Recovery from auditory and visual neglect after optokinetic stimulation with pursuit eye movements--transient modulation and enduring treatment effects.
Optokinetic stimulation (OKS) modulates many facets of the neglect syndrome. This sensory stimulation technique is known to activate multiple brain regions (temporo-parietal cortex, basal ganglia, brain stem, cerebellum) some of which are involved in auditory and visual space coding. Here, we evaluated whether OKS modulates auditory neglect transiently and induces a sustained effect (Study 1), and whether repetitive OKS permanently recovers auditory neglect (Study 2). In Study 1, 20 patients with visuospatial neglect and auditory neglect in an auditory midline task following rightsided stroke were randomly allocated to an experimental and a control group matched for neglect severity and socio-demographic factors. Both groups showed a stable, pathological shift of their auditory subjective median plane (ASMP) in front space to the right side. During leftward OKS the experimental group showed a complete normalization of the shift of the ASMP, which endured until 30 min poststimulation, and returned almost to baseline values 24h after OKS. In contrast, the control group who viewed the identical but static dot pattern, showed neither change in their ASMP during this condition, nor any significant change at 30 min or 24h poststimulation. In Study 2, we show in two samples of neglect patients (N = 3 each) that repetitive leftward OKS with smooth pursuit eye movements as a therapy induces lasting improvements in auditory (the ASMP) and visual neglect while visual scanning therapy yielded no measurable effects on auditory and significantly smaller effects on visual neglect. In conclusion, the experiments show that a single session of OKS induces rapid though transient recovery from auditory neglect including a sustained effect after termination of stimulation, while repetitive OKS therapy yields enduring and multimodal recovery from auditory and visual neglect. OKS therapy with pursuit eye movements therefore represents a multimodally effective and easily applicable technique for the treatment of auditory and visual neglect.


Changes in Food and Beverage Purchases Associated With the Coronavirus Disease Pandemic in Mexico.
Public policies to contain the spread of coronavirus disease in Mexico could have had an effect on food purchase patterns. The objective of the study was to assess changes in the quantity of food and beverages purchased and proportion spent on food consumed away from home during the coronavirus disease pandemic in Mexican households. This study is a secondary analysis of cross-sectional data from the National Household Income and Expenditure Survey 2014-2020. The study included 234,631 households with information on food and beverages purchases from 2014 to 2020. Food and beverage purchases were classified into six categories: basic, nonbasic energy-dense foods, prepared food for consumption at home, water, milk, and sugar-sweetened beverages. In the National Household Income and Expenditure Survey 2014-2020, expenditures on food and beverages consumed away from home are not classified into any specific items but represents more than 10% of food and beverage expenditures; therefore, the analyses included the proportion of food and beverage expenditures spent on food consumed away from home. A two-part model was used to evaluate changes in the quantity of food purchased and the proportion spent away from home during the coronavirus disease pandemic in 2020 compared with 2018, adjusting for socio-demographic variables, gross domestic product and previous survey rounds. Results are presented at the national level, by income quintile and by place of residence. Purchases of basic food increased by 17 g/capita/day at the national level and 22.4 g/capita/day in urban areas (P < 0.001). Purchases of nonbasic energy-dense foods decreased both at the national level (-4.2 g/capita/day; P < 0.001) and by place of residence (-4.8 g/capita/day; P < 0.001 in urban areas and -2.5 g/capita/day; P = 0.001 in rural settings). Purchases of prepared food increased 16 g/capita/day (P < 0.001). In rural areas, purchases of sugar-sweetened beverages increased 7.2 mL/per capita/day (P < 0.001). For the lowest income quintile purchases of processed meat increased 2.4 g/capita/day (P < 0.001). The proportion spent on food consumed away from home decreased by -44.9% (P < 0.001). Results of this study show that during the coronavirus disease lockdown there was an increase in basic and prepared food purchases, whereas purchases of nonbasic energy-dense foods and the proportion spent on food consumed away from home decreased. However, findings showed an increase in sugar-sweetened beverages purchases among rural dwellers and an increase in purchases of processed meat among the lowest income quintile. Various factors such as income reductions, unemployment, mobility restrictions, or increases in prices may have led the observed changes. Future research should be conducted to analyze these potential pathways.


Vaccine and Psychological Booster: Factors Associated With Older Adults' Compliance to the Booster COVID-19 Vaccine in Israel.
Israel became the first country to offer the booster COVID-19 vaccination. The study tested for the first time the role of sense of control (SOC) due to vaccinations, trust and vaccination hesitancy (VH), and their association with compliance to the booster COVID-19 vaccine among older adults, during the first 2 weeks of the campaign. 400 Israeli citizens (≥ 6 years old), eligible for the booster vaccine, responded online. They completed demographics, self-reports, and booster vaccination status (already vaccinated, booked-a-slot, vaccination intent, and vaccination opposers). Multinomial logistic regression was conducted with pseudo R2 = .498. Higher SOC and lower VH were related to the difference between early and delayed vaccination (booked-a-slot, OR = 0.7 [0.49-0.99]; 2.2 [1.32-3.62], intent OR = 0.6 [0.42-0.98]; 2.7 [1.52-4.86]), as well as to rejection (OR = 0.3 [0.11-0.89]; 8.5 [3.39-21.16]). Increased trust was only related to the difference between early vaccinations and vaccine rejection (OR = 0.3 [0.11-0.89]). We suggest that SOC, as well as low VH, can be used as positive motivators, encouraging earlier vaccinations in older age.


Novel peptide derivatives of bleomycin A5: synthesis, antitumor activity and interaction with DNA.
A series of novel amino acid and peptide derivatives of bleomycin (BLM) A(5) were synthesized. All the compounds possessed significant antitumor activities in vitro against HL-60, BGC-823, PC-3MIE8, and MDA-MB-435 cell lines. Their antitumor activities against MDA-MB-435 were 10-fold higher than BLM A5. The DNA cleavage studies indicated that the hydrophobic amino acid or peptide derivatives of BLM A5 could induce higher cleavage ratio of double to single strand DNA than BLM A5. From the DNA binding studies, we found that the derivatives containing either D-conformation amino acid or basic amino acid could facilitate DNA binding of BLM.


Use of rhodamine 123 to investigate alterations in mitochondrial activity in isolated mouse liver mitochondria.
The fluorescent dye Rhodamine-123, which selectively stains mitochondria depending on the mitochondrial membrane potential, was used with flow cytometry to evaluate alterations in activity of mitochondria isolated from mouse liver. Under in vitro conditions, with succinate and ADP present in the buffer, mitochondrial activity was affected by a variety of metabolic inhibitors that modify membrane potential. These results demonstrate clearly that flow cytometric techniques using Rhodamine-123 can be employed to study activity in isolated mitochondria.


Enumeration of antigen-specific IgE responses at the single-cell level by an ELISA plaque assay.
In vitro elicitation and enumeration of antigen-specific IgE-secreting cells in antigen-primed murine lymphocyte cultures can be reproducibly and accurately quantitated. Rat anti-mouse IgE monoclonal antibodies (Mab anti-epsilon) were developed. Antigen-specific IgE-secreting cells can be detected on antigen or MAb anti-epsilon coated nitrocellulose discs pasted to 24-well culture plates. This IgE ELISA-plaque assay (EP epsilon) is more reliable than antigen capture or total IgE ELISAs in monitoring de novo induction of antigen-specific IgE memory responses in cultures of antigen-primed lymphocytes elicited with antigens.


Detective work in continuous ambulatory peritoneal dialysis.
We report five cases of continuous ambulatory peritoneal dialysis in which the mechanisms and sources of infection were established. We show how diligent enquiry and environmental investigation can explain the pathogenesis of infection and help in prevention by motivation of the patient.


Schistosomiasis in African infants and preschool children: let them now be treated!
The occurrence of schistosomiasis within African infants and preschool children has been much better documented in recent years, revealing an important burden of disease previously overlooked. Despite mounting evidence showing that treatment with praziquantel is safe, beneficial, and could be delivered within ongoing public health interventions, young children still do not have satisfactory access to this drug, and a significant treatment gap exists. Progress towards resolution of this unfortunate health inequity is highlighted, including the development of an appropriate paediatric praziquantel formulation, and present blocks are identified on securing this issue within the international health agenda.


Postcataract endophthalmitis in South India incidence and outcome.
To determine the incidence of acute-onset postcataract endophthalmitis, identify risk factors, and determine clinical outcomes in a tertiary eye care center in South India. Retrospective, interventional, observational case series. All patients who underwent cataract extraction from January 2002 to December 2003 at Aravind Eye Hospital, Madurai. The records of patients with acute endophthalmitis after cataract surgery were reviewed. Acute-onset postcataract endophthalmitis, incidence rates, risk factors, organisms cultured, and visual acuity outcomes after treatment. During the study period, 36072 cataract surgeries were performed; these included 22294 cases of phacoemulsification and 9503 cases of extracapsular cataract extraction. A total of 19 eyes developed acute endophthalmitis after cataract surgery (average 2-year incidence, 0.05%). Ten cases were culture positive (average 2-year incidence, 0.03%). In multivariate analysis, increased risk of endophthalmitis was associated with intraoperative complications, such as posterior capsular rent and vitreous loss (relative risk [RR], 6.57; 95% confidence interval [CI], 1.5-28.5; P = 0.05) for all endophthalmitis cases, age >60 years for culture-positive endophthalmitis cases (RR, 6; 95% CI, 0.7-47.8; P = 0.04), and an extracapsular cataract extraction technique for culture-positive endophthalmitis cases (RR, 4.9; 95% CI, 1.2-19.3; P = 0.001). After follow-up of 37 days, 5 (29.41%) of the 17 patients achieved a best-corrected visual acuity (BCVA) of 20/40, and the remaining 7 (32.3%) had a BCVA better than 20/200. Of the culture-positive cases, Nocardia species was the most common organism isolated, accounting for more than half of these cases (6/10 [60%]). This study found the incidence of acute postoperative endophthalmitis after cataract surgery to be 0.05%. Extracapsular cataract extraction technique and the occurrence of intraoperative complications are major risk factors for developing endophthalmitis. Visual outcome after endophthalmitis was generally poor. Nocardia is a lesser-known but virulent organism causing endophthalmitis, the management of which still poses a therapeutic dilemma.


