented viral propagation in culture, reduced LC3 levels, and increased LAMP2 expression. We therefore describe a drug-able pathway whereby MDM2 ubiquitinates and degrades KRT10, increasing NR4A1 expression and allowing VZV replication and propagation.


Randomised controlled trial: comparison of colloid or crystalloid for partial exchange transfusion for treatment of neonatal polycythaemia.
To compare the efficacy of using isotonic saline (crystalloid) or 5% albumin (colloid) as replacement fluid in partial exchange transfusion (PET) for the treatment of neonatal polycythaemia. One hundred and two polycythaemic full term infants were randomly allocated to receive PET with either isotonic saline or 5% albumin. The criteria for PET were: (a) venous haematocrit > or = 0.7; or (b) venous haematocrit 0.65-0.69 with symptoms or signs attributable to polycythaemia. PET with either saline (n = 53) or 5% albumin (n = 50) resulted in a significant and sustained decline in haematocrit up to 24 hours after PET. Although the immediate haemodilution effect of isotonic saline was statistically smaller than that of 5% albumin (decline in haematocrit 19.3% vs 22.8% of pre-PET value), the difference was too small to be of any clinical significance, and the haematocrit at 4 or 24 hours after PET did not differ significantly between the two groups. PET with either replacement fluid was not associated with any complication. The serum sodium and potassium concentrations were not significantly affected by the PET in either group. Both isotonic saline and 5% albumin are effective when used as replacement fluid in PET for the treatment of neonatal polycythaemia. Isotonic saline, which is cheaper and free of infection, should be the replacement fluid of choice.


Predictors of relapse following a stepwise psychopharmacotherapy regime in patients with depressive disorders.
Real world predictors of relapse following routine treatment for depression remain under-researched. We sought to investigate this in an outpatient clinical sample with depressive disorders receiving stepwise pharmacotherapy based on early clinical decision-making, applying a naturalistic 24-month prospective design. Patients were recruited at a University hospital in South Korea from March 2012 to April 2017. After 3-week antidepressant monotherapy (N = 1262), next treatment steps (1, 2, 3, and 4 or over) with alternative strategies (switching, augmentation, combination, and mixtures of these approaches) were administered based on measurements and patient preference at 3-week points in the acute treatment phase (3, 6, 9, and 12 weeks) (N = 1246). For those who responded [Hamilton Depression Rating Scale (HAMD) score of≤14] (N = 937), relapse (HAMD>14) was identified every 3 months from 6 to 24 months (N = 816). Predictors of relapse were evaluated using multi-variate Cox proportional hazards models. Four independent relapse predictors were identified: higher number of previous depressive episodes, higher anxiety at baseline, higher number of treatment steps, and poor medication adherence. In particular, treatment Step 4 was significantly associated with relapse compared to treatment Step 1, 2, and 3 after adjustment for relevant covariates. Withdrawal syndromes after discontinuing psychotropic drugs, known to confound the determination of relapse, were not evaluated. The study was conducted at a single site, which maximised consistency but may limit generalizability. Predictors of relapse reported from more restricted trial or cohort samples were replicated in this long-term naturalistic prospective design.


Chronic progressive HIV-1 infection is associated with elevated levels of myeloid-derived suppressor cells.
Myeloid-derived suppressor cells (MDSCs) have been described as suppressors of T-cell functions in many tumor models. However, MDSC in HIV-1 infection have not been studied to date. As impaired T-cell function is a hallmark of chronic progressive HIV-1 infection, we hypothesized that MDSC also play a role here. Surface staining and flow cytometry analysis were performed on freshly isolated peripheral blood mononuclear cells (PBMC) of HIV-infected individuals and compared to healthy controls and individuals with lung carcinoma. MDSC of late-stage HIV-infected individuals were isolated using magnetic beads and cocultured with the respective CD8 T cells for evaluation of proliferative capacity. We found that chronically HIV-infected HAART-naive individuals had significantly higher CD11bCD14CD33CD15 MDSC levels than healthy controls (P = 0.01). MDSC frequencies showed a positive correlation with viral load (r = 0.24, P = 0.0002) and a negative correlation with CD4 cell count (r = 0.29, P < 0.0001). Initiation of HAART led to a rapid drop in MDSC levels. MDSC from HIV-infected progressors restricted the proliferative capacity of CD8 T cells from healthy donors and of Gag/Nef-specific CD8 T cells from HIV-controllers in vitro. Furthermore, CD11bCD14CD33CD15 MDSC induced the expansion of CD4CD25FoxP3 regulatory T cells when coincubated with PBMC from controllers in vitro. We conclude that chronic uncontrolled HIV-infection is associated with elevated levels of MDSC, which potentially contribute to the impaired T-cell responses characteristic for the progressive disease stage.


Effect of human endogenous retrovirus-K env gene knockout on proliferation of ovarian cancer cells.
Among various human endogenous retroviruses (HERVs), the HERV-K (HML-2) group has been reported to be highly related to cancer. In pancreatic cancer cells, shRNA-mediated downregulation of HERV-K env RNA decreases cell proliferation and tumor growth through the RAS-ERK-RSK pathway; in colorectal cancer, CRISPR-Cas9 knockout (KO) of the HERV-K env gene affects tumorigenic characteristics through the nupr-1 gene. The effect of HERV-K env KO has not been studied in ovarian cancer cell lines. In this study, we analyzed the tumorigenic characteristics of ovarian cancer cell lines, including cell proliferation, migration, and invasion, and the expression patterns of related proteins after CRISPR-Cas9 KO of the HERV-K env gene. The HERV-K env gene KO was achieved using the CRISPR-Cas9 system in ovarian cancer cell lines SKOV3 and OVCAR3. Tumorigenic characteristics including cell proliferation, migration, and invasion were analyzed, and related protein expression was investigated by western blot analysis. The expression of the HERV-K env gene in KO cells was significantly reduced at RNA and protein levels, and tumorigenic characteristics including cell proliferation, migration, and invasion were significantly reduced. In HERV-K env KO SKOV3 cells, the expression of the RB protein was significantly up-regulated and the cyclin B1 protein level was significantly reduced. In contrast, in HERV-K env KO OVCAR3 cells, the level of phospho-RB protein was significantly reduced, but other protein levels were not changed. The results of this study showed that HERV-K env gene KO affects cell proliferation, invasion, and migration of ovarian cells through RB and Cyclin B1 proteins, but the specific regulation pattern can differ by cell line.


A clinical comparison of two different prednisolone acetate formulations in patients undergoing cataract surgery.
This study was conducted to evaluate the efficacy of two topical steroid prednisolone preparations (Econopred Plus 1%, prednisolone acetate 1%: EPP; Pred Fortedagger 1%, prednisolone acetate 1%: PF) in reducing postoperative inflammation in cataract patients. This was a 4 week, randomized, parallel-group, single-center, active-controlled study. One group of patients received postoperative topical EPP while the other group received postoperative topical PF. Both medications were dosed 4 times per day for 14 days and then BID until the container was empty. Both groups of patients received diclofenac sodium QID for 14 days and hydroxypropyl guar (HP-Guar, Systane) QID for 7 days then PRN (or as directed). The presence of corneal surface keratitis, anterior chamber cells and flare (scales 0-3 for keratitis, 0-5 for cells and 0-4 for flare; 0 = none) was evaluated by slit lamp biomicroscopy. EPP produced significantly lower (P < 0.05) anterior chamber flare scores 14 days following surgery (mean +/- SD: 0.86 +/- 0.53) than PF (1.08 +/- 0.40). Otherwise, there were no differences observed between the 2 treatments with respect to keratitis, anterior chamber flare or cells at postop days 1, 7, or 28. This comparative trial demonstrated that both formulations of prednisolone acetate 1% have similar efficacy in the treatment of postoperative ophthalmologic inflammation.


