The cerebrospinal fluid neutrophil to lymphocyte ratio is a sensitive biomarker for bacterial meningitis in children.
The cerebrospinal fluid neutrophil-to-lymphocyte ratio (CSF NLR) as a diagnostic biomarker of bacterial meningitis has been reported in adult trials. The aim of this study was to evaluate the CSF NLR as a diagnostic biomarker of bacterial meningitis in children and to define an optimal CSF NLR concentration. We performed a retrospective cohort study of children with clinical findings compatible with meningitis. CSF NLR was calculated as the ratio of neutrophil count to lymphocyte count in cerebrospinal fluid (CSF). Initial data included clinical, radiological, and laboratory diagnostics. We determined CSF parameters from children with infectious meningitis (n = 348) and subdivided them into bacterial meningitis (n = 112) and viral meningitis (n = 236). CSF NLR was significantly higher in bacterial meningitis than in viral meningitis (P < 0.001), and its level was higher in Gram-negative bacterial infections than in Gram-positive bacterial infections (P = 0.01). In the receiver operating characteristic curve analysis, CSF NLR was better than CSF protein/sugar/WBC in the ability to distinguish bacterial meningitis from viral meningitis (AUC 0.91 ± 0.02 versus 0.88 ± 0.03/0.87 ± 0.03/0.86 ± 0.03), and using a cutoff point of 0.68, the sensitivity was 0.90, and the specificity was 0.75. Compared with Gram-positive infection, CSF NLR with Gram-negative infection was higher (media, IQR (1.18 (0.19-2.33) versus 3.90 (1.50-8.91), P = 0.01). CSF NLR is a more useful diagnostic tool to distinguish between bacterial meningitis and viral meningitis in children. While at a cutoff value of 0.68, CSF NLR has better sensitivity and specificity for bacterial meningitis, and the higher level of CSF NLR could be related to Gram-negative bacterial infection.


Serologic evaluation of celiac disease in patients with beta thalassemia major and control.
This study reports evaluated prevalence of CD in patients with Beta-thalassemia major. Celiac Disease (CD) is an autoimmune disorder triggered by ingestion of gluten in genetically predisposed individuals. In this case-control study in a period of 3 years, which was performed on 620 children in two groups of Beta-thalassemia major patients (n=200) and control (n=420), serum tissue transglutamianse (tTG) IgA levels were measured. The two groups were compared together in terms of tTG IgA levels, and p<0.05 was considered significant. The means of serum tTG IgA levels in patients with Beta-thalassemia major and control groups were 28.81±68.44 and 6.94±6.68 U/mL, respectively. There was a significant difference in favor of the case group (p=0.000). Body mass index in the two case and control groups had a significant difference (t=3.859, p=0.001). Belonging to each group will change the probability of having less than 20 in tTG IgA (odds=0.285) and it means that belonging to the control group has a protective role. There is only a significant association in the case of all population (r=0.102, p=0.011). Body mass index in the two case and control groups had a significant difference (t=3.859, p=0.001). Probability of CD should be considered since the prevalence of CD is high in patients with and Beta-thalassemia major. Patients with thalassemia major are recommended for screening for CD.


Correction of pectus excavatum without prostheses or splints: objective measurement of severity and management of asymmetrical deformities.
From 1949 to 1977, 254 children underwent surgical reconstruction of pectus excavatum by means of a variety of operations at The Johns Hopkins Hospital. From 1970 to 1977, 68 children had a modified Ravitch repair, with the addition of a tripod internal fixation technique for support of the sternum. These children obtained excellent cosmetic reconstruction without prosthetic support or splints. During an 18-month period we used a new system of caliper measurement of the spatial anatomy of the thoracic cage in more than 50 children. During the same period, we originated an operative step to correct the not uncommon asymmetrical excavatum that is usually deeper on the right and associated with a troublesome rotation of the sternum, found in 9 of the last 27 children seen. Correction was accomplished with an oblique anterior sternal osteotomy. The groups were analyzed and compared with respect to age, postoperative complications, and end results in order to identify trends in the management of children with this condition. On the basis of this experience, we feel confident in recommending a standardized operation for all forms of pectus excavatum at an elective age between 4 and 6 years and without prosthetic splints.


Enhancing bone formation using absorbable AZ31B magnesium alloy membranes during distraction osteogenesis: A new material study.
To investigate whether the use of absorble AZ31B magnesium alloys over distraction gaps improves the quality and quantity of regenerated bone better than the use of Collagen membranes. Fifteen mixed-breed dogs were randomly divided into the experimental (n = 10) and control (n = 5) groups. In the experimental group, two devices were implanted along the mandible; one side with absorble AZ31B and the other side with Collagen. The control animals did not undergo osteotomy or distraction. After a consolidation time of two months, 30 specimens were harvested, and newly created bone was identified using CBCT and micro-CT. The Collagen membranes were absorbed completely, and the AZ31B membranes became irregular and rough. Mandible length was successfully extended approximately 1 cm. More bone formation was found after using AZ31B than Collagen, and there was a significant difference in width reduction between experimental sites treated with AZ31B (0.11 ± 0.04 cm) and Collagen (0.42 ± 0.06 cm) (p < 0.05). Trabecular thickness was also significantly higher in AZ31B (0.338 ± 0.08 cm) and control (0.417 ± 0.05 cm) than Collagen (0.178 ± 0.04 cm) (p < 0.05). An AZ31B membrane barrier is biocompatible and absorbable which can maintain the distraction gap and provide support to the attached osteoprogenitors by providing space for them to proliferate.