Dynamic organization of mixed Langmuir films of glucose oxidase and stearylamine at the air-water interface.
The structure and the dynamic organization of a mixed Langmuir film of glucose oxidase and stearylamine at the air-water interface have been studied. The film has been first characterized at the air-water interface by surface pressure/area isotherms. The dynamics of the mixed film was studied by following the evolution of the film area at a constant pressure and the evolution of the pressure at a constant area. After transfer of the films on solid substrates, the chemical composition of the mixed film has been quantified by UV-vis and IR spectroscopies. These characterizations were carried out in order to study the incorporation of glucose oxidase into the stearylamine film, and its influence on the structural evolution of the film. From these results, the dynamic organization of this mixed film may be described. For short times, glucose oxidase molecules interact with stearylamine molecules in solution or at the interface; these interactions would lead to the formation of a complex between stearylamine and glucose oxidase molecules. For long times (at least 3 h), a homogeneous mixed film constituted essentially of this complex is obtained at the air-water interface. A detailed analysis by atomic force microscopy allowed us to support this model and the existence of the glucose oxidase/stearylamine complex.


Effects of calcitriol, seocalcitol, and medium-chain triglyceride on a canine transitional cell carcinoma cell line.
Transitional cell carcinoma (TCC) in dogs is associated with high morbidity and mortality. Calcitriol and its analog seocalcitol, combined with medium-chain triglyceride (MCT), have potential for the treatment of this disease. TCC cells were treated with calcitriol or seocalcitol, alone or combined with MCT. Cell growth, cell cycle kinetics, vitamin D receptor (VDR) localization and expression, and Bcl-2 expression were measured. Canine TCC expresses high levels of nuclear VDR. Furthermore, calcitriol and seocalcitol significantly inhibited cell growth and calcitriol caused G0/G1 cell cycle arrest. Bcl-2 expression was slightly decreased in cells treated with these compounds, although no significant changes in VDR expression were observed. MCT enhanced the growth inhibitory effect of both compounds. Calcitriol and seocalcitol inhibited TCC cell growth via induction of cell cycle arrest and MCT enhanced this effect. Therefore, calcitriol and seocalcitol with MCT may have therapeutic potential for canine bladder cancer.


Premature Ventricular Contraction Ablation: How Aggressive Should We Be?
This article explores the prevalence of premature ventricular contractions (PVCs) and their association with underlying heart disease; examines proposed indications for therapy, particularly for catheter ablation; and evaluates the existing data regarding outcomes of ablation in these patients. The aim is to highlight the subset of patients most likely to benefit from catheter ablation targeting PVCs. The article also discusses the implications of symptoms, underlying heart disease, and characteristics of PVCs on clinical management.


Abdominal lymphatic pathway in Fontan circulation using non-invasive magnetic resonance lymphangiography.
Lymphatic congestion is known to play an important role in the development of late Fontan complications. This study aimed to (1) develop a gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) contrast three-dimensional heavily T2-weighed MR technique that can detect abnormal lymphatic pathway in the abdomen while simultaneously evaluating hepatocellular carcinoma (HCC) and to (2) propose a new classification of abnormal abdominal lymphatic pathway using a non-invasive method in adults with Fontan circulation. Twenty-seven adults with Fontan circulation who underwent Gd-EOB-DTPA abdominal MR imaging were prospectively enrolled in this study. We proposed MR lymphangiography that suppresses the vascular signal on heavily T2-weighted imaging after EOB contrast. The patients were classified as follows: grade 1 with almost no lymphatic pathway, grade 2 with a lymphatic pathway mainly around the bile duct and liver surface, and grade 3 with a lymphatic pathway mainly around the vertebral body and inferior vena cava. The grade 3 group showed the lowest oxygen saturation level, highest central venous pressure, highest incidence of massive ascites, HCC, and focal nodular hyperplasia. This group also tended to have patients with the oldest age and highest cardiac index; however, the difference was not statistically significant. As for the blood test, the grade 3 group showed the lowest platelet count and serum albumin level and the highest fibrosis-4 index. A novel technique, Gd-EOB-DTPA MR lymphangiography, can detect abnormal abdominal lymphatic pathways in Fontan circulation, which can reflect the severity of failing Fontan.


Sudomotor deficits in Parkinson's disease with special reference to motor subtypes.
Parkinson's disease which shows clinically heterogeneous motor derangement may also accompany various autonomic disorders, but results of previous research on incidence and degree of each autonomic dysfunction have been inconsistent. As for sudomotor dysfunction, some investigators emphasize hypo- or anhidrois, whereas others stress hyperhidrosis. To elucidate sudomotor dysfunctions in Parkinson's disease (PD) with respect to subtypes, 225 clinically probable patients PD patients were stratified by motor phenotype (tremor-dominant group: 33; mixed group: 105; and akinesia-rigidity group: 87) and subjected to thermal and acetylcholine-induced (focal) sweating tests. Thermal sweating was qualitatively assessed with a modified version of Minor's colorimetric methods. Thermoregulatory and acetylcholine-induced focal sweat rates were measured with capacitance hydrometers. Thermoregulatory sweating was almost normal without anhidrotic area in 29.8% of PD patients, slightly defective in 38.7%, with anhidrotic area across <1/4 of the body surface, moderately defective in 22.2% with anhidrotic area across approximately 1/2 of the body surface, and extremely defective in 9.3% with anhidrotic area across more than 3/4 of the body surface. Patchy sweating was observed in 104 patients, implicating involvement of the hypothalamo-spinal and/or preganglionic systems in the disease process. Hyperhidrosis was seen in 15% of patients. Tremor-dominant group showed least impairment. This study suggests that PD is associated with various patterns and degree of sudomotor abnormalities, and that sudomotor sympathetic deficits may be related with the pathophysiology of akinesia and rigidity rather than that of resting tremor.


[Transcriptional inactivation of RASSF1A in lung cancer and its clinical significance].
To explore the relationship between the transcriptional expression of RASSF1A (Ras association domain family 1A gene) and oncogenesis and development of lung cancer. RT-PCR was used to detect the expression of RASSF1A mRNA in 47 human lung cancer tissues and matched 47 non-cancer tissues. (1). The RASSF1A mRNA was identified in all non-cancer tissues but not found in 53.2% carcinoma tissues. (2). The rate of loss of RASSF1A mRNA was significantly higher in the patients with positive lymph node metastasis (70.4%) than in those without lymph node metastasis (30.0%) (P < 0.01). (3). Much more frequent in advanced tumor tissues, loss of RASSF1A mRNA was correlated with TNM stage (P < 0.05). (4). No significant association of abnormal RASSF1A expression was identified with histological type, differentiation grade of tumors or age, sex, and smoking index of the patients (all P > 0.05). RASSF1A is one of the new candidates of tumor suppressor genes. Loss or abnormal down-regulation of RASSF1A mRNA is a frequent event in lung carcinogenesis, which may play an important role in the malignant progression and prognosis of lung cancer.


Adherence to anti-retroviral therapy & factors associated with it: A community based cross-sectional study from West Bengal, India.
Failure to adhere to anti-retroviral therapy (ART) can lead to a range of unfavourable consequences impacting upon people living with HIV (PLH) and society. It is, therefore, paramount that ART adherence is measured in a reliable manner and factors associated with adherence are identified. Lack of such data from West Bengal necessitated undertaking the current study. Participants were included during August-October, 2011 from three Drop-In-Centres (DICs) from the three districts of West Bengal, India. ART-adherence was calculated by using formula based on pill-count and records collected from ART-card in possession of each of the 128 consenting adult PLH. Information on self-reported adherence, socio-demography, and adherence influencing issues was also collected through interviewer-administered questionnaire. Of the 128 PLH, 99 (77%) and 93 (73%) PLH had ≥90 per cent and ≥95 per cent adherence, respectively to ART. Conversely, subjective reporting captured much higher proportion of PLH as 'well adherent'; a finding having implications for ongoing ART programme. Factors, independently associated with poor adherence (<90%), were '7 th to 12 th month period of ART intake' (adjusted OR=9.5; 90% CI 1.9 - 47.3; p0 =0.02) and 'non-disclosure of HIV status to family members' (adjusted OR=4; 90% CI 1.3 - 13; P=0.05. Results at 95 per cent adherence cut-off were similar. Enabling environment, which would encourage people to disclose their HIV status and in turn seek adherence partners from families and beyond and ongoing adherence-counselling appear to be important issues in the programme. Relevance of these study findings in wider context is conceivable.


Machine Learning for Health: Algorithm Auditing & Quality Control.
Developers proposing new machine learning for health (ML4H) tools often pledge to match or even surpass the performance of existing tools, yet the reality is usually more complicated. Reliable deployment of ML4H to the real world is challenging as examples from diabetic retinopathy or Covid-19 screening show. We envision an integrated framework of algorithm auditing and quality control that provides a path towards the effective and reliable application of ML systems in healthcare. In this editorial, we give a summary of ongoing work towards that vision and announce a call for participation to the special issue Machine Learning for Health: Algorithm Auditing & Quality Control in this journal to advance the practice of ML4H auditing.


Practical application of ABPM in the pediatric nephrology clinic.
The use of 24-h ABPM has become commonplace when diagnosing and managing hypertension in the pediatric population. Multiple clinical guidelines recommend ABPM as the preferred method for identifying white-coat hypertension, masked hypertension, and determining degree of blood pressure (BP) control. Accurate, timely diagnosis and optimal management are particularly important in certain populations, such as children with chronic kidney disease (CKD), diabetes, and other conditions with increased risk for cardiovascular disease. Understanding how best to utilize ABPM to achieve these goals is important for pediatric nephrologists and other hypertension specialists. This review will provide practical information on the equipment, application, interpretation, and documentation of ABPM in the specialty clinic.


Non-invasive and surgical penile enhancement interventions for aesthetic or therapeutic purposes: a systematic review.
To systematically review the literature in order to investigate the efficacy and safety of surgical and non-invasive penile enhancement procedures for aesthetic and therapeutic purposes. A systematic search for papers investigating penile enhancement procedures was performed using the MEDLINE database. Articles published from January 2010 to December 2019, written in English, including >10 cases, and reporting objective length and/or girth outcomes, were included. Studies without primary data and conference abstracts were excluded. The main outcome measure was objective length and/or girth improvement. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Out of 220 unique records, a total of 57 were reviewed. Eighteen studies assessed interventions for penile enhancement in 1764 healthy men complaining of small penis. Thirty-nine studies investigated 2587 men with concomitant pathologies consisting mostly of Peyronie's disease and erectile dysfunction. Twenty-five studies evaluated non-invasive interventions and 32 studies assessed surgical interventions, for a total of 2192 and 2159 men, respectively. Non-invasive interventions, including traction therapies and injection of fillers, were safe and mostly efficacious, whereas surgical interventions were associated with minor complications and mostly increased penile dimensions and/or corrected penile curvature. Overall, the quality of studies was low, and standardized criteria to evaluate and report efficacy and safety of procedures, as well as patient satisfaction, were missing. The quality of the studies on penile enhancement procedures published in the last decade is still low. This prevents us from establishing recommendations based on scientific evidence regarding the efficacy and safety of interventions that are performed to increase the penis size for aesthetic or therapeutic indications.