Apoptosis induced in human colorectal carcinoma by anti-Fas antibody.
Apoptosis or programmed cell death has been shown to play an important role in the progression from polyps to carcinomas. Fas/APO-1 is a cell surface protein that can induce apoptosis in a variety of cell types upon specific binding. In this study seven human colorectal carcinoma (HCRC) cell lines of varying differentiation were analyzed for cell surface Fas expression. Fas-mediated apoptosis, and correlation of apoptosis with bcl-2 expression. Using flow cytometry, all seven lines expressed varying amounts of cell surface Fas antigen. Exposure to anti-Fas antibody induced cell death in all the cell lines, albeit to varying degrees. The rate of apoptosis was quantitated using flow cytometry with propidium iodide staining of nuclear DNA. The poorly differentiated cell lines had a significantly decreased (p < 0.05) anti-Fas sensitivity as compared with the well-differentiated lines. Measurement of bcl-2 expression by flow cytometry showed an inverse correlation with anti-Fas sensitivity. This study confirms that HCRC cell lines express Fas antigen and, more importantly, provides the first evidence that exposure to anti-Fas antibody can induce apoptosis. Fas-mediated apoptosis in HCRC cell lines may be regulated by bcl-2 and may correlate with the degree of differentiation.


Inversion of direction-selectivity to anterior fields in neurons of nucleus of the optic tract in rabbits with ocular albinism.
Extracellular recordings were made of 46 well-isolated single units in the nucleus of the optic tract (NOT) from 27 rabbits which were paralyzed but unanesthetized. Rabbits were selected from 3 varieties with ocular albinism. These units showed short latencies (mean = 2.2 msec, S.D. = 0.4) to chiasmic stimulation suggestive of monosynaptic innervation from retinal ganglion cells. Receptive fields were large and receptive field centers were confined to the projection of the visual streak. All units showed direction selectivity in which preferred stimulus motions were always nearly horizontal in the anterior or posterior direction. The direction selectivity of the units was broad in that excitatory acceptance angles were 180 degrees. Single units recorded from NOT in albino rabbits could be classified into 4 types based on regions of direction selectivity. The most common (64%) type of unit had receptive fields with two regions of opposed direction selectivity. The preferred direction of motion was anterior in lateral and posterior visual fields and was posterior in anterior visual fields. Two smaller groups of units (13% and 11%) had receptive fields with only one preferred direction. When the receptive field was anterior, the preferred direction was posterior. When the receptive field was lateral or posterior, the preferred direction was anterior. The least commonly encountered type of unit (7%) had receptive fields with two regions of direction selectivity. Anterior visual fields gave rise to anterior direction selectivity and lateral and posterior visual fields gave rise to posterior direction selectivity. The characteristics of NOT units are similar to those described for NOT units in pigmented rabbits except for an inversion of direction selectivity to stimulation from anterior visual fields. NOT units in albino rabbits show posterior direction selectivity when stimulation arises from anterior visual fields. The difference in directional preference in the visual receptive fields of the units in the NOT of albino rabbit may be responsible for the inversion of optokinetic pursuit eye movements characteristic of albino rabbits.


Pancreatic neuroendocrine tumors in MEN1 disease: a mono-centric longitudinal and prognostic study.
Multiple endocrine neoplasia type 1 (MEN1) is an inherited endocrine neoplastic syndrome associated with a greater risk of endocrine tumor development like pancreatic neuroendocrine tumors (p-NET), with different clinical characteristics from sporadic ones. This paper aims to compare clinical, hystological and morphological aspects of p-NET in patients affected from MEN1 (MEN1+) and not-affected ones (MEN1-). We performed a retrospective observational study. Data was collected between December 2010 and December 2015, including patients with a histological diagnosis of p-NET and radiological imaging. We compared clinical, histological, radiological, and prognostic aspects of MEN+ p-NET with MEN-1 p-NET. Of the 45 patients enrolled, 13 MEN1+ and 21 MEN1- cases were analyzed. Frequency of not secreting p-NETs and insulin secreting p-NETs, histopathological grades and Ki67 expression were superimposable between MEN1+ and MEN1- patients. MEN1+ pNETs are more often multicentric compared to MEN1- pNETs. Frequency of liver and nodes metastatic spread was higher in MEN1- p-NET compared to MEN1+ p-NET. Analyzing p-NET according to the disease outcome, we found that recovered and stable p-NETs in MEN1+ patients, compared to MEN1- cases, are diagnosed at lower age (p = 0.04/p = 0.002) and that are more frequently multifocal lesions (p = 0.009/p = 0.002). In our study pNETs in MEN1+ and pNETs in MEN1- don't significantly differ for prognosis but only for clinical features. p-NET stage disease and prognosis can be positively influenced by early diagnosis and screening in index patients' first-degree relatives.


Spatial distribution and determinants of PM2.5 in China's cities: fresh evidence from IDW and GWR.
While numerous studies have explored the spatial patterns and underlying causes of PM2.5 at the urban scale, little attention has been paid to the spatial heterogeneity affecting PM2.5 factors. In order to enrich this research field, we collected PM2.5 monitoring data from 367 cities across China in 2016 and combined inverse distance weighted interpolation (IDW) and geographically weighted regression (GWR) model. As a result, we could dynamically describe the spatial distribution pattern of urban PM2.5 at monthly, seasonal, and annual scales and investigate the spatial heterogeneity of the influential factors on urban PM2.5. Furthermore, in order to make the result more scientific and reasonable, the paper used selection.gwr function and bw.gwr function, respectively, to optimize model, thereby avoiding local collinearity caused by independent variables. The main results are as follows: (1) PM2.5 in Chinese cities is characterized as time-space non-equilibrium pattern. The Beijing-Tianjin-Hebei region, the Yangtze River corner region, the Pearl River Delta region, and the northeast region have formed a pollution-concentrating core area with Beijing-Tianjin-Hebei region as the axis, which brings greater difficulties and challenges to PM2.5 governance. (2) The effects of various factors of socio-economic activities on the concentration of PM2.5 have significant spatial heterogeneity among Chinese cities. (3) There is an inverted "U" curve between economic growth and PM2.5. When the per capita income reaches 47,000 yuan, the PM2.5 emission reaches the peak, which proves the existence of environmental Kuznets curve (EKC). These findings could provide a significant reference for policy makers in China to facilitate targeted and differentiated regional PM2.5 governance measures.


Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice.
Liver regeneration following hepatectomy is complicated and involves a variety of interacting factors. The present study was designed to study the roles of proliferation and hypertrophy of hepatocytes in liver regeneration following hepatectomy in liver-specific STAT3-knockout (LS3-KO) mice lacking mitogenic activity. Partial hepatectomy was performed in LS3-KO and control mice. Liver regeneration was estimated by the liver weight, cell proliferation and cell size, and the related cellular signals were analyzed. Proliferation of hepatocytes following PH was markedly suppressed in LS3-KO mice with reduced cyclinD1 transcript. However, liver mass recovered sufficiently following PH in LS3-KO mice almost equal to that of control mice. Analysis of hepatocellular growth revealed that cell size following hepatectomy was significantly larger in LS3-KO mice than in control mice. Hepatectomy induced immediate but transient phosphorylation of Akt, p70S6K, mTOR and GSK-3beta in LS3-KO mice much more than in control mice. Additionally, adenoviral transfection of dominant negative mutant of Akt to control and LS3-KO mice led to insufficient liver regeneration following hepatectomy. PI3-K/Akt-mediated responsive hepatocellular hypertrophy may be essential for liver regeneration following hepatectomy and sufficiently compensated liver regeneration even in STAT3-deficient liver, in which cell proliferation is impaired.


Multiple Endocrine Neoplasia Type 1 (NEM1) is related to mutations of the menin gene. It is an autosomal dominant disease. Its prevalence is about 1/30 000 with a hugh penetrance. There is no genotype-phenotype correlation. This hereditary syndrome is characterized by the presence of tumors of the endocrine system (parathyroid, endocrine pancreas, pituitary and adrenal gland). Other disorders have also been described (bronchial and thymic carcinoid tumor, breast cancer, skin lesions). Management must take into account the specificities of these pathologies in NEM1 compared to sporadic forms (young age at diagnosis, multiple lesions within the same gland, multi-focal disease). © 2019 Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Les Must de l'Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.


Mixed ovarian germ cell tumor in a child: A case report of a rare association.
ovarian tumors and especially mixed ovarian germ cell tumors are rarely seen in the paediatric population. we report the case of a 13-year-old girl which was successfully treated for a mixed ovarian germ cell tumor with a favorable evolution. the incidence of mixed ovarian germ cell tumors, clinical manifestations, histologic distribution and prognosis are predominentely distinct in children and adolescents as compared to adult population. The diagnosis should be suspected in young girls with chronic abdominal pain and palpable swelling of the lower abdomen. Conservative surgery is the first therapeutic procedure that consists of a total resection of the mass with preservation of the reproductive function. Circulating tumor markers have the potential in diagnosis, prognostic stratification and for follow-up. mixed ovarian germ cell tumors are uncommen in children. Their management must be multidisciplinary and conservative surgery by laparotomy represent the standard of care.


Optimization of a human milk-directed quantitative sIgA ELISA method substantiated by mass spectrometry.
Immunoglobulins are the primary protective products in human milk and are responsible for transferring maternal pathogen memory to the infant, providing protection by binding to recognized pathogens and inhibiting virulence. To better understand potentially protective/anti-infective compounds in human milk, the establishment of human milk-tailored analytical approaches is crucial, as most contemporary analytical methods have been optimized for plasma or serum. One of the most prominent immunoglobulins in human milk is secretory immunoglobulin A (sIgA), which may be relevant for the protection of breastfed infants from harmful pathogens. Advanced sIgA detection methods can help monitor the immune status and development of the mother-infant dyad. We therefore developed an enzyme-linked immunosorbent assay (ELISA) sIgA method for the quantitative analysis of IgA plus secretory component (SC), validated with sIgA standards and substantiated by mass spectrometry (MS)-based proteomics. A very strong correlation was observed between the MS-detected IgA1 and the human milk-specific sIgA ELISA (r = 0.82). Overall, the MS data indicate that the developed human milk sIgA ELISA does not differentiate between sIgA1 and sIgA2 and is, therefore, a reflection of total sIgA. Furthermore, our MS data and the human milk-derived sIgA ELISA data are better correlated than data derived from a standard serum IgA ELISA kit (relative to MS IgA1 r = 0.82 and r = 0.42, respectively). We therefore propose our human milk-specific sIgA ELISA as an ideal quantitative indicator of total sIgA with advantages over current serum IgA ELISA kits.


Stabilization of polymer lipid complexes prepared with lipids of lactic acid bacteria upon preservation and internalization into eukaryotic cells.
The physicochemical characterization of polymer liposome complexes (PLCs) prepared with lipids of lactic acid bacteria and poly(N,N-dimethylaminoethyl methacrylate) covalently bound to cholesterol (CHO-PDMAEMA) was carried out in an integrated approach, including their stability upon preservation and incorporation into eukaryotic cells. PLCs were prepared with different polymer:lipid molar ratios (0, 0.05 and 0.10). Zeta potential, particle size distribution and polydispersity index were determined. The optimal polymer:lipid ratio and the stability of both bare liposomes and PLCs were evaluated at 37 °C and at different pHs, as well as after storage at 4 °C, -80 °C and freeze-drying in the presence or absence of trehalose 250 mM. Internalization of PLCs by eukaryotic cells was assessed to give a complete picture of the system. Incorporation of CHO-PDMAEMA onto bacterial lipids (ratio 0.05 and 0.10) led to stabilization at 37 °C and pH 7. A slight decrease of pH led to their strong destabilization. Bacteria PLCs showed to be more stable than lecithin (LEC) PLCs (used for comparison) upon preservation at 4 and -80 °C. The harmful nature of the preservation processes led to a strong decrease in the stability of PLCs, bacterial formulations being more stable than LEC PLCs. The addition of trehalose to the suspension of liposomes stabilized LEC PLC and did not have effect on bacterial PLCs. In vitro studies on Raw 264.7 and Caco-2/TC7 cells demonstrated an efficient incorporation of PLCs into the cells. Preparations with higher stability were the ones that showed a better cell-uptake. The nature of the lipid composition is determinant for the stability of PLCs. Lipids from lactic acid bacteria are composed of glycolipids and phospholipids like cardiolipin and phosphatidylglycerol. The presence of negatively charged lipids strongly improves the interaction with the positively charged CHO-PDMAEMA, thus stabilizing liposomes. In addition, glycolipids and phosphatidylglycerol act as intrinsic protectants of PLCs upon preservation. This particular lipid composition of lactic acid bacteria makes them natural formulations potentially useful as drug delivery systems.


Postnatal cardiovascular and metabolic responses to a single intramuscular dose of betamethasone in fetal sheep born prematurely by cesarean section.
Although the benefits of antenatal hormone treatment are well accepted, most studies have reported only pulmonary effects. There is evidence of beneficial cardiovascular and metabolic effects in studies using chronically catheterized animals; however because of the route of administration, the results are not directly applicable to clinical strategies. We previously demonstrated significant pulmonary effects in animals treated antenatally with a single, direct fetal, intramuscular injection of glucocorticoids. This study was performed to determine the effects of a single fetal injection of betamethasone (BETA) alone or in combination with thyroxine (T4) on cardiovascular and metabolic responses after preterm birth. Hemodynamic and metabolic responses at birth were determined in fetuses (126-d gestation; term = 150 d) treated with ultrasound-guided intramuscular injections of 0.5 mg/kg BETA (n = 7), BETA plus 60 g/kg T4 (n = 7), or saline (SAL, n = 9). After 48 h, lambs were delivered by cesarean section and studied for 3 h. BETA treatment increased mean arterial blood pressure [56 +/- 6 (SEM) versus 42 +/- 3 mm Hg], heart rate (152 +/- 5 versus 123 +/- 4 beats/min), and cardiac output (467 +/- 17 versus 349 +/- 36 mL/min/kg) versus SAL. Responses of BETA+T4-treated animals were not different from animals treated with BETA alone. Glucose and FFA were similar among all groups. The increase in catecholamine levels normally seen at birth was significantly attenuated in both the BETA and BETA+T4-treated animals. A single, intramuscular injection of glucocorticoids 48 h before delivery improves cardiovascular responses to preterm birth. This effect is not augmented by concomitant administration of T4.