[Thyroid dysfunction in hospital worker population].
The prevalence of thyroid dysfunction (TD) and thyroid autoimmunity (TA) in hospital employees in our country is unknown. To study the prevalence of TD and TA in a group of hospital employees. We studied thyroid function (thyrotropin, TSH, free thyroxine, T4, and free triiodothyronine, T3) and thyroid autoimmunity (anti-thyroglobulin, antiTg and anti-thyroid peroxidase, antiTPO) in 310 adult subjects (18-70 years) from the hospital General, Segovia, Spain during 2007. Eleven subjects (3.5%, 10 women) had previously known TD. Thirty-four subjects (11.0%) were diagnosed of unknown TD, mainly subclinical hypothyroidism (8.4%). Prevalence of total TD was 14.2%. TA was positive in 44 (14.2%) subjects. Both TD (P<0.05) and TA (P<0.05) were associated with female sex, and antiTPO levels were related to the presence of unknown TD (OR 1.007; 95% CI, 1.004-1.010; P<0.001). In this population, total prevalence of TD and TA is similar (14%). Increased antiTPO titers are predictors of unknown TD.


Design and synthesis of releasable folate-drug conjugates using a novel heterobifunctional disulfide-containing linker.
Cellular uptake of vitamin folic acid occurs via folate-receptor mediated endocytosis. Many types of cancer cells express high levels of folate receptors as they need continuous supply of this vitamin for their proliferation. With an objective to use folic acid as a 'Trojan Horse' to transport anticancer drugs into cancer cells, a novel heterobifunctional disulfide-containing linker was synthesized and utilized to covalently link an amino- and hydroxyl-containing anticancer drug, and an appropriately functionalized folic acid to create novel targetable folate-drug conjugates that are shown to release free drugs under biologically relevant pH via sulfhydryl-assisted cleavage of the self-immolative disulfide-containing linker.


Comparative life-cycle assessments for biomass-to-ethanol production from different regional feedstocks.
This study compares life-cycle (cradle-to-gate) energy consumption and environmental impacts for producing ethanol via fermentation-based processes starting with two lignocellulosic feedstocks: virgin timber resources or recycled newsprint from an urban area. The life-cycle assessment in this study employed a novel combination of computer-aided tools. These tools include fermentation process simulation coupled with an impact assessment software tool for the manufacturing process life-cycle stage impacts. The process simulation file was provided by the National Renewable Energy Laboratory (NREL) and was modified slightly to accommodate these different feedstocks. For the premanufacturing process life-cycle stage impacts, such as the fuels and process chemicals used, transportation, and some preparatory steps (wood chipping, etc.), a life-cycle inventory database (the Boustead Model) coupled with an impact assessment software tool were used (the Environmental Fate and Risk Assessment Tool). The Newsprint process has a slightly lower overall composite environmental index (created from eight impact categories) compared to the Timber process. However, the Timber process consumes less electricity, produces fewer emissions in total, and has less of a human health impact. The amount of life-cycle fossil energy required to produce ethanol is 14% of the energy content of the product, making the overall efficiency 86%. Process improvement strategies were evaluated for both feedstock processes, including recycle of reactor vent air and heat integration. Heat integration has the greatest potential to reduce fossil-derived energy consumption, to an extent that fossil-derived energy over the life cycle is actually saved per unit of ethanol produced. These energy efficiency values are superior to those observed in conventional fossil-based transportation fuels.


Venous complications of sclerotherapy for esophageal varices.
Although endoscopic sclerotherapy is effective in controlling bleeding from esophageal varices, the effects of sclerosing agents on the extrahepatic portal and splenic veins have not previously been investigated. This study of 21 men with portal hypertension and variceal bleeding compares the morphology of the portal and splenic veins in 11 who had received endoscopic sclerotherapy versus 10 patients who did not. The mean number of injections per patient was 11 +/- 5, the mean volume of 1.5 percent sodium tetradecyl injected was 23 +/- 15 ml, and the interval between the last injection and surgery was 15 +/- 6.5 days. Among the 11 patients who had endoscopic sclerotherapy, portal vein thrombosis occurred in 4 (36 percent). Two of these patients died from acute liver failure; the other two had shunt procedures. Histologic changes included intimal thickening and medial fibrosis in seven patients, thrombus in four patients, and destruction of the venous architecture in two patients. Of the 10 patients with portal hypertension who did not have endoscopic sclerotherapy, all had medial fibrosis of the portal vein, with thrombus and intimal thickening present in only 1. These findings suggest that endoscopic sclerotherapy for esophageal varices should be used cautiously in patients who may later require a shunt. Moreover, further studies are necessary to evaluate the long-term effects of injecting sclerosing agents into the portal circulation before widespread use of prophylactic sclerotherapy can be recommended.


Evaluation of the Yeast Traffic Light PNA FISH probes for identification of Candida species from positive blood cultures.
The Yeast Traffic Light PNA FISH kit (YTL) correctly identified Candida spp. in 207/216 (96%) positive blood cultures. Discordant results were seen with known cross-reacting species and cultures containing Candida lambica and Rhodotorula mucilaginosa. The YTL provides rapid, reliable identification of the five common Candida species found in blood cultures.