The age-related emergence of cranial morphological variation.
Evaluation of ancestry from skeletal remains is problematic for subadults because of a lack of systematic research on the topic. This paper addresses the need for systematic research into geographical variation through childhood and puberty through the examination of the emergence of cranial morphological traits through an analysis of 756 subadults from 4 months in utero to <20 years of age. The first appearance of a trait, changes in the morphology of a trait through time, age stability as related to the age of maturation of the structure, and the developmental mechanisms and processes that cause traits to appear together are addressed. Most traits are influenced by patterns of growth and development and become age stable in conjunction with the larger growth complexes of which they are a part. Geographic cranial variation is present from an early age. Population specific differences in the expression of most traits are apparent from their first appearance.


Use of lambda gt11 and monoclonal antibodies to map the gene for the 60,000 dalton glycoprotein of infectious laryngotracheitis virus.
To localize the gene encoding the 60 kD glycoprotein (gp60) of infectious laryngotracheitis virus (ILTV), a library of the ILTV genome was constructed in the lambda gt11 expression vector. Twelve recombinant bacteriophages expressing gp60 epitopes as fusion products with beta-galactosidase were detected by immunoscreening with monoclonal antibodies specific for gp60. The ILTV DNA sequence contained in one of these recombinants lambda 24-4 was used as a hybridization probe for mapping the insert sequence on the viral genome. The gene for the gp60 was located at map unit 0.72-0.77 in the unique long region (UL) of the ILTV genome. The DNA sequence of the 1.2 kb insert of lambda 24-4 containing the gp60 epitope was determined. The majority of deduced gp60 amino acid sequence has no homology with any of the known alphaherpesvirus glycoproteins.


Use of a Reverse Bohlman Technique for Low-Grade Spondylolisthesis.
Treatment of spondylolisthesis can be difficult with regard to patients with high sacral slopes that may prohibit placement of interbody grafts for fusions across that segment. Here, we describe placement of a reverse Bohlman technique from an anterior approach to obtain fusion across a low-grade spondylolisthesis with a high sacral slope to obtain anterior fusion. A chart review was conducted on this single patient regarding his clinical course and outcome. A 54-year-old male presented with low-back pain associated with bilateral leg pain dating back several years. Plain films demonstrated a Grade II isthmic spondylolisthesis at L5-S1 with spinopelvic measurements of 73° sacral slope, 82° lumbar lordosis, 12° pelvic tilt, and 94° pelvic incidence. Magnetic resonance imaging showed bilateral L5 pars defects with diffuse degenerative disease from L4 through S1 and significant ligamentous and facet hypertrophy. He underwent an L4-5 anterior lumbar interbody fusion and an L5-S1 reverse Bohlman placement of a transvertebral transsacral titanium mesh cage. This was supplemented with a posterior decompression and instrumentation from L4-ilium. He had resolution of his radiculopathy and has maintained a good clinical outcome at 3 years follow up. We present here a patient with low-grade spondylolisthesis and a steep sacral slope who underwent a successful reverse Bohlman approach with long-term follow up. This report highlights the potential utility of this method as a viable alternative for patients with low-grade spondylolisthesis. IV. Technical description of surgical technique.


Roles of neuronal nitric oxide synthase and inducible nitric oxide synthase in intestinal transplantation of rats.
The study was designed to evaluate the role of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) in ischemia-reperfusion injury (IRI) and acute rejection (AR) in rat intestinal transplantation, by administration of nitric oxide inhibitor N(G)-nitro-L-arginine methyl ester (LNAME). Rats that underwent orthotopic intestinal transplantation were assigned to 2 sets of groups: (1) iso-geneic group (Lewis-Lewis), L-NAME 0 mg/kg/d group (1-1), 4 mg/kg/d (group 1-2), or 8 mg/kg/d (group 1-3) injected intraperitoneally or (2) allogeneic group (Dark Agouti-Lewis), L-NAME 0 mg/kg/d (group 2-1) or 8 mg/kg/d (group 2-2) injected intraperitoneally. We examined survival times, light microscopy as well as maltose absorption tests. The nNOS and iNOS activities were measured by immunohistochemical methods. Histologic examination showed inhibited iNOS activity compared with group l-l, and Park scores decreased significantly in group 1-2 at 30 minutes after reperfusion (1.42 ± 0.38 vs 2.58 ± 0.49, P < .01). Both iNOS and nNOS activities were inhibited and Park scores increased significantly in group 1-3 from 30 minutes to day 3 after reperfusion (P < .0l). nNOS activity decreased and iNOS activity increased among group 2-1 during AR. Compared with group 2-1, iNOS activity was inhibited, progression of AR delayed, and survival significantly prolonged in group 2-2 (10.17 ± 0.98 vs 6.83 ± 0.75, P < .01). This study suggested that decreased nNOS and increased iNOS activity both contributed to IRI and AR. More importantly, nNOS more importantly than iNOS activity was closely related to graft structure and function.


Identification of members of the genera Panaeolus and Psilocybe by a DNA test. A preliminary test for hallucinogenic fungi.
Abuse of hallucinogens produced by the fungal genera Psilocybe and Panaeolus are a growing problem. Five species from each of the two genera were examined in this preliminary research and a method that will unambiguously identify fungal samples as being of one of these two genera has been developed. The method uses genus specific DNA sequences within the Internal Transcribed Spacer of the ribosomal gene complex. Amplification of a common DNA product and a genus specific product results in two identifiable products, which facilitates the unambiguous identification of material from these two fungi to generic level.


Egg Mortality in Pterostichus oblongopunctatus (Fabricius) (Col., Carabidae).
Eggs of the carabid beetle Pterostichus oblongopunctatus kept under 'optimum' conditions in petri dishes had a mean mortality of 8% (n=200), while the mortality of eggs incubated in fresh litter was 83% (n=250). Heating the litter up to 70° C and thus eliminating other organisms from the litter fauna reduced mortality to 18% (n=250). When eggs were deposited by the females themselves in a perspex cylinder containing an undisturbed soil sample, the mean egg mortality was 70% (n≈235), but when predators had been eliminated the mortality was only 7% (n≈235). The assumption of Grüm (1975) that egg mortality can be neglected does not hold for P. oblongopunctatus. The predators of the eggs must be common species, but it is not yet known to which family they belong.


Adsorption of volatile organic compounds by pecan shell- and almond shell-based granular activated carbons.
The objective of this research was to determine the effectiveness of using pecan and almond shell-based granular activated carbons (GACs) in the adsorption of volatile organic compounds (VOCs) of health concern and known toxic compounds (such as bromo-dichloromethane, benzene, carbon tetrachloride, 1,1,1-trichloromethane, chloroform, and 1,1-dichloromethane) compared to the adsorption efficiency of commercially used carbons (such as Filtrasorb 200, Calgon GRC-20, and Waterlinks 206C AW) in simulated test medium. The pecan shell-based GACs were activated using steam, carbon dioxide or phosphoric acid. An almond shell-based GAC was activated with phosphoric acid. Our results indicated that steam- or carbon dioxide-activated pecan shell carbons were superior in total VOC adsorption to phosphoric acid-activated pecan shell or almond shell carbons, inferring that the method of activation selected for the preparation of activated carbons affected the adsorption of VOCs and hence are factors to be considered in any adsorption process. The steam-activated, pecan shell carbon adsorbed more total VOCs than the other experimental carbons and had an adsorption profile similar to the two coconut shell-based commercial carbons, but had greater adsorption than the coal-based commercial carbon. All the carbons studied adsorbed benzene more effectively than the other organics. Pecan shell, steam-activated and acid-activated GACs showed higher adsorption of 1,1,1-trichloroethane than the other carbons studied. Multivariate analysis was conducted to group experimental carbons and commercial carbons based on their physical, chemical, and adsorptive properties. The results of the analysis conclude that steam-activated and acid-activated pecan shell carbons clustered together with coal-based and coconut shell-based commercial carbons, thus inferring that these experimental carbons could potentially be used as alternative sources for VOC adsorption in an aqueous environment.


The dual role of neutrophils in cancer.
For the past decade, the role and importance of neutrophils in cancer is being increasingly appreciated. Research has focused on the ability of cancer-related neutrophils to either support tumor growth or interfere with it, showing diverse mechanisms through which the effects of neutrophils take place. In contrast to the historic view of neutrophils as terminally differentiated cells, mounting evidence has demonstrated that neutrophils are a plastic and diverse population of cells. These dynamic and plastic abilities allow them to perform varied and sometimes opposite functions simultaneously. In this review, we summarize and detail clinical and experimental evidence for, and underlying mechanisms of, the dual impact of neutrophils' functions, both supporting and inhibiting cancer development. We first discuss the effects of various basic functions of neutrophils, namely direct cytotoxicity, secretion of reactive oxygen species (ROS), nitric oxide (NO) and proteases, NETosis, autophagy and modulation of other immune cells, on tumor growth and metastatic progression. We then describe the clinical evidence for pro- vs anti-tumor functions of neutrophils in human cancer. We believe and show that the "net" impact of neutrophils in cancer is the sum of a complex balance between contradicting effects which occur simultaneously.


Coastal seawater bacteria harbor a large reservoir of plasmid-mediated quinolone resistance determinants in Jiaozhou Bay, China.
Diversity and prevalence of plasmid-mediated quinolone resistance determinants were investigated in environmental bacteria isolated from surface seawater of Jiaozhou Bay, China. Five qnr gene alleles were identified in 34 isolates by PCR amplification, including qnrA3 gene in a Shewanella algae isolate, qnrB9 gene in a Citrobacter freundii isolate, qnrD gene in 22 Proteus vulgaris isolates, qnrS1 gene in 1 Enterobacter sp. and 4 Klebsiella spp. isolates, and qnrS2 gene in 1 Pseudomonas sp. and 4 Pseudoalteromonas sp. isolates. The qnrC, aac(6')-Ib-cr, and qepA genes could not be detected in this study. The 22 qnrD-positive Proteus vulgaris isolates could be differentiated into four genotypes based on ERIC-PCR assay. The qnrS1 and qnrD genes could be transferred to Escherichia coli J53 Azi(R) or E. coli TOP10 recipient strains using conjugation or transformation methods. Among the 34 qnr-positive isolates, 30 had a single point mutation in the QRDRs of GyrA protein (Ala67Ser, Ser83Ile, or Ser83Thr), indicating that cooperation of chromosome- and plasmid-mediated resistance contributed to the spread and evolution of quinolone resistance in this coastal bay. Eighty-five percent of the isolates were also found to be resistant to ampicillin, and bla(CMY), bla(OXY), bla(SHV), and bla(TEM) genes were detected in five isolates that also harbored the qnrB9 or qnrS1 gene. Our current study is the first identification of qnrS2 gene in Pseudoalteromonas and Pseudomonas strains, and qnrD gene in Proteus vulgaris strains. High prevalence of diverse qnr genes in Jiaozhou Bay indicates that coastal seawater may serve as an important reservoir, natural source, and dissemination vehicle of quinolone resistance determinants.