Social Isolation and Loneliness as Risk Factors for Grip Strength Decline Among Older Women and Men in China.
The purpose of this study was to examine the relationships of social isolation and loneliness, both individually and simultaneously, on changes in grip strength among Chinese older adults and whether these relations vary by gender. A 4-year prospective observational study. This study used data from the China Health and Retirement Longitudinal Study (CHARLS). Analyses were conducted with data from 2 waves (2011 and 2015) and were restricted to those respondents aged 50 and older [n = 7025, mean age (SD) = 61.46 (7.59); male, 48.4%]. Social isolation, loneliness, and grip strength were measured at baseline. Follow-up measures of grip strength were obtained 4 years later. Multiple linear regression was used to evaluate the associations among baseline isolation, loneliness, and decline of grip strength between 2 waves after adjustment for age, gender, education, body mass index, chronic diseases, smoking and drinking status, activities of daily living (ADL) and instrumental ADL disabilities, and depressive symptoms. For women, baseline loneliness (β = 0.04, P = .035) rather than isolation (β = 0.03, P = .110) significantly predicted grip strength decline after 4 years when other confounding variables were taken into account. For men, baseline isolation (β = 0.05, P = .005) rather than loneliness (β = 0.01, P = .570) significantly predicted grip strength decline. No synergistic effect of isolation and loneliness on grip strength was found for either women or men. In this prospective study, gender differences were found for the associations of social isolation and loneliness with grip strength decline. Our results suggest that older women and men may benefit from different social enhancement strategies for prevention of physical function decline.


How challenging could be preoperative and intraoperative diagnosis of endometrial cancer?
Aim of this study was to rate the misdiagnosis of histological type between preoperative endometrial biopsy and final postoperative pathology focusing on non-endometrioid endometrial cancer (NEEC). Secondary objective is to assess the concordance between intraoperative assessment and final pathology in a subgroup of patients. A multicenter retrospective study was conducted in patients with histological diagnosis of endometrial cancer who underwent surgical staging between 2011 and 2016. The concordance rate and the Kappa Cohen coefficient were calculated to assess the correlation concerning the histological type between endometrial biopsy and final pathology, and between intraoperative assessment and final pathology in a subgroup of patients. Two hundred ninety-five patients were enrolled, 226 were endometrioid carcinomas and 61 NEEC at final pathology. The concordance rate between pre-operative and final pathology for NEEC and the Kappa Cohen coefficient were 81.4% and 0.41 (CI 95% 0.3059-0.5122), respectively. 26 out of 61 (42.6%) NEEC were preoperatively misdiagnosed. The frozen section was performed in a subgroup of 86 patients (29.15%): the concordance rate between frozen section and final pathology for NEEC was 80% and the Kappa Cohen coefficient was 0.28 (CI 95% 0.212-0.347). Preoperative pathological histotype assessment predicts final pathology with a moderate grade of accuracy and the identification of NEEC could be challenging. Efforts should be directed toward molecular characterization of diagnostic samples in order to improve diagnostic accuracy and guide therapeutic decisions.


Application of Cerenkov radiation for the assay of 226Ra in natural water.
A Cerenkov based method has been developed for the determination of 226Ra via its beta-emitting daughters, 214Bi and 214Pb. Radium isotopes are separated from interfering elements by coprecipitation on barium sulphate. The precipitate is dissolved in an alkaline solution of EDTA and the Cerenkov signal produced by the build-up of daughter beta activities is counted after 25 days using the tritium channel of a liquid scintillation counter. To correct for any contribution from the daughters of the radium isotopes 224Ra and 228Ra present in the sample, the barium(radium) sulphate is reprecipitated, dissolved in EDTA, and counted 2 days later. Using this procedure, 228Ra can be determined in the same sample. Cerenkov counting efficiency was found to be 77.25%. A lower limit of detection of 17.4 mBq l-1 (based on 3 sigma of the background with 500 min counting time) was achieved. Any liquid scintillation counter can be used. Chemical recoveries in the range 75-95% were determined gravimetrically. Data from both artificial spiked samples and natural samples are presented.


[Prevalence of diarrhea in adult patients in intensive care and its relationship with ready-to-use enteral formulas]
Diarrhea is a frequent complication in critically ill patients. Its origin is multifactorial. The objective of this work is to analyze the relationship between 5 ready-to-use formulas and the development of diarrhea in critically ill patients. Retrospective study where the volume of the stools of 315 patients and the presence of diarrhea defined with a cut-off point of a volume of 250 ml/day were evaluated. 35.34% of the patients presented diarrhea with said cut-off point. The mean volume of stools was 269.20 ml (95% CI: 255.05-283.06). It was observed that all the formulas analyzed had a slight correlation with the Spearman test between the volume provided and the volume of stools, being: Nutricia Nutrison ® (R: 0.159; P: 0.053), Nutricia Multifibra ® (R: 0.296; <0.001), Nutricia Peptisorb ® (R: 0.323; P<0.001), Nutricia Protison ® (R: 0.108; P<0.001), Fresenius Supportan ® (R: 0.152; P<0.001). Multivariate analysis was performed and it was observed that there were no differences in the incidence of diarrhea between the different enteral formulas during the first 10 days. The change of formulas during hospitalization would be a predisposing factor for diarrhea. Therefore, the formula and the volume provided are factors that could influence whether patients have diarrhoea. Understanding these possible influences in a deeper way will allow the safest choice of enteral formulas for a patient with diarrhea.


[Evaluation of the treatment of cystic lymphangioma by percutaneous injection of Ethibloc in 20 patients].
Surgical treatment of cystic lymphangioma (CL) is so often followed by local and general complications that non invasive treatment must be considered. Between 1987 and 1993, 20 patients with a superficial macrocystic lymphangioma were treated by percutaneous injection of Ethibloc in order to reduce the volume of the CL, with a minimum follow-up of 1 year. Fourteen CL were cervico-facial and six were located in the upper half of the body. The size of the lesion was determined by echography: three CL were less than 5 cm in diameter, 12 between 5 and 10 cm, five more than 10 cm. Two to 5 mL of Ethibloc were injected during one (15 cases) or several sessions (five cases). Reduction in volume was excellent in 12 patients after one session and in four patients after several sessions. Four patients had a poor result. All the patients suffered from an important inflammatory reaction for 2 or 3 days followed by exteriorisation of the Ethibloc in seven patients, with a discrete final scar. These fair results suggest that intracystic injection of Ethibloc represents an effective alternative to surgery.


Testicular toxicity in vitro: Sertoli-germ cell co-cultures as a model system.
Testicular damage is a comparatively common finding in toxicity studies. Part of the susceptibility of the testis to chemical toxicity stems from the complexity of its normal structure, function and regulatory control. This complexity has stimulated the development and extensive use of testicular cell cultures in the study of normal testicular function. However, the potential of such systems for investigating chemically induced testicular toxicity has only recently been considered. Using primary co-cultures of Sertoli and germ cells many features of the well characterized testicular damage produced by phthalate esters and glycol ethers could be reproduced in vitro. These encouraging findings are discussed in relation to some of the likely limitations to the application of in vitro models for testicular toxicity.