Infliximab Therapeutic Drug Monitoring in Inflammatory Bowel Disease Virtual Biologics Clinic Leads to Durable Clinical Results.
Therapeutic drug monitoring (TDM) of infliximab (IFX) trough levels and anti-drug antibodies in conjunction with symptoms, disease history, and investigations can aid decision-making. This study evaluated 1-year outcomes of patients with decisions that were altered on the basis of TDM results, in order to investigate whether outcomes from TDM-based decisions to adjust or stop IFX treatment are durable. We retrospectively collected clinical outcomes 12 months post treatment decisions based on proactive TDM. Patients whose initial treatment decisions were altered on the basis of TDM results were compared with those where the decision remained unchanged. Events of interest were inpatient admissions with active inflammatory bowel disease (IBD), further changes to biologic therapy, and IBD-related health-care costs. Of 189 patients, 54 (28%) had initial treatment decisions altered in the light of TDM results. The 135 patients whose initial decision was not altered in light of TDM results served as the comparator. There were no differences in hospitalization rates or subsequent biologic switches between the altered decision groups and the comparator group. IBD-related health-care costs were higher in those whose initial decision was altered (median GBP 7,912 vs. GBP 6,521; p < 0.0001) due to higher drug costs (median GBP 7,062 vs. GBP 6,012; p < 0.0001). Our study demonstrates good outcomes from changes to IFX treatment based on TDM. Patients with a decision to stop, switch, or continue with an adjusted IFX dose experienced comparable clinical outcomes but had higher drug-related expenditure than those whose treatment decision was not altered in light of TDM.


Coronary reserve and right ventricular function in awake newborn lambs with persistent right ventricular hypertension.
Right ventricular function curves as measured by right ventricular stroke work were normal in all control lambs, whereas three of five lambs with banded pulmonary arteries had relatively flat curves. Left ventricular function was similarly normal in the control group as compared to a near zero slope function curve in the banded group. Regional myocardial blood flow to the septum and right and left ventricles was similar in control and banded lambs. At rest right ventricular coronary vascular resistance was lower in the banded than in the control group and decreased in both groups during both isoproterenol and dextran stress states. In general, both groups had a similar ratio of right to left ventricular oxygen supply to demand ratio. These results show first that there is minimal, if any, biventricular functional reserve in lambs with persistent right ventricular hypertension, and second, that there is substantial coronary vascular reserve in both normal and banded groups.


Normal and abnormal mechanisms of gene splicing and relevance to inherited skin diseases.
The process of excising introns from pre-mRNA complexes is directed by specific genomic DNA sequences at intron-exon borders known as splice sites. These regions contain well-conserved motifs which allow the splicing process to proceed in a regulated and structured manner. However, as well as conventional splicing, several genes have the inherent capacity to undergo alternative splicing, thus allowing synthesis of multiple gene transcripts, perhaps with different functional properties. Within the human genome, therefore, through alternative splicing, it is possible to generate over 100,000 physiological gene products from the 35,000 or so known genes. Abnormalities in normal or alternative splicing, however, account for about 15% of all inherited single gene disorders, including many with a skin phenotype. These splicing abnormalities may arise through inherited mutations in constitutive splice sites or other critical intronic or exonic regions. This review article examines the process of normal intron-exon splicing, as well as what is known about alternative splicing of human genes. The review then addresses pathological disruption of normal intron-exon splicing that leads to inherited skin diseases, either resulting from mutations in sequences that have a direct influence on splicing or that generate cryptic splice sites. Examples of aberrant splicing, especially for the COL7A1 gene in patients with dystrophic epidermolysis bullosa, are discussed and illustrated. The review also examines a number of recently introduced computational tools that can be used to predict whether genomic DNA sequences changes may affect splice site selection and how robust the influence of such mutations might be on splicing.


Percutaneous large-bore axillary access is a safe alternative to surgical approach: A systematic review.
To systematically review relevant literature regarding cardiovascular outcomes of large-bore axillary arterial access via percutaneous and surgical approaches. In patients with severe peripheral arterial disease (PAD) undergoing cardiac interventions, large-bore femoral access may be prohibitive. The axillary artery provides an alternative vascular access for transcatheter aortic valve replacement (TAVR) or mechanical circulatory support. There have been limited comparisons of percutaneous transaxillary (pTAX) approach with the more traditional surgical transaxillary (sTAX) approach. Pubmed and Medline databases were queried through January 2019 for studies describing pTAX or sTAX approaches with TAVR or Impella insertion. Primary outcomes were access-related mortality, 30-day mortality, stroke, major vascular complications, and major bleeding. One hundred and fifty five studies were reviewed, with additional unpublished data from 1 institution. Twenty-two studies met the inclusion criteria. Patient data was heterogeneous, with 69% TAVR and 31% Impella use in the pTAX group, and 96% TAVR and 4% Impella use in the sTAX group. There was more cardiogenic shock in the pTAX group. When compared to surgical approach, the percutaneous approach had similar 30-day mortality for TAVR (5.6% vs 4.6%, OR non-significant) and Impella (43.4% vs 38.6%, OR non-significant), similar stroke rates (4.3% vs 4.2%, OR non-significant), similar major vascular complications (2.8% vs 2.3%, OR non-significant) and less major bleeding (2.7% vs 17.9%, OR significant). Data suggests large-bore pTAX access has similar 30-day mortality, stroke rates, and major vascular complications as sTAX access, with less major bleeding. Additional studies are needed to validate results.


Western diet, obesity and bariatric surgery sequentially modulated anxiety, eating patterns and brain responses to sucrose in adult Yucatan minipigs.
Palatable sweet/fatty foods overconsumption is a major risk factor for obesity and eating disorders, also having an impact on neuro-behavioural hedonic and cognitive components comparable to what is described for substance abuse. We hypothesized that Yucatan minipigs would show hedonic, cognitive, and affective neuro-behavioral shifts when subjected to western diet (WD) exposure without weight gain, after the onset of obesity, and finally after weight loss induced by caloric restriction with (RYGB) or without (Sham) gastric bypass. Eating behavior, cognitive and affective abilities were assessed with a spatial discrimination task (holeboard test) and two-choice feed tests. Brain responses to oral sucrose were mapped using 18F-FDG positron emission tomography. WD exposure impaired working memory and led to an "addiction-type" neuronal pattern involving hippocampal and cortical brain areas. Obesity induced anxiety-like behavior, loss of motivation, and snacking-type eating behavior. Weight loss interventions normalized the motivational and affective states but not eating behavior patterns. Brain glucose metabolism increased in gustatory (insula) and executive control (aPFC) areas after weight loss, but RYGB showed higher responses in inhibition-related areas (dorsal striatum). These results showed that diet quality, weight loss, and the type of weight loss intervention differently impacted brain responses to sucrose in the Yucatan minipig model.