Effect of cimetidine on exogenous histamine inhibition of histamine release in vivo.
We previously reported that exogenous histamine inhibits in vivo histamine release and eosinophil accumulation in ragweed-challenged skin sites of sensitive human subjects. The mechanism(s) involved were unclear. In this study, we repeated similar approaches in four of the same subjects pretreated for 3 days with cimetidine, an H2 receptor antagonist. The pattern of exogenous histamine effects was now different in that local exogenous histamine (50 ng/ml) did not significantly alter ragweed-induced mast cell alteration, histamine release, or the degree of eosinophil accumulation in skin challenge sites. These findings suggest that the observed exogenous histamine inhibitory effects may be mediated through the H2 receptor.


Defecation syncope secondary to functional inferior vena caval obstruction during a Valsalva maneuver.
This report describes a case of defecation syncope secondary to functional inferior vena cava (IVC) obstruction. Preoperative hemodynamic assessment revealed a marked decrease in blood pressure and IVC obstruction when the patient performed a Valsalva maneuver. The intraoperative approach included continuous hemodynamic monitoring as well as transesophageal ultrasonography to assess IVC patency during surgical mobilization of the IVC. Functional obstruction of the IVC at the diaphragmatic hiatus was identified, and this obstruction was relieved with extensive mobilization of the IVC and right crural myotomy. This report describes an effective surgical approach to a rare functional disorder involving the IVC.


Determination of ochratoxin A by immunoaffinity column clean-up and HPLC In wheat and pig liver.
Determination of ochratoxin A (OTA) by immunoaffinity column clean-up and HPLC detection was performed on wheat and pig liver. Several extraction protocols involving methanol and ethyl acetate were investigated. The optimum experimental conditions for analysis of OTA in artificially contaminated wheat (87.4% recovery) using immunoaffinity column clean-up was found to be the methanol: PBS (1∶1 v/v) protocol. These conditions, however, gave low recoveries for pig liver (40.4%).


Characterizing experiences of non-medical switching to trastuzumab biosimilars using data from internet-based surveys with US-based oncologists and breast cancer patients.
To characterize current experiences with communication and decision-making practices when non-medical switching to a biosimilar trastuzumab is proposed or required by cancer center or insurer. We developed and launched 60- and 51-item internet surveys to elicit US breast cancer patient and medical oncologist lived experiences with trastuzumab biosimilars and patient information needs and seeking practices. We recruited participants using social media and administered via REDCap in 2020-2021. 143 breast cancer patients and 33 medical oncologists completed the surveys. 63.9% patients reported having switched to a trastuzumab biosimilar and 40.8% reported receiving no prior notification about switching. 44% of patients reported learning about biosimilars primarily through self-directed learning and 41% wanting more time to discuss with oncologist. None of the oncologists reported that the decision to switch a patient to a biosimilar was initiated by them, but rather more frequently by the insurer (45.2%). About 54.8% reported not receiving any pharmaceutical manufacturer material related to the selected biosimilar. Patients and oncologists diverged in their responses to items regarding patient opportunities to ask questions, adequacy of resources, effectiveness of treatment, patient worry, and magnitude of change. There is a need for tailored and effective patient and oncologist information and education on trastuzumab biosimilars, along with improved healthcare communication regarding switching. The discrepancy between patient-reported experiences and oncologist perceptions of the patient experience, suggests a lack of adequate information that may be a challenge not only to the uptake of trastuzumab biosimilars, but to the patient-oncologist relationship.


Doxorubicin-Loaded Physalis Mottle Virus Particles Function as a pH-Responsive Prodrug Enabling Cancer Therapy.
The controlled release of drugs using nanoparticle-based delivery vehicles is a promising strategy to improve the safety and efficacy of chemotherapy. A simple, scalable, and reproducible strategy is developed to synthesize a drug delivery system (DDS) by loading 6-maleimidocaproyl-hydrazone doxorubicin (DOX-EMCH) into the empty core of virus-like particles (VLPs) derived from Physalis mottle virus (PhMV) via a combination of chemical conjugation to cysteine residues and π-π stacking interactions with the anchored doxorubicin molecule. The DOX-EMCH prodrug features an acid-sensitive hydrazine linker that triggers the release of doxorubicin in the slightly acidic extracellular tumor microenvironment or acidic endosomal or lysosomal compartments following cellular uptake. The VLP external surface is coated with polyethylene glycol (PEG) to prevent non-specific uptake and improve biocompatibility. The DOX-PhMV-PEG particles are stable in vitro and show greater efficacy in vivo compared to free doxorubicin in a breast tumor mouse model (using MDA-MB-231 cells and nude mice): 92% of the tumor-bearing mice treated with DOX-PhMV-PEG are completely cured compared to 27% of those treated with free doxorubicin under the same conditions, representing a 3.4-fold improvement. These results lay a foundation for the further development of this biological drug delivery system for a new generation of chemotherapy products.


Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease.
Recent evidence shows increased and decreased expression of Ezh2 in cancer, suggesting a dual role as an oncogene or tumour suppressor. To investigate the mechanism by which Ezh2-mediated H3K27 methylation leads to cancer, we generated conditional Ezh2 knock-in (Ezh2-KI) mice. Here we show that induced Ezh2 haematopoietic expression increases the number and proliferation of repopulating haematopoietic stem cells. Ezh2-KI mice develop myeloproliferative disorder, featuring excessive myeloid expansion in bone marrow and spleen, leukocytosis and splenomegaly. Competitive and serial transplantations demonstrate progressive myeloid commitment of Ezh2-KI haematopoietic stem cells. Transplanted self-renewing haematopoietic stem cells from Ezh2-KI mice induce myeloproliferative disorder, suggesting that the Ezh2 gain-of-function arises in the haematopoietic stem cell pool, and not at later stages of myelopoiesis. At the molecular level, Ezh2 regulates haematopoietic stem cell-specific genes such as Evi-1 and Ntrk3, aberrantly found in haematologic malignancies. These results demonstrate a stem cell-specific Ezh2 oncogenic role in myeloid disorders, and suggest possible therapeutic applications in Ezh2-related haematological malignancies.


Ambulatory blood pressure monitoring: mean blood pressure and blood pressure load.
Ambulatory blood pressure monitoring (ABPM) is commonly used to diagnose pediatric hypertension. Using ABPM, hypertension is usually defined as a mean BP greater than the 95th percentile for height. A BP load >30% (% of BP readings greater than the 95th percentile) is also used for the diagnosis of hypertension. The objective of this study was to determine the agreement between mean BP greater than the 95th percentile and 30% BP load for the diagnosis of hypertension using ABPM. All ABPM records (n =1,009) of patients referred for hypertension to a pediatric center were retrieved. Scans were excluded if: age was >19 and height <115 cm or >185 cm. Mean BP and BP loads were calculated for 728 scans. Agreement between mean BP greater than the 95th percentile for height and various BP loads were calculated using the kappa coefficient. The kappa coefficient of agreement between mean BP greater than the 95th percentile and 30% BP load was 0.56 and 0.57 for daytime systolic and diastolic BP, respectively. The agreement between mean night-time BP greater than the 95th percentile and 30% BP load was 0.70 and 0.66 for systolic and diastolic BP, respectively. Agreement between mean BP greater than the 95th percentile and 30% BP load is only moderate to good. Maximum agreement between mean BP greater than the 95th percentile and BP load is achieved at 50% BP load.


MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value.
Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O6-methylguanine-DNA methyltransferase (MGMT). To date, it has not been entirely resolved which methylation pattern of MGMT is most relevant to predict response to temozolomide treatment and outcome. In this retrospective study, we compared the methylation patterns, analyzed by Sanger sequencing, of 27 isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients that survived more than 3 years (long-term survivors) with those of 24 patients who survived less than a year after initial surgery (short-term survivors). Random Forest-, Correlation-, and ROC-curve analyses were performed. The data showed that MGMT is typically methylated in long-term survivors, whereas no prominent methylation is observed in short-term survivors. The methylation status of CpGs, especially in the promoter and exon1/enhancer region correlated highly with outcome. In addition, age and temozolomide treatment were strongly associated with overall survival. Some CpGs in the enhancer region, in particular CpG 86 (bp + 154), demonstrated high values associated with overall survival in the Random Forest analysis. Our data confirm previously published prognostic factors in IDH-wildtype glioblastoma patients, including age and temozolomide treatment as well as the global MGMT methylation status. The area frequently used for decision making to administer temozolomide at the end of exon1 of MGMT, was associated with outcome. However, our data also suggest that the enhancer region, especially CpG 86 (bp + 154) is of strong prognostic value. Therefore, we propose further investigation of the enhancer region in a large prospective study in order to confirm our findings, which might result in an optimized prediction of survival in glioblastoma patients, likely linked to response to temozolomide treatment.


Evaluation of optical genome mapping for detecting chromosomal translocation in clinical cytogenetics.
Balanced reciprocal translocation is one of the most common chromosomal abnormalities in humans that may lead to infertility, recurrent pregnancy loss, or having children with physical or mental abnormalities. Karyotyping and FISH are traditional detection approaches with a low resolution. Bionano optical genome mapping (OGM) developed in recent years can be used to analyze chromosomal abnormalities at a higher resolution, providing the possibility of more in-depth analyses of balanced chromosome translocations. To evaluate the feasibility of OGM to detect chromosome balanced translocations, 10 genetic outpatients were collected and detected simultaneously by karyotype analysis, FISH, CNV-seq, and Bionano OGM in this study. The results showed that the karyotypes of the patients were detected by karyotype analysis, FISH, and Bionano OGM, but one patient with karyotype t(Y,19) was not correctly detected by OGM. There were not find any chromosome abnormality by CNV-seq. More importantly, OGM allowed the location of the mutation to the gene level, which is important for aiding diagnoses, compared to karyotype analysis, and FISH. This study shows that OGM can be a high adjunctive diagnostic method for detecting balanced chromosome translocations, but the accuracy and precision of OGM detecting mutations need to be gradually improved in telomere and centromere regions.