The 2HA line of Medicago truncatula has characteristics of an epigenetic mutant that is weakly ethylene insensitive.
The Medicago truncatula 2HA seed line is highly embryogenic while the parental line Jemalong rarely produces embryos. The 2HA line was developed from one of the rare Jemalong regenerates and this method for obtaining a highly regenerable genotype in M. truncatula is readily reproducible suggesting an epigenetic mechanism. Microarray transcriptomic analysis showed down regulation of an ETHYLENE INSENSITIVE 3-like gene in 2HA callus which provided an approach to investigating epigenetic regulation of genes related to ethylene signalling and the 2HA phenotype. Ethylene is involved in many developmental processes including somatic embryogenesis (SE) and is associated with stress responses. Microarray transcriptomic analysis showed a significant number of up-regulated transcripts in 2HA tissue culture, including nodule and embryo specific genes and transposon-like genes, while only a few genes were down-regulated, including an EIN3-like gene we called MtEIL1. This reduced expression was associated with ethylene insensitivity of 2HA plants that was further investigated. The weak ethylene insensitivity affected root and nodule development. Sequencing of MtEIL1 found no difference between 2HA and wild-type plants. DNA methylation analysis of MtEIL1 revealed significant difference between 2HA and wild-type plants. Tiling arrays demonstrated an elevated level of miRNA in 2HA plants that hybridised to the antisense strand of the MtEIL1 gene. AFLP-like methylation profiling revealed more differences in DNA methylation between 2HA and wild-type. Segregation analysis demonstrated the recessive nature of the eil1 phenotype and the dominant nature of the SE trait. We have demonstrated that EIL1 of Medicago truncatula (MtEIL1) is epigenetically silenced in the 2HA seed line. The possible cause is an elevated level of miRNA that targets its 3'UTR and is also associated with DNA methylation of MtEIL1. Down regulation of MtEIL1 makes it possible to form nodules in the presence of ethylene and affects root growth under normal conditions. Segregation analysis showed no association between MtEIL1 expression and SE in culture but the role and mechanism of ethylene signalling in the process of plant regeneration through SE requires further investigation. The work also suggests that epigenetic changes to a particular gene induced in culture can be fixed in regenerated plants.


Droughts in India from 1981 to 2013 and Implications to Wheat Production.
Understanding drought from multiple perspectives is critical due to its complex interactions with crop production, especially in India. However, most studies only provide singular view of drought and lack the integration with specific crop phenology. In this study, four time series of monthly meteorological, hydrological, soil moisture, and vegetation droughts from 1981 to 2013 were reconstructed for the first time. The wheat growth season (from October to April) was particularly analyzed. In this study, not only the most severe and widespread droughts were identified, but their spatial-temporal distributions were also analyzed alone and concurrently. The relationship and evolutionary process among these four types of droughts were also quantified. The role that the Green Revolution played in drought evolution was also studied. Additionally, the trends of drought duration, frequency, extent, and severity were obtained. Finally, the relationship between crop yield anomalies and all four kinds of drought during the wheat growing season was established. These results provide the knowledge of the most influential drought type, conjunction, spatial-temporal distributions and variations for wheat production in India. This study demonstrates a novel approach to study drought from multiple views and integrate it with crop growth, thus providing valuable guidance for local drought mitigation.


Pharmacokinetics of amiloride after inhalation and oral administration in adolescents and adults with cystic fibrosis.
To compare the pharmacokinetics and systemic exposure of nebulized and oral amiloride in adolescents and adults with mild to moderate cystic fibrosis (CF). Open-label, randomized, two-way crossover, single-dose pharmacokinetic study. University hospital clinical research unit. Nine adolescents and 10 adults with mild to moderate CF (forced expiratory volume in 1 sec > or = 50% predicted, Brasfield score > or = 15). Patients received amiloride solution orally (10 mg of amiloride 1-mg/ml solution) and by inhalation [4.5 ml amiloride of 1-mg/ml solution in 12% saline (approximately 3.8 mmol/L) by DeVilbiss 646 nebulizer] during two study phases separated by a 7- to 28-day washout period. Serial blood and urine samples were collected for 48 and 72 hours, respectively. After oral dosing, the mean +/- SD maximum peak concentration (Cmax) was 20.6 +/- 10.0 ng/ml at 3.2 +/- 1.2 hours in adults and 21.7 +/- 4.88 at 2.9 +/- 0.6 hours in the adolescents. Mean area under the concentration-time curve (AUC) from time zero to infinity hours was 275 +/- 115 and 254 +/- 60 ng.hr/ml in the adult and adolescent groups; half-life was 16.0 +/- 0.7 and 13.4 +/- 1.4 hours, respectively. After nebulization, 14 of 19 subjects exhibited two concentration peaks (Cmax1 and Cmax2) with mean values of 1.57 +/- 1.67 ng/ml at 0.5 +/- 0.2 hours and 1.37 +/- 1.21 ng/ml at 4.0 +/- 1.0 hours for adults, and 1.49 +/- 0.99 ng/ml at 0.5 +/- 0.1 hours and 1.52 +/- 0.81 ng/ml at 3.3 +/- 0.5 hours for adolescents. Estimated mean +/- SD dose nebulized was 1.91 +/- 0.66 and 2.28 +/- 0.30 mg in the adult and adolescent groups, respectively. Mean +/- SD AUC from time zero to the last measurable plasma amiloride concentration after inhalation was 14.4 +/- 17.6 and 15.4 +/- 10.1 ng.hr/ml in the adults and adolescents. No significant adverse events occurred during the study. Pharmacokinetic parameters were not statistically different between the adolescent and adult groups by route of administration. However significant differences in peak amiloride concentration, AUC, and urinary amiloride excretion were evident when comparing oral versus inhalation administration within each group. Mean amiloride plasma concentration peaks and AUC after inhalation were significantly lower than after oral dosing. In addition, the second amiloride plasma concentration peak may be due to oral ingestion of the nebulized amiloride, whereas the earlier Cmax1 after inhalation may be due to pulmonary absorption of amiloride. These results suggest that single-dose amiloride inhalation in patients with mild to moderate CF results in minimal systemic exposure compared with oral dosing, and that drug disposition is similar in adolescents and adults with CF.


The Relationship of Risk to Rules, Values, Virtues, and Moral Complexity: What We can Learn from the Moral Struggles of Military Leaders.
Leaders are faced with ethical and moral dilemmas daily, like those within the military who must span from large-scale combat operations to security cooperation and deterrence. For businesses, these dilemmas can include social and environmental impact such as those in mining; and for governments, the social and economic impact of their decision-making in their response to COVID-19. The move by Western defence forces to align their foundational principles, policies, and "soldier" dispositions with the changing values of the countries they serve are starkly illustrative of challenges faced by all leaders. While admirable, such changes face the apparent contradiction of enhancing individual moral agency within a hierarchical organization that maintain enforceable codes of conduct. Ethical leadership theory provides aspirational goals, but lacks empirically based guidance on how to implement policies that facilitate values-based behavior. Using a discourse theory analysis of a moral dilemma vignette with Royal Australian Air Force personnel, this research identifies important aspects of agency and subject position that must be addressed if such policies are to succeed. These findings show that the potential contradiction can be addressed by acknowledging the contrasting tendency to bureaucratic process by leaders at upper levels, while lower-level leaders address moral issues by incorporating their subjectivity and making a conscious deontological choice between humanity and comrade loyalty.