Gender differences in bone mineral density in obese children during pubertal development.
To investigate whether body mass index (BMI) and body composition can affect peak bone mass in a population of obese (OB) (BMI SDS>2.0) and normal weight (NORM) (BMI-SD score <2.0) pubertal subjects (Tanner stage T3 to T5). 151 subjects (81 OB, age 14.5±2.4 yr) were analyzed using dual-X-ray absorbiometry technique to study Lumbar and whole body bone mineral density (BMD) (areal, normalized for height) and Z-score, lean mass (LM) and lean/fat ratio. As a whole group, OB males did not show any significant difference in bone parameters vs NORM, while OB females showed higher bone density parameters (p<0.05). When grouped according to T, while OB males showed higher bone density at T3-4 stage (p<0.01), and lower at T5 (p<0.01) compared to NORM, OB females showed a tendency through increased BMD at T3-4 and T5 although statistically different only at T5. BMD was independently correlated to LM, lean/fat ratio, and testosterone in NORM males and, at lower level, in OB males, while to LM in NORM females and only to age in OB females. Our data seem to confirm the possible negative influence of obesity on bone density in boys, a possible explanation could be an unfavorable body composition during sexual maturation that seems not to affect bone development in adolescents girls.


Ureteral trauma: effects of ureteral ligation with and without deligation--experimental studies and case reports.
Inadvertent ureteral ligation is a well recognized risk during abdominal, retroperitoneal and pelvic operations. The feasibility and the safety of ureteral ligation treated with deligation have been documented. Herein is presented an over-all evaluation of the experience with ureteral ligation treated by deligation in 32 dogs and 4 women.


Toward practical causal epidemiology.
Population attributable fraction (PAF), probability of causation, burden of disease, and related quantities derived from relative risk ratios are widely used in applied epidemiology and health risk analysis to quantify the extent to which reducing or eliminating exposures would reduce disease risks. This causal interpretation conflates association with causation. It has sometimes led to demonstrably mistaken predictions and ineffective risk management recommendations. Causal artificial intelligence (CAI) methods developed at the intersection of many scientific disciplines over the past century instead use quantitative high-level descriptions of networks of causal mechanisms (typically represented by conditional probability tables or structural equations) to predict the effects caused by interventions. We summarize these developments and discuss how CAI methods can be applied to realistically imperfect data and knowledge - e.g., with unobserved (latent) variables, missing data, measurement errors, interindividual heterogeneity in exposure-response functions, and model uncertainty. We recommend that CAI methods can help to improve the conceptual foundations and practical value of epidemiological calculations by replacing association-based attributions of risk to exposures or other risk factors with causal predictions of the changes in health effects caused by interventions.


The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development.
Conserved metallo β-Lactamase and β-CASP (CPSF-Artemis-Snm1-Pso2) domain nuclease family member SNM1B/Apollo is a shelterin-associated protein that localizes to telomeres through its interaction with TRF2. To study its in vivo role, we generated a knockout of SNM1B/Apollo in a mouse model. Snm1B/Apollo homozygous null mice die at birth with developmental delay and defects in multiple organ systems. Cell proliferation defects were observed in Snm1B/Apollo mutant mouse embryonic fibroblasts (MEFs) owing to high levels of telomeric end-to-end fusions. Deficiency of the nonhomologous end-joining (NHEJ) factor Ku70, but not p53, rescued the developmental defects and lethality observed in Snm1B/Apollo mutant mice as well as the impaired proliferation of Snm1B/Apollo-deficient MEFs. These findings demonstrate that SNM1B/Apollo is required to protect telomeres against NHEJ-mediated repair, which results in genomic instability and the consequent multi-organ developmental failure. Although Snm1B/Apollo-deficient MEFs exhibited high levels of apoptosis, abrogation of p53-dependent programmed cell death did not rescue the multi-organ developmental failure in the mice.


Study protocol: a single-blind, multi-center, randomized controlled trial comparing dynamic intraligamentary stabilization, internal brace ligament augmentation and reconstruction in individuals with an acute anterior cruciate ligament rupture: LIBRƎ study.
The current gold standard for the treatment of an anterior cruciate ligament (ACL) rupture is reconstruction with tendon graft. Recently, two surgical ACL repair techniques have been developed for treating an acute ACL rupture: Dynamic Intraligamentary Stabilization (DIS, Ligamys®) and Internal Brace Ligament Augmentation (IBLA, InternalBrace™). We will conduct a single-blind, multi-center, randomized controlled trial which compares DIS, IBLA and reconstruction for relative clinical efficacy and economic benefit. Subjects, aged 18-50 years, with a proximal, primary and repairable ACL rupture will be included. DIS is preferably performed within 4 weeks post-rupture, IBLA within 12 weeks and reconstruction after 4 weeks post-rupture. Patients are included in study 1 if they present within 0-4 weeks post-rupture and surgery is feasible within 4 weeks post-rupture. Patients of study 1 will be randomized to either DIS or IBLA. Patients are included in study 2 if they present after 4 weeks post-rupture and surgery is feasible between 5 and 12 weeks post-rupture. Patients of study 2 will be randomized to either IBLA or reconstruction. A total of 96 patients will be included, with 48 patients per study and 24 patients per study arm. Patients will be followed-up for 2 years. The primary outcome is change from baseline (pre-rupture) in International Knee Documentation Committee score to 6 months post-operatively. The main secondary outcomes are the EQ-5D-5 L, Tegner score, Lysholm score, Lachman test, isokinetic and proprioceptive measurements, magnetic resonance imaging outcome, return to work and sports, and re-rupture/failure rates. The statistical analysis will be based on the intention-to-treat principle. The economic impact of the surgery techniques will be evaluated by the cost-utility analysis. The LIBRƎ study is to be conducted between 2018 and 2022. This LIBRƎ study protocol is the first study to compare DIS, IBLA and ACL reconstruction for relative clinical efficacy and economic benefit. The outcomes of this study will provide data which could aid orthopaedic surgeons to choose between the different treatment options for the surgical treatment of an acute ACL rupture. This study is registered at ClinicalTrials.gov; NCT03441295. Date registered 13.02.2018.