Femoral Neck Bone Mineral Density in Persons Over 50 Years Performing Shiftwork: An Epidemiological Study.
Shiftwork has been associated with bone loss due to hormonal fluctuations. Our aim was to assess the femoral neck bone mineral density and content in persons over 50 years performing shiftwork. We performed analysis on the femoral neck bone mineral parameters in persons over age 50 years from the National Health and Nutrition Examination Survey cross-sectional data for 2010 to 2011 in regular and shiftworkers. We also assessed the degree of moderate physical activity and smoking in both groups. Middle-aged men performing shiftwork had significantly higher total femur bone mineral content (37.33 ± 11.00 vs 34.09 ± 10.45, P = 0.01) and femoral neck bone mineral content (4.57 ± 1.07 vs 4.29 ± 1.0, P = 0.03). This difference was not seen in middle aged women. Shiftwork does not seem to affect bone mineral density in those performing moderate physical activity.


Development and implementation of an international proficiency testing program for a neutralizing antibody assay for HIV-1 in TZM-bl cells.
Recent advances in assay technology have led to major improvements in how HIV-1 neutralizing antibodies are measured. A luciferase reporter gene assay performed in TZM-bl (JC53bl-13) cells has been optimized and validated. Because this assay has been adopted by multiple laboratories worldwide, an external proficiency testing program was developed to ensure data equivalency across laboratories performing this neutralizing antibody assay for HIV/AIDS vaccine clinical trials. The program was optimized by conducting three independent rounds of testing, with an increased level of stringency from the first to third round. Results from the participating domestic and international laboratories improved each round as factors that contributed to inter-assay variability were identified and minimized. Key contributors to increased agreement were experience among laboratories and standardization of reagents. A statistical qualification rule was developed using a simulation procedure based on the three optimization rounds of testing, where a laboratory qualifies if at least 25 of the 30 ID50 values lie within the acceptance ranges. This ensures no more than a 20% risk that a participating laboratory fails to qualify when it should, as defined by the simulation procedure. Five experienced reference laboratories were identified and tested a series of standardized reagents to derive the acceptance ranges for pass-fail criteria. This Standardized Proficiency Testing Program is the first available for the evaluation and documentation of assay equivalency for laboratories performing HIV-1 neutralizing antibody assays and may provide guidance for the development of future proficiency testing programs for other assay platforms.


Long noncoding RNA-dependent regulation of vascular smooth muscle cell proliferation and migration in hypertension.
Hypertension is one of the main risks causing cardiovascular diseases. Long noncoding RNAs (lncRNAs) play a critical role in many physiological and pathological conditions. However, their role in hypertension is still unclear. In this study, 460 lncRNAs and 522 mRNA were identified to have different expressions in the thoracic aortas of spontaneously hypertensive rats compared with normotensive Wistar-Kyoto rats through next-generation sequencing. Several randomly selected lncRNAs including NONRATT011842 were validated by qRT-PCR and their potential functions were predicted by co-expression analysis with the help of bioinformatics. Moreover, this study focused on the function of lncRNA NONRATT011842 in the vascular smooth muscle cells (VSMCs) during hypertension and confirmed that NONRATT011842 could interact with PABPC1 to regulate the functions of VSMCs. Therefore, the intervention or utilization of certain lncRNAs could be a new biomarker for the diagnosis and prevention of hypertension.


Redetermination of di-ammonium trivanadate, (NH4)2V3O8.
The crystal structure of (NH4)2V3O8 has been reported twice using single-crystal X-ray data [Theobald et al. (1984 ▸). J. Phys. Chem. Solids, 45, 581-587; Range et al. (1988 ▸). Z. Naturforsch. Teil B, 43, 309-317]. In both cases, the orientation of the ammonium cation in the asymmetric unit was poorly defined: in Theobald's study, the shape and dimensions were constrained for NH4 +, while in Range's study, H atoms were not included. In the present study, we collected a highly redundant data set for this ternary oxide, at 0.61 Å resolution, using Ag Kα radiation. These accurate data reveal that the NH4 + cation is disordered by rotation around a non-crystallographic axis. The rotation axis coincides with one N-H bond lying in the mirror m symmetry element of space-group type P4bm, and the remaining H sites were modelled over two disordered positions, with equal occupancy. It therefore follows that the NH4 + cations filling the space available in the (001) layered structure formed by (V3O8)2- ions do not form strong N-H⋯O hydrogen bonds with the mixed-valent oxidovanadate(IV,V) anions. This feature could have consequences for the Li-ion inter-calation properties of this material, which is used as a cathode for supercapacitors.


Increasing specific biomass nitrogen load facilitated nitrite accumulation in mainstream wastewater treatment.
By regulating influent nitrogen loading rate (NLR) and solids retention time (SRT), the effect of specific biomass nitrogen load (BNL) on the start-up of mainstream partial nitrification (PN) was investigated in five parallel sequencing batch reactors inoculated with ordinary nitrification sludge. The results showed that increasing BNL by both methods could achieve nitrite accumulation. Moreover, a high initial activity of ammonium oxidizing bacteria (AOB) accelerated nitrite accumulation. Increasing influent NLR (ammonium: 55-70 mg N/L) achieved only 30%-40% of nitrite accumulation ratio (NAR) and gradually decreased with reactor operation. By increasing BNL via controlling SRT (30 days), desirable PN with an average NAR of 81.7 ± 4.4% (effluent nitrite: ∼10 mg N/L) was obtained. Nitrite oxidizing bacteria (NOB) were effectively inhibited, and the AOB to NOB activity ratio increased from 1.5 to 7.8, promoting efficient nitrite accumulation. Overall, increasing BNL by regulating SRT was a potential method for start-up of mainstream PN.


Nitric oxide donor sodium nitroprusside dilates rat small arteries by activation of inward rectifier potassium channels.
The role of vascular smooth muscle inward rectifier K+ (K(IR)) channels in the mechanisms underlying vasodilation is still unclear. The hypothesis that K(IR) channels are involved in sodium nitroprusside (SNP)-induced dilation of rat-tail small arteries was tested. SNP relaxed tail small arteries with an EC50 of 2.6x10(-8) mol/L. Endothelium removal did not attenuate this effect. Vessel pretreatment with hydroxocobalamin, a nitric oxide (NO) scavenger, but not with rhodanese and sodium thiosulfate, inactivators of cyanide (CN), abolished the SNP effect. Vessel pretreatment with 10(-5) mol/L Ba2+, a specific blocker of K(IR) channels at micromolar concentrations, reduced the SNP effect. Low concentrations of K+ dilated the vessels; this effect was attenuated largely after pretreatment with 3x10(-5) mol/L Ba2+. In freshly isolated smooth muscle cells, a barium-sensitive current was observed at potentials negative to the potassium equilibrium potential. Application of 10(-4) mol/L SNP increased the barium-sensitive current 1.79+/-0.23-fold at -100 mV and hyperpolarized the membrane potential by 8.6+/-0.5 mV. In tissue from freshly dissected vessels, transcripts for K(IR) 2.1 and 2.2, but not for K(IR) 2.3 and 2.4, were found. However, only K(IR) 2.1 antibodies immunostained the tunica media of the vessel. These data suggest that vascular smooth muscle K(IR) 2.1 channels are involved in the SNP-induced dilation of rat-tail small arteries.


Evidence-based clinical update: Which local anesthetic drug for pediatric caudal block provides optimal efficacy with the fewest side effects?
The purpose of this evidence-based clinical update is to identify the best evidence when selecting a long-acting local anesthetic agent for single-shot pediatric caudal anesthesia in children. A structured literature search was conducted using PubMed and Medline (OVID) using the terms "caudal" and combinations of at least two of "bupivacaine", "ropivacaine", and "levobupivacaine". The search limits included "randomized controlled trials" (RCTs), "meta-analysis", "evidence-based reviews" or "reviews", "human", and "all child: 0-18 yr". Seventeen RCTs were identified that concerned single-shot pediatric caudal anesthesia with at least two of the three drugs in question. Data were extracted for the areas of clinical efficacy and side effects. Study findings were assigned levels of evidence, and grades of recommendation were made according to Centre for Evidence-Based Medicine criteria. The three drugs investigated were found to be equivalent in terms of efficacy. Evidence showed bupivacaine with the highest incidence of motor block and ropivacaine with the lowest. Adverse effects were rare and unrelated to the choice of drug. There were no serious adverse events. None of the three agents was shown to be superior in terms of efficacy. Bupivacaine is preferred if motor block is desired, ropivacaine is preferred if motor block is to be minimized. Adverse effects in human studies are rare, mild, and unrelated to the choice of drug. Despite encountering the absence of serious adverse events in each of the studies reviewed, it is noted that animal studies suggest a safer profile with ropivacaine or levobupivacaine than with bupivacaine.


The restless legs syndrome.
The restless legs syndrome is a common disorder that encompasses an idiopathic form of genetic or unknown origin and symptomatic forms associated with many causes. Symptomatic forms occur during pregnancy and are coincident with uraemia, iron depletion, polyneuropathy, spinal disorders, and rheumatoid arthritis. For the hereditary forms, at least three gene loci, located on chromosomes 12, 14, and 9, have been traced so far. Prevalence in the general population is between 3% and 9%, increases with age, and is higher in women than in men. Treatment is needed only in the moderate to severe forms of the disorder and mostly in elderly people. Pathophysiology and treatment may be closely linked to the dopaminergic system and iron metabolism. Dopaminergic treatment with levodopa and dopamine agonists is the first choice in idiopathic restless legs syndrome, but augmentation and rebound should be monitored in long-term treatment. Various other drugs, such as opioids, gabapentin, and benzodiazepines, provide alternative treatment possibilities.


Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis.
In recent years, the adipose tissue has emerged as an important endocrine organ. It is now recognized that besides storing energy the adipocytes also secrete several bioactive peptides, collectively called adipocytokines. Among these adipocytokines, leptin, the product of the ob gene, has been extensively investigated over the last decade. Skeletal muscle and adipose tissue, two major tissues involved in the regulation of glucose and fatty acids metabolism, have been consistently demonstrated to be directly affected by leptin. By binding to its receptors located in skeletal muscle and fat cells, leptin promotes energy dissipation and prevents fatty acid accumulation and 'lipotoxicity' in these tissues. On the other hand, under conditions of peripheral leptin resistance, such as observed in obese humans, the activation of pathways involved in fatty acid oxidation may be impaired. This leads to intracellular accumulation of lipid intermediates and causes insulin resistance. This review examines the metabolic pathways that are directly activated by leptin and how it regulates glucose and fatty acids metabolism in skeletal muscle and fat tissue. Furthermore, the impact of peripheral leptin resistance in these tissues leading to dysfunctional metabolic adaptations is also discussed.