Evolution of PM2.5 bacterial community structure in Beijing's suburban atmosphere.
Biosafety has become one of the greatest challenges facing humanity. Outbreaks of infectious diseases caused by bacteria and viruses have had a huge impact on public health. In addition, non-severe polluted air quality has gradually become the norm; however, literature on the impacts of bioaerosols under long-term exposure to low concentrations of PM2.5 in China is limited. This study analyzed the evolution of the PM2.5 bacterial community in the Huairou district of Beijing under different pollution conditions. We used high-throughput sequencing to seasonally analyze samples over a year (from July 2018 to May 2019) and winter samples from different years (2015, 2016, 2018, and 2019). The results showed that the bacterial diversity and community composition of PM2.5 were significantly different in different seasons, whereas under different pollution levels, there were no significant differences. During the observation period, the number of bacterial species decreased with the increase in pollution; however, a high proportion of bacteria can exist as core species under different pollution levels for a long time. Furthermore, bacteria can be relatively stable in the local environment during the same season but in different years. Although the relative abundances of different bacteria change differently with the variation in pollution level, there is no statistical difference. Importantly, there was a higher abundance of opportunistic pathogenic bacteria when the air quality index was 0-100 in winter. This study comprehensively revealed the characteristics of the evolution of bacterial communities under different pollution levels and in different years and emphasized the health effects of non-pollution air quality. This study can provide a theoretical basis for establishing a sound environmental microbial monitoring and defense system.


Coherence assessment of accident database kinematic data.
The analysis and research of accidents aimed at improving the safety of vehicles and infrastructures are typically based on the retrospective investigation of data that are collected in in-depth accident databases. In particular, kinematic data related to accidents (impact velocity, velocity change of the vehicles, etc.) make possible the identification of correlations between impact severity and injury risk (IR), as well as assessing the effectiveness of vehicle protection systems. The necessary condition to conduct suitable and significant analyses is to utilise data which are correct and representative of national statistics, i.e., congruent with physical laws governing the accident phenomena. Whereas representativeness can generally be retrospectively verified, the checks on kinematic data coherence during codification are rarely performed. The present work describes a procedure to verify the internal coherence of kinematic data collected in in-depth accident databases. The introduced checks allow the identification of parameters, which are not internally coherent because the accident reconstruction model employed is inappropriate or improperly used. These checks pertain to physical laws on which road accident reconstruction is based, i.e., momentum conservation, compatibility of velocity triangles, and energy conservation. Moreover, they can be modified and expanded to consider other parameters, making the methodology virtually applicable to any database. In the case of vehicle-to-vehicle collisions, the application of the procedure to detect incongruent data inside two real databases demonstrates how their number is often not negligible. Furthermore, consequences can be substantial for both direct and secondary analysis, i.e., determining IR curves (for example, logistic regression on input data) and identifying IR associated to an accident. Accordingly, the application of checks is particularly recommended during both analysis and collection phases to confirm the congruence of collected data; consequently, the quality of investigation is enhanced.


Parent-Child Engagement in Decision Making and the Development of Adolescent Affective Decision Capacity and Binge Drinking.
The goal of this study was to investigate how parents' engagement of their child in everyday decision-making influenced their adolescent's development on two neuropsychological functions, namely, affective decision-making and working memory, and its effect on adolescent binge-drinking behavior.We conducted a longitudinal study of 192 Chinese adolescents. In 10(th) grade, the adolescents were tested for their affective decision-making ability using the Iowa Gambling Task (IGT) and working memory capacity using the Self-ordered Pointing Test (SOPT). Questionnaires were used to assess perceived parent-child engagement in decision-making, academic performance and drinking behavior. At one-year follow-up, the same neuropsychological tasks and questionnaires were repeated.Results indicate that working memory and academic performance were uninfluenced by parent-child engagement in decision-making. However, compared to adolescents whose parents made solitary decisions for them, adolescents engaged in everyday decision-making showed significant improvement on affective decision capacity and significantly less binge-drinking one year later.These findings suggest that parental engagement of children in everyday decision-making might foster the development of neurocognitive functioning relative to affective decision-making and reduce adolescent substance use behaviors.


Optimising concentrations of antimicrobial agents in pharmaceutical preparations: Case of an oral solution of glycerol and an ophthalmic solution containing cysteamine.
In the context of current distrust of antimicrobial preservatives, the quantities of these substances in two pharmaceutical formulas were studied: an ophthalmic solution of cysteamine preserved benzalkonium chloride at 1mg/5mL and Glycerotone(®) preserved with sorbic acid at 0.1g/100g. The purpose of this work was to verify that a reduction of the quantities of preservative continues to fulfil the requirements for antimicrobial preservation. The Test of efficacy of antimicrobial preservation, section 5.1.3 of the 8th edition of the European Pharmacopoeia, was carried out on each formulation prepared with decreasing quantities of preservative. The results show that formulations whose preservative concentration was reduced by a factor of four remained compliant with standards. It is to be noted that in formulas without preservative, fungal growth was observed in both the solution of Glycerotone(®) and the ophthalmic solution containing cysteamine. Although there is no question that an antimicrobial preservative is necessary, the quantity of preservative can be reduced without deteriorating the quality of the pharmaceutical product but the minimal effective concentration remains to be determined. The formulations of many pharmaceutical products should therefore be examined in order to limit the quantities of preservative while continuing to guarantee patient's safety.


Graphene oxide exposure alters gut microbial community composition and metabolism in an in vitro human model.
Graphene oxide (GO) nanomaterials have unique physicochemical properties that make them highly promising for biomedical, environmental, and agricultural applications. There is growing interest in the use of GO and extensive in vitro and in vivo studies have been conducted to assess its nanotoxicity. Although it is known that GO can alter the composition of the gut microbiota in mice and zebrafish, studies on the potential impacts of GO on the human gut microbiome are largely lacking. This study addresses an important knowledge gap by investigating the impact of GO exposure- at low (25 mg/L) and high (250 mg/L) doses under both fed (nutrient rich) and fasted (nutrient deplete) conditions- on the gut microbial communitys' structure and function, using an in vitro model. This model includes simulated oral, gastric, small intestinal phase digestion of GO followed by incubation in a colon bioreactor. 16S rRNA amplicon sequencing revealed that GO exposure resulted in a restructuring of community composition. 25 mg/L GO induced a marked decrease in the Bacteroidota phylum and increased the ratio of Firmicutes to Bacteroidota (F/B). Untargeted metabolomics on the supernatants indicated that 25 mg/L GO impaired microbial utilization and metabolism of substrates (amino acids, carbohydrate metabolites) and reduced production of beneficial microbial metabolites such as 5-hydroxyindole-3-acetic acid and GABA. Exposure to 250 mg/L GO resulted in community composition and metabolome profiles that were very similar to the controls that lacked both GO and digestive enzymes. Differential abundance analyses revealed that 3 genera from the phylum Bacteroidota (Bacteroides, Dysgonomonas, and Parabacteroides) were more abundant after 250 mg/L GO exposure, irrespective of feed state. Integrative correlation network analysis indicated that the phylum Bacteroidota showed strong positive correlations to multiple microbial metabolites including GABA and 3-indoleacetic acid, are much larger number of correlations compared to other phyla. These results show that GO exposure has a significant impact on gut microbial community composition and metabolism at both low and high GO concentrations.