IRX3 is a genetic modifier for birth weight, adolescent obesity and transaminase metabolism.
IRX3 expression has been functionally associated in obesity-associated long-distance susceptibility loci, but the effect of the IRX3 genetic variants on human obesity and obesity-related metabolism remains uncertain. To determine the genetic role of IRX3, we conducted a molecular epidemiological analysis using three haplotype tagging single nucleotide polymorphisms (SNPs; rs8053360, rs3751723 and rs12445085) and one nonsynonymous SNP (rs1126960) at the IRX3 locus in 333 junior and senior high school students from a northeast Chinese population. We identified significant associations between IRX3 SNPs and birth weight, body mass index (BMI), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and AST/ALT ratio. The rs8053360 CC and rs1126960 GG genotypes were associated with increased birth weight and BMI, especially in females. Individuals with the rs12445085 TT genotype had significantly higher levels of AST and ALT, whereas individuals with the rs1126960 GG genotype had a significantly lower AST/ALT ratio than did individuals with other genotypes. However, no significant relationships were found between any of the IRX3 SNPs and metabolic syndrome or diabetes. IRX3 genetic variants associate with birth weight, BMI and AST/ALT-related transaminase metabolism, supporting the role of IRX3 as an obesity-associated susceptibility gene.


Chronic electrical stimulation of the left ventrointermediate (Vim) thalamic nucleus for the treatment of pharmacotherapy-resistant Parkinson's disease: a differential impact on access to semantic and episodic memory?
Thalamotomy for medically refractory Parkinson's disease (PD) is considered to be efficacious and relatively safe. Because a minority of patients experience decrements in language and memory (often mild and transient) after thalamotomy, chronic thalamic deep brain stimulation (DBS) might be a safer treatment given its reversibility and the modifiability of stimulation parameters. Two preliminary studies support the relative cognitive safety of unilateral DBS of the ventral intermediate (Vim) thalamic nucleus, but it is unclear whether possibly subtle changes in language and memory represent effects of "microthalamotomy" or of stimulation per se. This report provides preliminary data concerning effects of left thalamic stimulation on information processing speed, semantic memory (verbal fluency and visual confrontation naming), and verbal episodic memory in a patient with PD. In addition to being evaluated before and 3 and 6 months after surgery, the patient was tested 18 months after surgery either on or off medications and with the stimulator turned either on or off (order counterbalanced across medication conditions). Test performance differences between the stimulation conditions were attenuated "off" as compared to "on" medication. Vim stimulation consistently, albeit subtly, improved semantic verbal fluency but interfered with immediate recall of word lists. Parallels to findings from acute, intraoperative thalamic stimulation studies are explored. The hypothesis is offered that left Vim stimulation might facilitate access to semantic memory, but interfere with episodic memory processes.


Rhein lysinate decreases inflammation and adipose infiltration in KK/HlJ diabetic mice with non-alcoholic fatty liver disease.
The objective of this study was to investigate the protective effects of rhein lysinate (RHL) on the liver. Mice were divided into four groups: C57BL/J control, the KK/HlJ diabetic model, and 25 and 50 mg/kg/day RHL-treated KK/HlJ groups. The KK/HlJ diabetic mouse model was made by injecting STZ and feeding mice diabetic food. At 16 weeks, mice were sacrificed and their livers were harvested. The results indicated that compared with the C57BL/J control group, the body weights, liver weights and liver weight-to-body weight ratio were increased in KK/HlJ diabetic mice; however, these values were decreased following treatment with RHL. Compared with the C57BL/J control, KK/HlJ diabetic mice had a significantly lower level of SOD and GSH-px in their livers, but had a significantly higher level of MDA. However, these effects were ameliorated by RHL. Hepatic adipose infiltration was observed in KK/HlJ mice, but not in C57BL/J mice. RHL decreased the incidence of hepatic adipose infiltration and significantly decreased the expression of TNF-α, IL-6, NF-κB, SREBP-1c, and Fas, as well as the phosphorylation of NF-κB in the liver. In conclusion, RHL can improve hepatic function by decreasing hepatic adipose infiltration and the expression of inflammatory factors.