Receptors in the ventral tegmental area mediating nicotine-induced dopamine release in the nucleus accumbens.
Nicotine or cocaine, when administered intravenously, induces an increase of extracellular dopamine in the nucleus accumbens. The nicotine-mediated increase was shown to occur at least in part through increase of the activity of dopamine neurons in the ventral tegmental area. As part of our continuing studies of the mechanisms of nicotine effects in the brain, in particular, effects on reward and cognitive mechanisms, in the present study we examined the role of various receptors in the ventral tegmental area in nicotine and cocaine reward. We assayed inhibition of the increase of dopamine in the nucleus accumbens induced by intravenous nicotine or cocaine administration by antagonists administered into the ventral tegmental area. Nicotine-induced increase of accumbal dopamine release was inhibited by intrategmental nicotinic (mecamylamine), muscarinic (atropine), dopaminergic (D1: SCH 23390, D2: eticlopride), and NMDA glutamatergic (MK 801) and GABAB (saclofen) antagonists, but not by AMPA-kainate (CNQX, GYKI52466) antagonists under our experimental circumstances. The intravenous cocaine-induced increase of dopamine in the nucleus accumbens was inhibited by muscarinic (atropine), dopamine 2 (eticlopride), and GABAB (saclofen) antagonists but not by antagonists to nicotinic (mecamylamine), dopamine D1 (SCH 23390), glutamate (MK 801), or AMPA-kainate (CNQX, GYKI52466) receptors. Antagonists administered in the ventral tegmental area in the present study had somewhat different effects when they were previously administered intravenously. When administered intravenously atropine did not inhibit cocaine effects. The inhibition by atropine may be indirect, since this compound, when administered intrategmentally, decreased basal dopamine levels in the accumbens. The findings indicate that a number of receptors in the ventral tegmental area mediate nicotine-induced dopamine changes in the nucleus accumbens, a major component of the nicotine reward mechanism. Some, but not all, of these receptors in the ventral tegmental area also seem to participate in the reward mechanism of cocaine. The importance of local receptors in the ventral tegmental area was further indicated by the increase in accumbal dopamine levels after intrategmental administration of nicotine or also cocaine.


Chemical synthesis of the human blood-group P1-antigenic determinant.
Condensation of known benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-4-O-(2,3,6-tri-O-benzyl-beta-D- galactopyranosyl)-alpha-D-glucopyranoside with 2,3,4,6-tetra-O-benzyl-alpha-D-galactopyranosyl chloride in dichloromethane in the presence of 2,4,6-trimethylpyridine, silver triflate, and molecular sieve 4A gave benzyl O-(2,3,4,6-tetra-O-benzyl-alpha-D-galactopyranosyl)-(1 leads to 4)-O-(2,3,6-tri-O-benzyl-beta-D-galactopyranosyl)-(1 leads to 4)-2-acetamido-3,6-di-O-benzyl-2-deoxy-alpha-D-glucopyranoside. Catalytic hydrogenolysis gave crystalline O-alpha-D-galactopyranosyl-(1 leads to 4)-O-beta-D-galactopyranosyl-(1 leads to 4)-2-acetamido-2-deoxy-alpha -D-glucopyranose, the human blood-group P1-antigenic determinant. A similar sequence of reactions was performed starting from allyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-beta-D-glucopyranoside, in order to prepare a derivative of this determinant suitable for linkage to carrier molecules.


m6A RNA Methylation in Cardiovascular Diseases.
Cardiovascular diseases (CVDs) remain the leading cause of death and disability worldwide, despite marked improvements in prevention, diagnosis, and early intervention. There is an urgent need to discover more effective therapeutic strategies, which would be facilitated by a more in-depth understanding of CVDs and their underlying molecular mechanisms. Recent advances in knowledge about epigenetic mechanisms, especially RNA methylation, have revealed a close relationship between epigenetic modifications and CVDs and have brought to potential novel targets for diagnosis and treatment. Here, we provide a review of recent studies exploring RNA N6-methyladenosine (m6A) modification, with particular emphasis on its role in CVDs, such as coronary heart disease, hypertension, cardiac hypertrophy, and heart failure. We also introduce the "life cycle" of m6A and its dominant function in several biological processes. Finally, we highlight the prospects of treatment based on interfering with m6A, which could have a transformative effect on clinical medicine.


Yogurt for treating antibiotic-associated diarrhea: Systematic review and meta-analysis.
Antibiotic-associated diarrhea (AAD) is a common complication in individuals treated with antibiotics. The aim of this review was to systematically evaluate the efficacy of yogurt consumption for the prevention of AAD. In this systematic review, a number of databases including MEDLINE, EMBASE, and the Cochrane Library, with no language restrictions, were searched up to September 2014 for randomized controlled trials (RCTs) evaluating the effect of yogurt consumption in adults and children who were receiving antibiotics. The risk for bias was assessed using the Cochrane risk of bias tool. Two RCTs, both low in methodological quality, were included. Compared with no intervention, yogurt consumption reduced the risk for diarrhea in the fixed effect model (two RCTs, n = 314, relative risk [RR], 0.56; 95% confidence interval [CI], 0.31-1.00). Significant heterogeneity between the trials was detected (I(2) = 67%). The significant reduction in the risk for diarrhea was lost in the random effects model (RR, 0.45; 95% CI, 0.11-1.75). Given the simple nature of the intervention, the scarcity of data is noteworthy. No consistent effect of yogurt consumption for preventing AAD was shown. However, the data are limited and the included trials had methodological limitations. Results from large, rigorously designed RCTs are needed to assess the effect of yogurt consumption on AAD prevention.


Study of cathepsin A, B and D activities in the skin wound edges. Its application to the differential diagnosis between vital and postmortem wounds.
The aims of the authors in this paper has been to check the diagnostic ability of the Cathepsin A, B and D concentrations in the skin wound edges to the differential diagnosis between vital and postmortem wounds. We have studied 56 domestic pigs grouped in seven experimental series consisting of 8 animals in each, according to the time (0, 5, 15, 30 min and 1, 3 and 6 h) after the injury. The enzymatic activities were investigated following the methods by Bowen and Davison Biochem. J., 131 (1973) 417-419, Suhar and Marks J. Biochem., 101 (1979) 23-30 and by Anson (modified by Yamamoto, Eur. J. Biochem., 95 (1979) 459-467) for Cathepsin A, B and D, respectively. For the differential diagnosis between vital and postmortem wounds, our results showed that the most useful markers studied are the Cathepsin A and D activities, Cathepsin D that of the first one.


Tissue-specific responses that constrain glucose oxidation and increase lactate production with the severity of hypoxemia in fetal sheep.
Fetal hypoxemia decreases insulin and increases cortisol and norepinephrine concentrations and may restrict growth by decreasing glucose utilization and altering substrate oxidation. Specifically, we hypothesized that hypoxemia would decrease fetal glucose oxidation and increase lactate and pyruvate production. We tested this by measuring whole body glucose oxidation and lactate production, and molecular pathways in liver, muscle, adipose, and pancreas tissues of fetuses exposed to maternal hypoxemia for 9 days (HOX) compared with control fetal sheep (CON) in late gestation. Fetuses with more severe hypoxemia had lower whole body glucose oxidation rates, and HOX fetuses had increased lactate production from glucose. In muscle and adipose tissue, expression of the glucose transporter GLUT4 was decreased. In muscle, pyruvate kinase (PKM) and lactate dehydrogenase B (LDHB) expression was decreased. In adipose tissue, LDHA and lactate transporter (MCT1) expression was increased. In liver, there was decreased gene expression of PKLR and MPC2 and phosphorylation of PDH, and increased LDHA gene and LDH protein abundance. LDH activity, however, was decreased only in HOX skeletal muscle. There were no differences in basal insulin signaling across tissues, nor differences in pancreatic tissue insulin content, β-cell area, or genes regulating β-cell function. Collectively, these results demonstrate coordinated metabolic responses across tissues in the hypoxemic fetus that limit glucose oxidation and increase lactate and pyruvate production. These responses may be mediated by hypoxemia-induced endocrine responses including increased norepinephrine and cortisol, which inhibit pancreatic insulin secretion resulting in lower insulin concentrations and decreased stimulation of glucose utilization.NEW & NOTEWORTHY Hypoxemia lowered fetal glucose oxidation rates, based on severity of hypoxemia, and increased lactate production. This was supported by tissue-specific metabolic responses that may result from increased norepinephrine and cortisol concentrations, which decrease pancreatic insulin secretion and insulin concentrations and decrease glucose utilization. This highlights the vulnerability of metabolic pathways in the fetus and demonstrates that constrained glucose oxidation may represent an early event in response to sustained hypoxemia and fetal growth restriction.


Regional homogeneity (ReHo) changes in new onset versus chronic benign epilepsy of childhood with centrotemporal spikes (BECTS): A resting state fMRI study.
The purpose of this study was to investigate regional homogeneity (ReHo) in children with new-onset drug-naïve Benign Epilepsy with Centrotemporal Spikes (BECTS), chronic BECTS and healthy controls (HC) using the Regional Homogeneity (ReHo) method applied to resting state fMRI data. Resting state fMRI data was collected from three groups of children aged 6-13, including new onset drug naïve BECTS, chronic BECTS with medication, and HC; the data analyzed by ReHo method. Mandarin school exams scores were acquired and compared across groups. There were three main findings. Firstly, compared with HC, abnormally increased ReHo was observed in bilateral sensorimotor regions in new onset BECTS which normalized or even reversed in the chronic BECTS group. Secondly, enhanced ReHo was found in the left frontal language region in the two BECTS groups, with even higher ReHo value in the chronic group. Lastly, decreased ReHo was found in regions of the default mode network (DMN), bilateral occipital lobes and cerebellum in both the new onset and chronic BECTS groups, lower in chronic BECTS. Behavioral analyses of school scores showed the chronic BECTS group presented significantly lower scores compared to HC (p<.05). The coherence of low frequency fluctuations is disrupted in sensorimotor, language and DMN-related regions in new-onset BECTS. Some of these effects seem to be selectively normalized in chronic BECTS, thus allowing us to explore possible chronicity and AED-induced effects on BECTS. Abnormal ReHo in left language and DMN regions could be responsible for impairments of cognitive function.