Effect of Cobalt and Chromium Content on Microstructure and Properties of WC-Co-Cr Coatings Prepared by High-Velocity Oxy-Fuel Spraying.
To explore the Co/Cr ratio impact on the high-velocity oxygen fuel (HVOF)-sprayed WC-Co-Cr coatings microstructure and performances, three kinds of WC-Co-Cr coatings, namely WC-4Co-10Cr, WC-7Co-7Cr, and WC-10Co-4Cr, were prepared by using a high-velocity oxygen fuel (HVOF) spraying process. The three coatings' phase composition, microstructure, basic mechanical properties, abrasive wear, and corrosion resistance were investigated. The results show that all three WC-Co-Cr coatings comprise the main phase WC, minor W2C, and amorphous W-Co-Cr phase, besides the WC-4Co-10Cr coating containing a small amount of CrxCy phase. In addition, WC-7Co-7Cr coating exhibited the highest hardness and abrasive wear resistance, followed by WC-10Co-4Cr and WC-4Co-10Cr coatings. The corrosion resistance as a hierarchy was found to be WC-10Co-4Cr > WC-7Co-7Cr > WC-4Co-10Cr.


Gunpowder is an exploding compound, frequently used in Morocco during fantasia shows for loading guns. If not deadly, its explosion is responsible for various and serious wounds, for which emergent care is difficult. We report two cases of such incidents and discuss wound aspects and prevention.


Cyclo(Dehydrohistidyl-L-tryptophyl), an inhibitor of nitric oxide production from a fungal strain, Fb956.
In the course of screening for nitric oxide inhibitors in activated microglial BV-2 cells, cyclo(dehydrohistidyl-Ltryptophyl) was isolated from solid-state fermentation cultures of an unidentified fungal strain, Fb956. Its structure was determined by spectroscopic methods including 2D NMR and chiral TLC analyses. Cyclo(dehydrohistidyl-L-tryptophyl) was found to have an inhibitory activity on nitric oxide production with an IC50 of 6.5 muM in activated BV-2 cells. The structure determination and biological activity of cyclo(dehydrohistidyl- L-tryptophyl) was reported for the first time in this study.


Serum and seminal markers in the diagnosis of disorders of the genital tract of the dog: a mini-review.
Serum and seminal biologic substances that are produced either by normal or abnormal tissues of the organism and that can be used to diagnose pathological conditions are usually referred as markers. The aim of this article is to briefly review the most relevant clinical features of the main genital markers in the male dog: alkaline phosphatase (AP), carnitine and canine prostate-specific arginine esterase (CPSE). Carnitine and AP are markers for the presence of epididymal fluid in the ejaculate and their measurement in azoospermic dogs has been used as an indicator of tubular patency of the ductal network. Although AP is not present in high concentrations in the testis, this does not preclude the possibility that testicular cells might secrete some AP. If this were true, AP could also reflect, at least in some degree, germ cell function in this species. Prostate-specific arginine esterase, the major secretory product of the canine prostate, is a known marker of gland secretion in the dog. Tumor markers frequently used in human medicine, such as prostatic acid phosphatase and prostate-specific antigen, are is still controversial in the diagnosis of prostatic carcinoma of the dog. Although further research is necessary to define the exact role of CPSE, it seems to be a promising diagnostic tool in nonneoplasic canine prostatic disorders. Future studies should also address the quantitative relationship among serum and prostatic androgen levels, prostatic androgen-dependent problems and how these are affected by anti-androgen treatment. The aim of this article is to briefly review the most relevant clinical features of three main genital markers of the male dog.


Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997.
Data compiled during the 1970s and early 1980s indicated that during these periods, membranous nephropathy was the most common cause of unexplained nephrotic syndrome in adults, followed in order of frequency by minimal-change nephropathy and focal segmental glomerulosclerosis (FSGS). However, we and others recently reported an increase in the incidence of FSGS over the past two decades, and the number of cases of FSGS diagnosed by renal biopsies in these centers now exceeds the number of cases of membranous nephropathy. Nonetheless, as a substantial fraction of patients with FSGS do not have the nephrotic syndrome, it remained unclear as to what extent the relative frequencies of FSGS and other glomerulopathies as causes of the nephrotic syndrome have changed over this time. To address this concern, we reviewed data from 1,000 adult native kidney biopsies performed between January 1976 and April 1979 and from 1,000 biopsies performed between January 1995 and January 1997, identified all cases with a full-blown nephrotic syndrome of unknown etiology at the time of biopsy, and compared the relative frequencies with which specific diseases were diagnosed in these latter cases between the two time intervals. The main findings of this study were that, first, during the 1976 to 1979 period, the relative frequencies of membranous (36%) and minimal-change (23%) nephropathies and of FSGS (15%) as causes of unexplained nephrotic syndrome were similar to those observed in previous studies during the 1970s and early 1980s. In contrast, from 1995 to 1997, FSGS was the most common cause of this syndrome, accounting for 35% of cases compared with 33% for membranous nephropathy. Second, during the 1995 to 1997 period, FSGS accounted for more than 50% of cases of unexplained nephrotic syndrome in black adults and for 67% of such cases in black adults younger than 45 years. Third, although the relative frequency of nephrotic syndrome due to FSGS was two to three times higher in black than in white patients during both study periods, the frequency of FSGS increased similarly among both racial groups from the earlier to the later period. Fourth, the frequency of minimal-change nephrotic syndrome decreased from the earlier to the later study period in both black and white adults. Fifth, the relative frequency of membranoproliferative glomerulonephritis as a cause of the nephrotic syndrome declined from the 1976 to 1979 period to the 1995 to 1997 period, whereas that of immunoglobulin A nephropathy appeared to increase; the latter accounted for 14% of cases of unexplained nephrotic syndrome in white adults during the latter study period. Finally, 10% of nephrotic adults older than 44 years had AL amyloid nephropathy; none of these patients had multiple myeloma or a known paraprotein at the time of renal biopsy.


Twisting of peripheral balloon appearing as a non-dilating peroneal artery lesion.
Peripheral arterial lesions are usually longer than coronary artery lesions and require longer balloons and stents. Theoretically while advancing a long balloon in a long, high grade lesion with aggressive manipulation, the balloon can twist inside the lesion, but this has not been described before in the literature. Herein we are reporting a case where peripheral balloon (PB) twisted and appeared as a non-dilating lesion.