Natural statistics of head roll: implications for Bayesian inference in spatial orientation.
We previously proposed a Bayesian model of multisensory integration in spatial orientation (Clemens IAH, de Vrijer M, Selen LPJ, van Gisbergen JAM, Medendorp WP. J Neurosci 31: 5365-5377, 2011). Using a Gaussian prior, centered on an upright head orientation, this model could explain various perceptual observations in roll-tilted participants, such as the subjective visual vertical, the subjective body tilt (Clemens IAH, de Vrijer M, Selen LPJ, van Gisbergen JAM, Medendorp WP. J Neurosci 31: 5365-5377, 2011), the rod-and-frame effect (Alberts BBGT, de Brouwer AJ, Selen LPJ, Medendorp WP. eNeuro 3: ENEURO.0093-16.2016, 2016), as well as their clinical (Alberts BBGT, Selen LPJ, Verhagen WIM, Medendorp WP. Physiol Rep 3: e12385, 2015) and age-related deficits (Alberts BBGT, Selen LPJ, Medendorp WP. J Neurophysiol 121: 1279-1288, 2019). Because it is generally assumed that the prior reflects an accumulated history of previous head orientations, and recent work on natural head motion suggests non-Gaussian statistics, we examined how the model would perform with a non-Gaussian prior. In the present study, we first experimentally generalized the previous observations in showing that also the natural statistics of head orientation are characterized by long tails, best quantified as a t-location-scale distribution. Next, we compared the performance of the Bayesian model and various model variants using such a t-distributed prior to the original model with the Gaussian prior on their accounts of previously published data of the subjective visual vertical and subjective body tilt tasks. All of these variants performed substantially worse than the original model, suggesting a special value of the Gaussian prior. We provide computational and neurophysiological reasons for the implementation of such a prior, in terms of its associated precision-accuracy trade-off in vertical perception across the tilt range.NEW & NOTEWORTHY It has been argued that the brain uses Bayesian computations to process multiple sensory cues in vertical perception, including a prior centered on upright head orientation which is usually taken to be Gaussian. Here, we show that non-Gaussian prior distributions, although more akin to the statistics of head orientation during natural activities, provide a much worse explanation of such perceptual observations than a Gaussian prior.


Synergistic effect of nitrate on UV-chlorine photochemical degradation of carbamazepine.
We investigated the use of UV-chlorine advanced oxidation process for the removal and transformation of carbamazepine (CBZ), and its photochemical synergy with NO3- for the production of .OH towards enhancing CBZ removal in aqueous solution. Production of .OH by UV-chlorine system with/without NO3- was studied under different conditions, by using salicylic acid (SA) as the chemical probe for .OH. Initial concentration of 30 mg/L SA, 5 and 10 mg/L chlorine, and 0-10 mg/L NO3- under irradiation at 254 nm (3.026 W/L) in a photochemical reactor was used. Aqueous solutions containing 10 mg/L chlorine and spiked with 4 mg/L NO3- gave the highest reproducible generation of .OH. Using initial concentrations of 10 mg/L CBZ and 10 mg/L chlorine, 60 % CBZ was removed after 10 min of irradiation without NO3-, while 72 % CBZ was removed with 4 mg/L NO3- added. There was no noticeable CBZ removal after 10 min of irradiation in the presence of NO3- without chlorine. Corresponding dark reactions were also conducted, with no noticeable degradation of CBZ. Samples were analyzed via UHPLC, LC-MS, and TOC (total organic carbon) analyzer for CBZ and TOC concentrations respectively. Although, there was significant reduction in CBZ concentration during both photochemical degradation processes, the was low TOC removal (~10%) in each case. The two photochemical degradation processes also seem to generate similar degradation products indicating that the addition NO3- of the UV-chlorine process might not have changed the degradation mechanism. The results indicate that NO3- could act synergistically in a UV-chlorine system to increase CBZ removal and reduce the quantity of free chlorine required to achieve a target removal efficiency. This could facilitate reduction in the potential production of chlorinated byproducts in the system.


Pathogenicity of the newly emerged Lagovirus europaeus GI.2 strain in China in experimentally infected rabbits.
In April 2020, rabbit hemorrhagic virus type 2 (Lagovirus europaeus GI.2), which causes highly infectious fatal rabbit hemorrhagic disease, was emerged in China. The phylogenetic analyses of the complete genome sequence of GI.2 showed that it belonged to the non-recombinant GI.3/GI.2 genotype. However, the pathogenicity of this GI.2 strain differed from that of early typical GI.2 strains in Europe. To prevent the spread of the new strain in China, its pathogenicity urgently needs to be studied. Thus, viral shedding and distribution as well as clinical symptoms, histopathological changes, and serum cytokines were studied in experimentally GI.2/SC2020-infected rabbit adults and kits. The kit group showed a shorter survival time after the challenge than the adult group did. The mortality rate was higher in the kits (80 %) than in the adults (30 %). Viral RNA could be detected in both nasal and fecal swabs, and the main dissemination route appeared to be the fecal route. Viral RNA rapidly increased in the blood of the adults and kits at 6 h post-infection, indicating that blood viral load testing can be used for early diagnosis. The most affected organs were the liver and spleen, and the lesions were more severe in the kits than in the adults. The liver contained the highest viral RNA levels. Moreover, serum interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-alpha levels were increased in the infected rabbits. In conclusion, our findings will help to understand the evolutionary trends and pathogenic characteristics of GI.2 strains in China.


Home management of the dying NICU patient.
Intensive aggressive medical therapy does not always result in cure. For some neonates it is a futile exercise that may prolong a short life of suffering. In this article, we will discuss the babies for whom aggressive therapy may not be appropriate, and how home centered palliative care can be effectively managed. We will outline the holistic multidisciplinary approach to care, with the parents as primary carers, empowered to make informed choices in the medical care of their dying baby. Symptom management will be discussed, based on the experience of an established palliative care team. We will also look at the practical and emotional preparation for death and bereavement support for the family. We hope that more families will be given the opportunity to spend time at home with their dying baby and that, through appropriate care and support, the memory of this time will be treasured.