Omega-3 polyunsaturated fatty acids exert anti-oxidant effects through the nuclear factor (erythroid-derived 2)-related factor 2 pathway in immortalized mouse Schwann cells.
Recent studies advocate that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have direct anti-oxidative and anti-inflammatory effects in the vasculature; however, the role of ω-3 PUFAs in Schwann cells remains undetermined. Immortalized mouse Schwann (IMS32) cells were incubated with the ω-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The messenger ribonucleic acid levels of several anti-oxidant enzymes (heme oxygenase-1 [Ho-1], nicotinamide adenine dinucleotide [phosphate] H quinone oxidoreductase 1, catalase, superoxide dismutase and glutathione peroxidase) were identified using real-time reverse transcription polymerase chain reaction. Ho-1 and nicotinamide adenine dinucleotide [phosphate] H quinone oxidoreductase 1 protein levels were evaluated using Western blotting. Nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) of the nuclear fraction was also quantified using western blotting. Catalase activity and glutathione content were determined by colorimetric assay kits. Nrf2 promoter-luciferase activity was evaluated by a dual luciferase assay system. Treatment with tert-butyl hydroperoxide decreased cell viability dose-dependently. DHA or EPA pretreatment significantly alleviated tert-butyl hydroperoxide-induced cytotoxicity. DHA or EPA increased the messenger ribonucleic acid levels of Ho-1, nicotinamide adenine dinucleotide (phosphate) H quinone oxidoreductase 1 and catalase dose-dependently. Ho-1 protein level, catalase activity, Nrf2 promoter-luciferase activity and intracellular glutathione content were significantly increased by DHA and EPA. These findings show that DHA and EPA can induce Ho-1 and catalase through Nrf2, thus protecting Schwann cells against oxidative stress. ω-3 PUFAs appear to exert their neuroprotective effect by increasing defense mechanisms against oxidative stress in diabetic neuropathies.


Lu AF21934, a positive allosteric modulator of mGlu4 receptors, reduces the harmaline-induced hyperactivity but not tremor in rats.
Harmaline induces tremor in animals resembling essential tremor which has been suggested to result from activation of the glutamatergic olivo-cerebellar projection. The aim of the present study was to examine the effects of systemic administration of Lu AF21934, a brain-penetrating positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu4), on the harmaline-induced tremor and other forms of motor activity in rats using fully automated Force Plate Actimeters. The influence of harmaline on the mGlu4 mRNA expression in the cerebellum and inferior olive was analysed by in situ hybridization. Harmaline at a dose of 15 mg/kg (ip) triggered tremor which was manifested by an increase in the power within 9-15 Hz band and in the tremor index (a difference in power between bands 9-15 Hz and 0-8 Hz). Harmaline induced a biphasic effect on mobility, initially inhibiting the exploratory locomotor activity of rats (0-30 min after administration), followed by an increase in their basic activity. Lu AF21934 (0.5-5 mg/kg sc) did not influence tremor but at doses of 0.5 and 2.5 mg/kg reversed harmaline-induced hyperactivity. MGlu4 mRNA expression was high in the cerebellar cortex and low in the inferior olive. Repeated harmaline (15 mg/kg ip once a day for 5 days] decreased mGlu4 mRNA in the cerebellum and inferior olive. The present study indicates that the mGlu4 stimulation counteracts hyperactivity induced by harmaline which suggests the involvement of cerebellar glutamatergic transmission in this process. In contrast, neuronal mechanisms involved in tremor seem to be insensitive to the stimulation of mGlu4.


Nickel(II) complexes with methyl(2-pyridyl)ketone oxime: synthesis, crystal structures and DFT calculations.
The synthesis and structural characterization of the three novel nickel(II) complexes [Ni(OOCPh)(2)(mpkoH)(2)] (1), [Ni(NO(3))(2)(mpkoH)(2)] (2) and [Ni(mpkoH)(3)](NO(3))(2)·½H(2)O (3·½H(2)O), with mpkoH=methyl(2-pyridyl)ketone oxime is reported. Geometry optimization and population analyses were performed by means of DFT calculations for the previously mentioned compounds as well as for [NiCl(2)(mpkoH)(2)] (4). Electronic UV-vis spectra were also simulated in the TD-DFT framework to assign the origin of the absorption bands and in doing so, to have a clear picture of the absorptive features of the coordination compounds under investigation.


Development of multiplex RT-PCR assay for simultaneous detection of four viruses infecting apple (Malus domestica).
The major viruses infecting apple cultivars throughout the world including India are apple mosaic virus (ApMV), apple stem pitting virus (ASPV), apple stem grooving virus (ASGV), apple chlorotic leaf spot virus (ACLSV), and recently, a new virus, apple necrotic mosaic virus (ApNMV), was reported from mosaic-infected apple cultivars in India. The aim of this study was to detect the ApNMV virus along with the other three viruses (ApMV, ASPV and ASGV) simultaneously by multiplex RT-PCR. Four primer-pair-produced amplicons of 670, 550, 350 and 210 bp corresponding to ApNMV, ApMV, ASPV and ASGV, respectively, were found to be specific for these viruses when tested individually. The annealing temperature (55°C), primer concentration (0·8 µl) and other components of the master mix were standardized for the development of one-step m-RT-PCR assay. The m-RT-PCR protocol developed was further validated with 30 samples from seven symptomatic or asymptomatic apple cultivars, which revealed the presence of more than one virus in these cultivars. Most of the viruses were found to be present either alone or in mixed infection; however, ASPV was more common in tested cultivars. An easy, cost-effective and rapid multiplex RT-RCR protocol was developed to detect the four viruses, which infect apple plants either in individually or together in the field. This assay will help in the surveying and indexing of apple germplasm and the distribution of all four viruses in the apple growing regions of India.


Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia.
Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a natural inhibitor of metalloproteinases involved in matrix degradation and ectodomain shedding of many cell-surface proteins, including death receptors and/or their ligands. In the present study, we examined the role of TIMP-3 in Fas-mediated neuronal cell death following cerebral ischemia, using both gene deletion and pharmacological approaches. In culture, exposure of primary cortical neurons to 2 h of oxygen-glucose deprivation (OGD) resulted in delayed neuronal cell death that was dependent on activation of the death receptor, Fas. Cortical cultures derived from timp-3(-/-) mice displayed partial resistance against OGD-induced neuronal cell death and also displayed increased shedding of Fas ligand (FasL) into the culture media, compared to wild-type control cultures. Both the increased neuroprotection and increased FasL shedding in timp-3(-/-) cultures were reversed by addition of exogenous metalloproteinase inhibitors, recombinant TIMP-3 or GM6001. In vivo, timp-3(-/-) mice showed marked resistance to a brief (30 min) middle cerebral artery occlusion (MCAO), but were not protected against more severe lesions induced by 90 min of MCAO. These studies demonstrate that TIMP-3 facilitates Fas-mediated neuronal cell death following OGD and plays a pro-apoptotic role in mild cerebral ischemia.


Driving native-like zonal enthesis formation in engineered ligaments using mechanical boundary conditions and β-tricalcium phosphate.
Fibrocartilaginous entheses are structurally complex tissues that translate load from elastic ligaments to stiff bone via complex zonal gradients in the organization, mineralization, and cell phenotype. Currently, these complex gradients necessary for long-term mechanical function are not recreated in soft tissue-to-bone healing or engineered replacements, contributing to high failure rates. Previously, we developed a culture system that guides ligament fibroblasts to develop aligned native-sized collagen fibers using high-density collagen gels and mechanical boundary conditions. These constructs are promising ligament replacements, however functional ligament-to-bone attachments, or entheses, are required for long-term function in vivo. The objective of this study was to investigate the effect of compressive mechanical boundary conditions and the addition of beta-tricalcium phosphate (βTCP), a known osteoconductive agent, on the development of zonal ligament-to-bone entheses. We found that compressive boundary clamps, that restrict cellular contraction and produce a zonal tensile-compressive environment, guide ligament fibroblasts to produce 3 unique zones of collagen organization and zonal accumulation of glycosaminoglycans (GAGs), type II, and type X collagen. Ultimately, by 6 weeks of culture these constructs had similar organization and composition as immature bovine entheses. Further, βTCP applied under the clamp enhanced maturation of these entheses, leading to significantly increased tensile moduli, and zonal GAG accumulation, ALP activity, and calcium-phosphate accumulation, suggesting the initiation of endochondral ossification. This culture system produced some of the most organized entheses to date, closely mirroring early postnatal enthesis development, and provides an in vitro platform to better understand the cues that drive enthesis maturation in vivo. STATEMENT OF SIGNIFICANCE: Ligaments are attached to bone via entheses. Entheses are complex tissues with gradients in organization, composition, and cell phenotype. Entheses are necessary for proper transfer of load from ligament-to-bone, but currently are not restored with healing or replacements. Here, we provide new insight into how tensile-compressive boundary conditions and βTCP drive zonal gradients in collagen organization, mineralization, and matrix composition, producing tissues similar to immature ligament-to-bone attachments. Collectively, this culture system uses a bottom-up approach with mechanical and biochemical cues to produce engineered replacements which closely mirror postnatal enthesis development. This culture system is a promising platform to better understanding the cues that regulate enthesis formation so to better drive enthesis regeneration following graft repair and in engineered replacements.


Activity of abrB310 promoter in wild type and spo0A-deficient strains of Clostridium acetobutylicum.
In Clostridium acetobutylicum, abrB310 is transcribed from two transcription start sites (designated A1 and A2) forming an abundant large, and a five- to tenfold less abundant small transcript, respectively throughout exponential, acidogenic growth and early in the transitional period to stationary, solventogenic growth. beta-galactosidase reporter vectors were constructed to compare the transcriptional activity of the entire abrB310 promoter and the A1 and A2 transcription start sites individually. In stark contrast to the primer extension data, the A2 start site was threefold more active than the entire promoter, which was threefold more active than the A1 start site in wild type C. acetobutylicum. The activity expressed from all three reporter vectors declined as the cultures transitioned from exponential to stationary growth. In the spo0A-deficient strain SKO1, reporter vector activity continued for 10 h into stationary growth. The removal of the putative Spo0A binding site from all three vectors had no significant effect on promoter activity in either wild type or SKO1. We conclude that the presence of both the A1 and A2 transcription start sites is required for the correct control of abrB310 expression, and that AbrB310 is necessary but not sufficient for the correct transition between acidogenic and solventogenic growth.


Paeoniflorin is a promising natural monomer for neurodegenerative diseases via modulation of Ca2+ and ROS homeostasis.
Neurodegenerative diseases (NDDs) are a range of neurological disorders featured by neuronal degeneration and apoptosis. Cellular Calcium (Ca2+) and reactive oxygen species (ROS) dyshomeostasis are the earliest and important events in the development of NDDs and may yield promising therapeutic targets for NDDs. Paeoniflorin, a water-soluble monoterpene glucoside, is the major bioactive monomer extracted from the root of Paeonia lactiflora pall. Increasing evidence has suggested that this natural compound might be used to treat various NDDs, and its potential molecular mechanisms are related to the modulation of Ca2+/ROS homeostasis in cells. In addition, paeoniflorin accounts for more than 40% of the total glucosides of herbaceous peonies with abundant herbaceous sources. Furthermore, it has also been validated as a safe extraction in clinical pharmacological research with a wide therapeutic window. Hence, it is rational to anticipate paeoniflorin being a promising candidate for the treatment of NDDs via regulating Ca2+/ROS dyshomeostasis.