Network-based analysis with primary cells reveals drug response landscape of acute myeloid leukemia.
Acute myeloid leukemia (AML) is one of the most common, complex, and heterogeneous hematological malignancies in adults. Despite progresses in understanding the pathology of AML, the 5-year survival rates still remain low compared with CML, CLL, etc. The relationship between genomic features and drug responses is critical for precision medication. Herein, we depicted a picture for response of 145 drugs against 33 primary cell samples derived from AML patients with full spectrum of genomic features assessed by whole exon sequencing and RNA sequencing. In general, most of the samples were much more sensitive to the combinatorial chemotherapy regimens than the single chemotherapy drugs. Overall, these samples were moderately sensitive to the Traditional Chinese Medicine (TCM) and the targeted drugs. In the weighted gene coexpression network analysis (WGCNA), the TCM and targeted therapies displayed similar genetic signatures in the gene module correlation. Meanwhile, the expression of miRNAs, lncRNAs, and mRNAs did not display apparent gene module correlations among those different types of therapies. In addition, the combinatorial chemotherapy bear more module correlations than the single drugs. Interestingly, we found that the gene mutations and drug response were not enriched in any WGCNA module analysis. Most of the sensitive drug response biomarkers were enriched in the ribosome, endocytosis, cell cycle, and p53 associated signaling pathways. This study showed that gene expression modules might show better correlation than gene mutations for drug efficacy predictions.


[Computer modeling of nonlinear heart rate dynamics during train extracardial impulsation in the sinoatrial node].
A computer model of excitation conduction in the heart has been employed to study the nonlinear heart rate dynamics under stress loads. The modeling was aimed to test the hypothesis explaining changes in the heart rate dynamics during nociceptive stress loads by the occurrence of train extracardial impulsation arriving at the sinoatrial node. The computer simulation shows that, with a particular set of parameters, the model imitates the dynamics of RR intervals observed in experiments. The present model provides a unified theoretical basis for further simulation of various types of ventricular disturbances under external extreme loads.


Subacute symptoms of sports-related concussion: outpatient management and return to play.
Most concussion symptoms resolve within the first week after injury. Athletes with persistent symptoms may manifest subtle behavioral and cognitive changes. The astute clinician uses various information to determine when these symptoms have cleared before allowing the athlete to return to athletic competition.


Synthesis and biochemical evaluation of triazole/tetrazole-containing sulfonamides against thrombin and related serine proteases.
A small library of 25 triazole/tetrazole-based sulfonamides have been synthesized and further evaluated for their inhibitory activity against thrombin, trypsin, tryptase and chymase. In general, the triazole-based sulfonamides inhibited thrombin more efficiently than the tetrazole counterparts. Particularly, compound 26 showed strong thrombin inhibition (K(i)=880 nM) and significant selectivity against other human related serine proteases like trypsin (K(i)=729 μM). Thrombin binding affinity of the same compound was determined by ITC and demonstrated that the binding of this new triazole-based scaffold is enthalpically driven, making it a good candidate for further development.


Human neural organoids: Models for developmental neurobiology and disease.
Human organoids stand at the forefront of basic and translational research, providing experimentally tractable systems to study human development and disease. These stem cell-derived, in vitro cultures can generate a multitude of tissue and organ types, including distinct brain regions and sensory systems. Neural organoid systems have provided fundamental insights into molecular mechanisms governing cell fate specification and neural circuit assembly and serve as promising tools for drug discovery and understanding disease pathogenesis. In this review, we discuss several human neural organoid systems, how they are generated, advances in 3D imaging and bioengineering, and the impact of organoid studies on our understanding of the human nervous system.


Impact of osteoporosis and vertebral fractures on quality-of-life. a population-based study in Valencia, Spain (The FRAVO Study).
To describe the health related quality of life in a population sample of postmenopausal women over the age of 50 and resident in the city of Valencia (Spain), according to the presence/absence of osteoporosis and the severity of prevalent morphometric vertebral fractures. A cross-sectional age-stratified population-based sample of 804 postmenopausal women of 50 years of age and older were assessed with the SF-12 questionnaire. Information about demographic features, lifestyle, clinical features, educational level, anti-osteoporotic and other treatments, comorbidities and risk factors for osteoporosis were collected using an interviewer-administered questionnaire and densitometric evaluation of spine and hip and spine x-rays were carried out. In the non-adjusted analysis, mild and moderate-severe vertebral fractures were associated with decreased scores in the SF-12 Physical Component Summary (PCS) but not in the Mental Component Summary (MCS), while densitometric osteoporosis with no accompanying fracture was not associated with a worse health related quality of life. In multivariate analysis worse PCS scores were associated to the age groups over 70 (-2.43 for 70-74 group and -2.97 for 75 and older), chronic conditions (-4.66, -6.79 and -11.8 according to the presence of 1, 2 or at least 3 conditions), obesity (-5.35), peripheral fracture antecedents (-3.28), hypoestrogenism antecedents (-2.61) and the presence of vertebral fracture (-2.05). After adjusting for confounding factors, the physical components of health related quality of life were significantly lower in women with prevalent osteoporotic vertebral fractures than in women--osteoporotic or not--without vertebral fractures.


Unexpected conformational consequences of weak hydrogen bonds on 1,3,7,9,13,15,19,21-octaazapentacyclo[22.214.171.124(3,7).1(9,13).1(15,19)]octacosane monohydrate.
In the title compound, C(20)H(40)N(8).H(2)O, the organic molecule crystallizes with one water molecule located within the molecular cavity of the octaaza macrocycle. The two molecules are linked via two weak O-H...N hydrogen bonds. The assembly has noncrystallographic C(2) axial symmetry.


The tumor suppressor NPRL2 in hepatocellular carcinoma plays an important role in progression and can be served as an independent prognostic factor.
Hepatocarcinogenesis is a multifactorial, multistep process that involves the activation of oncogenes or the inactivation of tumor suppressor genes throughout the different stages of hepatocellular carcinoma (HCC) progression. NPRL2 is one of the candidate tumor suppressor genes identified on chromosome 3p21.3, a region which frequently contains genetic abnormalities found in the early stages of the development of various human cancers. In the current study, we aimed to evaluate NPRL2 expression in HCC and to explore the prognostic significance of NPRL2. We investigated NPRL2 mRNA expression in 70 HCC specimens, using quantitative real-time reverse transcription polymerase chain reaction analysis, and the correlation between NPRL2 expression and clinicopathologic parameters. NPRL2 mRNA was found to be expressed equally in both HCC tissues and corresponding non-cancerous liver tissues. However, higher NPRL2 expression correlated significantly with tumor size (P = 0.0062) and serum PIVKA-II levels (P = 0.0002). Univariate and multivariate analyses revealed that higher NPRL2 mRNA expression was an independent prognostic factor for overall survival (risk ratio 0.39; P < 0.0001). Our results suggest that NPRL2 mRNA expression has prognostic significance for the survival of patients with HCC.


alpha-Fluoromethylhistidine decreases the histamine content of the rat right atrium under the influence of sympathetic activity.
alpha-Fluoromethylhistidine (alpha-FMH; 65 mg/kg, i.p.), a specific inhibitor of histidine decarboxylase, significantly decreased the histamine content of the rat right atrium in a time-dependent manner; the maximal decrease of 22.2% was observed 4 h after injection. However, alpha-FMH had no significant effect on the histamine content of the left atrium or the ventricles. The alpha-FMH-induced decrease in the right atrial histamine content was not observed in rats pretreated with 6-hydroxydopamine (25 mg/kg, i.p.). Two i.p. injections of 10 and 5 mg/kg of propranolol and the cardioselective beta 1-adrenoceptor antagonist metoprolol almost completely inhibited the alpha-FMH-induced histamine decrease. On the other hand, phentolamine (10 mg/kg, i.p.) had no influence on the histamine-decreasing action of alpha-FMH. These results suggest that in the rat right atrium there is a histamine pool where a rapid turnover of histamine is maintained by normal sympathetic activity.