Silencing of the SNARE protein NAPA sensitizes cancer cells to cisplatin by inducing ERK1/2 signaling, synoviolin ubiquitination and p53 accumulation.
We found earlier that NAPA represents an anti-apoptotic protein that promotes resistance to cisplatin in cancer cells by inducing the degradation of the tumor suppressor p53. In the present study, we investigated the cellular mechanism underlying the degradation of p53 by NAPA. Knockdown of NAPA using short-hairpin RNA was shown to induce p53 accumulation and to sensitize HEK293 cells to cisplatin. On the other hand, this sensitization effect was not found in H1299 lung carcinoma cells which lack p53. Expression of exogenous p53 in H1299 cells was increased following knockdown of NAPA and these cells showed increased sensitivity to cisplatin-induced apoptosis. Notably, knockdown of NAPA induced the ubiquitination and degradation of the E3 ubiquitin ligase synoviolin and the accumulation of p53 in unstressed HEK293 cells. Conversely, NAPA overexpression decreased the ubiquitination and degradation of synoviolin, and reduced p53 protein level. Knockdown of NAPA disrupted the interaction between synoviolin and proteins that form the endoplasmic reticulum-associated degradation (ERAD) complex and in turn decreased the ability of this complex to ubiquitinate p53. In addition, knockdown of NAPA induced the activation of the MAPK kinases ERK, JNK and p38, but only inhibition of ERK reduced synoviolin ubiquitination and p53 accumulation. These results indicate that NAPA promotes resistance to cisplatin through synoviolin and the ERAD complex which together induce the degradation of p53 and thus prevent apoptosis. Based on these findings, we propose that the combination of cisplatin and knockdown of NAPA represents a novel and attractive strategy to eradicate p53-sensitive cancer cells.


Life goals and purpose in life in cancer patients.
The purpose of the study was to analyze associations between life goals and purpose in life in cancer patients. A sample of 153 cancer patients was assessed before the start of chemotherapy and about 9 months later. Purpose in life was measured with a German version of Crumbaugh and Maholick's purpose in life test, and the perceived importance of social, psychological, materialistic, and health-related goals was assessed with Likert scales. High importance of social, psychological, and health-related goals was related to higher purpose in life. In addition, having high levels of social goals at the first time of measurement predicted an increase in purpose of life over time. However, higher importance of material goals was associated with lower purpose in life at the second time of measurement and with a decline of purpose in life over time. There is continuity and change in the sources of purpose in life during cancer therapy, and a lack of fit between goals and changed living conditions is a risk factor for a decline in purpose in life.


Agonistic behavior in crayfish in relation to temperature and reproductive period.
I examined the relationship between temperature and agonistic behavior in the crayfish Cambarus latimanus LeConte a species which is reproductively active in winter. Crayfish were acclimated for 2 wks at 9.5, 14, 22 and 30°C in summer and at 9.5 and 22°C in winter. Agonistic behavior of pairs of the same sex was recorded for 1 h following acclimation. The entire acclimation, testing, and temperature-readjustment procedure was repeated until all crayfish pairs had been tested at each acclimation temperature.Published information on lobsters and catfish indicate that agonistic behavior is directly related to temperature. In contrast, for C. latimanus in the present study, duration of total agonistic behavior, maximum duration of a single agonistic interaction, and average length of a agonistic encounter were all inversely related to acclimation temperature. I hypothesized that for ectothermic species whose agonistic behavior is closely associated with reproductive processes (including competition for mates) the level of agonism will vary either directly or inversely depending upon whether the reproductive period is cued by increasing or decreasing seasonal temperatures, respectively.


Whole tumor antigen vaccination using dendritic cells: comparison of RNA electroporation and pulsing with UV-irradiated tumor cells.
Because of the lack of full characterization of tumor associated antigens for solid tumors, whole antigen use is a convenient approach to tumor vaccination. Tumor RNA and apoptotic tumor cells have been used as a source of whole tumor antigen to prepare dendritic cell (DC) based tumor vaccines, but their efficacy has not been directly compared. Here we compare directly RNA electroporation and pulsing of DCs with whole tumor cells killed by ultraviolet (UV) B radiation using a convenient tumor model expressing human papilloma virus (HPV) E6 and E7 oncogenes. Although both approaches led to DCs presenting tumor antigen, electroporation with tumor cell total RNA induced a significantly higher frequency of tumor-reactive IFN-gamma secreting T cells, and E7-specific CD8+ lymphocytes compared to pulsing with UV-irradiated tumor cells. DCs electroporated with tumor cell RNA induced a larger tumor infiltration by T cells and produced a significantly stronger delay in tumor growth compared to DCs pulsed with UV-irradiated tumor cells. We conclude that electroporation with whole tumor cell RNA and pulsing with UV-irradiated tumor cells are both effective in eliciting antitumor immune response, but RNA electroporation results in more potent tumor vaccination under the examined experimental conditions.


Isolation and partial characterization of an interleukin-1-like factor from rat testis interstitial fluid.
Testicular interstitial fluid (ISF) was collected by in vivo perfusion of rat testes and analyzed for the presence of interleukin-1 (IL-1) activity by utilizing a murine thymocyte proliferation assay. IS obtained from nine rats were all positive with dose-response curves of IL-1 activity similar to those produced by rat testicular aqueous extracts, rat macrophage IL-1 and human recombinant IL-1 alpha. Chromato-focusing of pooled ISF revealed a single peak of IL-1 activity with an estimated isoelectric point of 6.1-6.3. HPLC size exclusion chromatography demonstrated two active peaks with apparent molecular ratios Mr of 15,000-18,000 and 5000-7000, respectively. The molecular properties of the 15,000-18,000 Mr component are very similar to those of an IL-1-like factor previously isolated from seminiferous tubules. Our results indicate that the testicular IL-1-like factor is secreted by the seminiferous tubules into the interstitial tissue. Its function in the testicular interstitium is unknown but it might be relevant for the tendency to testicular relapse of childhood lymphocytic leukemia.


Suppressive effects of natural and synthetic agents on dextran sulfate sodium-induced interleukin-1beta release from murine peritoneal macrophages.
Interleukin (IL)-1beta, an anti-apoptotic and pro-inflammatory cytokine, plays an important role in the onset of inflammation-associated disease. We examined the suppressive effects of a total of 39 synthetic or natural compounds on dextran sulfate sodium-induced IL-1beta production in murine peritoneal macrophages. Several compounds, including alpha-tocopherol, gallic acid, (-)-catechin and rutin, were found to be highly effective for attenuating IL-1beta production, suggesting that they would be useful for anti-inflammatory application.