Characteristics of burn patients transported by ambulance to treatment facilities in Akita Prefecture, Japan.
This study analyzes patient demographics and injury data of 342 patients transported by ambulance to emergency facilities in Akita Prefecture, Japan, between 1996 and 2000. Significant findings include the following. Fire was the most frequent cause of burn injury, and winter was the season with the highest incidence (40.6%) of cases. The suicide rate in Akita Prefecture is high, the percentage of burn patients due to suicide attempts was 7.9%. The mean time from burn injury to hospital arrival was significantly longer for patients who later died (44.6 +/- 35.3 min) than for those survived (33.0 +/- 22.5 min). Severely burned patients were not always transported directly to a core emergency facility and an unacceptable number (5.8%) of patients died at tertiary hospitals. This relatively high death rate is attributable to the limited facilities for treating burns in the tertiary hospitals and the long distance to core facilities, which sometimes precludes transport system for the prefecture will reduce transport time to the regional trauma center and thus enable more patients to undergo specialized treatment at an earlier injury stage. Additionally, tertiary facilities should improve their level of burn care (e.g., creating a burn unit and skin bank).


Use of an acellular allograft dermal matrix (AlloDerm) in the management of full-thickness burns.
Scarring and contracture are major long-term sequelae of meshed split-thickness autografting for full-thickness skin injury. In the absence of dermis, mature fibroblasts secrete collagen in the altered pattern of scar. This case report illustrates the use of an acellular dermal matrix processed from human allograft skin (AlloDerm) in the treatment of a full-thickness burn injury. The processing technique results in an acellular dermal matrix with normal collagen bundling and organization and an intact basement membrane complex. In these patients, AlloDerm exhibited a high percentage 'take' and supported an overlying meshed split-thickness skin autograft, applied simultaneously. The clinical observations of 'take' were confirmed with histological and electron-microscopic evaluation of biopsies which demonstrated host cell infiltration and neovascularization of the AlloDerm. No specific immune response was detected, either by histology or by lymphocyte proliferation assay. By providing a dermal replacement, the grafted dermal matrix permitted the use of a thin, widely meshed autograft from the donor site, without the undesirable scarring and contracture at the wound site that commonly results from this technique. If effective, this approach would markedly reduce the amount of donor skin required for split-thickness autografts in full-thickness burn injuries.


HIF-1α involves in neuronal apoptosis after traumatic brain injury in adult rats.
Hypoxia-inducible factor-1α (HIF-1α), a well-identified hypoxia-related protein, is involved in regulating the biological functions of various cell types including neurons. The traditional biological function of HIF-1α is promoting the transcription of some pro-survival genes when exposing to low oxygen conditions. Meanwhile, some studies also point out that HIF-1α shows the detrimental role in several central nervous system (CNS) disorders. Up to now, the knowledge of HIF-1α function in CNS is still limited. To investigate whether HIF-1α is involved in CNS impairment and repair, we employed a traumatic brain injury model in adult rats. Upregulation of HIF-1α was observed in the injured brain cortex by western blot analysis and immunohistochemistry staining. Terminal deoxynucleotidyl transferase deoxy-UTP nick-end labeling (TUNEL) and 4',6-diamidino-2-phenylindole (DAPI) staining suggested that HIF-1α was relevant to neuronal apoptosis after brain injury. In addition, glutamate excitotoxic model of primary cortex neurons was introduced to further investigate the role of HIF-1α in neuronal apoptosis; the result implied HIF-1α was associated with the regulation of p53 and BNIP3 in the apoptotic neurons. Based on our data, we suggested that HIF-1α might play an important role in neuronal apoptosis after traumatic brain injury in rat, which might also provide a basis for the further study on its role in regulating the transcription of target genes in apoptotic neurons, and might gain a novel strategy for the clinical therapy for traumatic brain injury.


Common genetic and environmental influences on major depressive disorder and conduct disorder.
The evidence for common genetic and environmental influences on conduct disorder (CD) and major depressive disorder (MDD) in adolescents was examined. A sample of 570 monozygotic twin pairs, 592 dizygotic twin pairs, and 426 non-twin siblings, aged 12-18 years, was recruited from the Colorado Twin Registry. For the past year data, there was a significant correlation between the genetic influences on MDD and CD and, for the lifetime data, there was a significant correlation between the genetic influences on MDD and CD, and a significant correlation between the nonshared environmental influences on MDD and CD. Our results suggest that some genetic factors will increase an individual's vulnerability to both MDD and CD in adolescence.


Inhibition of ribonucleotide reductase by antitumor agents related to levodopa and dopamine.
Using partially purified enzyme from L1210 cells, dihydroxybenzene derivatives related structurally to dopamine were shown to reversibly inactivate ribonucleotide reductase. A structure-activity analysis revealed that derivatives with side-chains, which contain a negatively-charged group, had significantly reduced inhibitory activity. The ability of these compounds to inhibit ribonucleotide reductase was dependent on the hydroxyl groups being in the ortho position and did not correlate with free radical inhibitory activity. A kinetic analysis by the method of Lineweaver-Burk indicated that the inhibition of ribonucleotide reductase by the derivative 3,4-dihydroxybenzylamine was competitive with the reducing substrate dithioerythritol. This analog, in combination with hydroxyurea, gave synergistic inhibition or ribonucleotide reductase, suggesting different sites of action. Using Tween 80-treated L1210 cells, it was found that these drugs had an immediate inhibitory effect on ribonucleotide reductase activity in intact, reversibly permeabilized cells. Furthermore, although these drugs had no immediate effect on DNA polymerase, in permeabilized L1210 cells (when the cells were preincubated with the dihydroxybenzene derivatives for 1 hr prior to permeabilization), there was significant inhibition of DNA polymerase activity. The two key enzymes for DNA synthesis appear to be sequentially inhibited by these analogs, with the reduced form (quinol) inhibiting ribonucleotide reductase and the oxidized form (quinone) inhibiting DNA polymerase.


Effect of mating frequency on sow reproductive performance under field conditions and natural mating in large outdoor production units.
The effect of mating frequency on fertility and litter size of sows, kept in outdoor production systems was investigated. Sows that were mated once or twice during a single oestrus were included in the study to compare the effect of number of matings on farrowing rate and litter size. Natural mating was used during the study period. Four groups of sows of parity two or more were either mated once 28-30 h after the onset of oestrus or were mated 28-30 h after the onset of oestrus and again 24 h later. The farrowing rate did not differ significantly between single- and double-mated sows, although a noticeable but non-significant depression in farrowing rate was evident between the groups of single-mated and double-mated animals. With the exception of total-born litter size (p > 0.05), the total number born and number of live-born piglets per litter were significantly (p < 0.05) lower in the group of sows that received only one mating compared with the double-mated animals. The implication of these results is that the double mating by natural service of sows kept in an outdoor production systems may improve litter size.


Outcomes with the Boston Type 1 Keratoprosthesis at Instituto de Microcirugía Ocular IMO.
To report the outcomes on the Boston Type 1 Keratoprosthesis at our institution. Retrospective analysis case series. We analyzed 54 eyes of 53 patients who previously underwent Boston Type 1 Keratoprosthesis surgery at our institution from July 2006 to March 2011. Preoperative and postoperative parameters were collected and analyzed. Visual acuity and keratoprosthesis stability. Common preoperative diagnoses were penetrating keratoplasty failure in 49 eyes (90.7%), chronic keratitis in 2 eyes (3.7%), ocular cicatricial pemphigoid in 1 eye (1.85%), Stevens Johnson syndrome in 1 eye (1.85%) and corneal vascularization in 1 eye (1.85%). Additionally, 40 eyes (74%) had preoperative glaucoma, and an Ahmed valve was implanted in 55% of them. Preoperative BCVA ranged from 20/200 to light perception. At an average follow-up of 20.15 months ± 12.7 (range, 1-56), postoperative vision improved to ⩾20/200 in 18 eyes (33.3%) and ⩾20/50 in 4 eyes (7.4%). The graft retention was 96%. The Boston Type 1 keratoprosthesis is a valid option for high-risk patients. The design improvements in the Boston keratoprosthesis, as well as the daily implementation of the therapeutic methods, have notably diminished occurrence of the most serious complications, such as corneal necrosis and endophthalmitis. As such, glaucoma and its subsequent complications now stand as the most prevalent prognostic factor in the long term.


Bilateral hypogastric artery ligation in emergency setting for intractable postpartum hemorrhage: a secondary care center experience.
To report the authors' experience in bilateral hypogastric (internal iliac) artery ligation which was performed for controlling intractable postpartum hemorrhage in a secondary care center. The patients that required bilateral hypogastric artery ligation for severe intractable postpartum hemorrhage from November 2007 to August 2009 were included in this retrospective study. Data were retrieved from patients' hospital records. A total of 26 cases required hypogastric artery ligation during the study period. Causes of postpartum hemorrhage included uterine atony, placental abruption, uterine rupture, and placenta accreta. Hemorrhage was effectively controlled in 20 of 26 cases (76.9%) and hysterectomy was avoided. Iliac vein injury occurred in one patient (3.8%) as an operative complication. There was one maternal death. Hypogastric artery ligation is an effective therapeutic option for severe postpartum hemorrhage and should be kept in mind during obstetric emergency conditions.


A critical analysis of health system in Nepal; Perspective's based on COVID-19 response.
Nepal moved from a unitary government to a federal system of government in 2015 under its constitution. Nepal is a federal democratic republic governed by three levels of government: a federal, provincial, and local level. The response to COVID-19 in Nepal has been majorly led and controlled by the federal government. All three levels of government are performing their responsibilities; however, they face various challenges in responding to COVID-19. This study aimed to critically analyze Nepal's health system in the context of the COVID-19 response. We conducted semi-structured in-depth interviews by telephone among the policymakers, health workers, and stakeholders at the federal, provincial, and local levels (n = 41) between January to July 2021. The interviews were audio recorded, transcribed into English, and coded using inductive-deductive approaches. COVID-19 considerably impacted routine health care, mainly maternity services and immunization. Inadequate financial resources, inadequate human resources, and the lack of ventilators, ICUs, and X-ray services were the significant challenges in tackling and managing COVID-19 effectively. The study found that all three levels of government perform their roles and responsibilities and effectively manage the pandemic. The federal and provincial governments focused more on the plans and policy development, while the local government demonstrated greater accountability in implementing those plans and policies. Therefore, all three tiers of government need to coordinate together for preparing and communicating information in times of emergency. Besides, it is imperative to empower local governments to maintain Nepal's federal health system.