Ischemic infarction of cerebral cortex in a child with scorpion sting envenomation.
Ischemic infarction in scorpion sting envenomation is rare and only few cases have been reported in adults. A 3-y-old child is reported who developed recurrent generalized tonic-clonic seizures 2 h after admission and hemiparesis on third day of admission following scorpion sting. Cranial tomography showed infarction in right and left frontoparietal lobes. The child was managed conservatively with prazosin, lorazepam and phenytoin sodium and made a complete recovery.


Postoperative analgesia: a comparison of intravenous on-demand fentanyl with epidural bupivacaine.
In a randomised trial postoperative pain relief was provided by either epidural injections of bupivacaine or an infusion of fentanyl adjusted by the patient to achieve adequate pain relief. Both techniques produced satisfactory analgesia without respiratory depression after peripheral arterial surgery. The technique of infusing intravenously a potent analgesic in a dose adjusted by the patient appears to offer several advantages in postoperative care.


Towards remote assessment and screening of acute abdominal pain using only a smartphone with native accelerometers.
Smartphone-based telehealth holds the promise of shifting healthcare from the clinic to the home, but the inability for clinicians to conduct remote palpation, or touching, a key component of the physical exam, remains a major limitation. This is exemplified in the assessment of acute abdominal pain, in which a physician's palpation determines if a patient's pain is life-threatening requiring emergency intervention/surgery or due to some less-urgent cause. In a step towards virtual physical examinations, we developed and report for the first time a "touch-capable" mHealth technology that enables a patient's own hands to serve as remote surrogates for the physician's in the screening of acute abdominal pain. Leveraging only a smartphone with its native accelerometers, our system guides a patient through an exact probing motion that precisely matches the palpation motion set by the physician. An integrated feedback algorithm, with 95% sensitivity and specificity, enabled 81% of tested patients to match a physician abdominal palpation curve with <20% error after 6 attempts. Overall, this work addresses a key issue in telehealth that will vastly improve its capabilities and adoption worldwide.


Otologic surgery following ear trauma.
To investigate common presentations and expected outcomes in patients with traumatically induced otologic dysfunction. Retrospective case review of patients who underwent otologic surgery for sequelae of otologic trauma over a 28-year period. Patients were stratified into major and minor trauma cohorts. Major trauma was designated as closed head injury with or without temporal bone fracture; lower-energy insults comprised the minor trauma group. Preoperative and postoperative audiograms were obtained and correlated with extent of injury. Tertiary referral center. Major trauma accounted for 44.9 percent of all patients. The remaining 55.1 percent suffered minor trauma, of which simple traumatic tympanic membrane perforation was the most common insult (33.6%). Two hundred twenty-seven cases were performed on 214 patients. Pure tone averages improved a significant 20.8 dB to essentially normal levels postoperatively. Regardless of injury extent, surgical rehabilitation of conductive losses attains excellent hearing results that surpass those historically reported for the chronic ear population.


Blood-Modified Carbapenem Inactivation Method: a Phenotypic Method for Detecting Carbapenemase-Producing Enterobacteriaceae Directly from Positive Blood Culture Broths.
A variant of the modified carbapenem inactivation method (mCIM) was developed to detect carbapenemase activity directly from positive blood culture broths. The method, termed "Blood-mCIM," was evaluated using Bactec blood culture bottles (Becton, Dickinson and Company, Franklin Lakes, NJ) inoculated with 27 different carbapenemase-producing Enterobacteriaceae (CPE) isolates and 34 different non-CPE isolates. The assay was positive for all blood culture broths inoculated with CPE isolates and negative for all blood culture broths inoculated with non-CPE isolates, corresponding to a diagnostic sensitivity and specificity of 100%, respectively. This assay is inexpensive using "off the shelf" reagents, does not require centrifugation or mechanical lysis, and can be readily implemented in any clinical microbiology laboratory. The Blood-mCIM should facilitate expedient administration of antimicrobial therapy targeted toward CPE bloodstream infections and assist infection control and public health surveillance.


Toxicity of human recombinant interferon-gamma in rats and dogs.
To study the acute and chronic toxicities of human recombinant interferon-gamma (Hu-rIFN-gamma) in mice, rats, and dogs. Twenty mice were administrated Hu-rIFN-gamma (i.m. or i.v.) 4.4 x 10(9) IU m-2 to observe the acute toxicity. In chronic studies, 1 x 10(7), 5 x 10(7), 1 x 10(8) IU m-2 d-1 were given to 80 rats and 5 x 10(5), 5 x 10(7) IU m-2 d-1 were injected to 14 dogs i.m. for 3 months, treatment-related changes were measured in the hematologic, chemical, urinalysis values, ECG and pathologic profile of organs and tissues. The maximal tolerance dose (MTD) i.m. or i.v. in mice was 4.4 x 10(9) IU m-2, 4400 times the recommended clinical dosage (1 x 10(6) IU m-2). No adverse effects were found in chronic toxicity studies. Human recombinant interferon-gamma did not produce toxic reaction in rats and dogs.


Budesonide reduces superoxide and peroxynitrite anion chemiluminescence during human neutrophil bursts.
Many lung disorders are characterized by airway inflammation involving the recruitment of inflammatory cells, and leading to the release of oxidant and inflammatory mediators. The overproduction of superoxide anion (O(2)(*-)) and nitric oxide (NO) during the respiratory bursts of neutrophils leads to production of peroxynitrite, a highly damaging oxidant with an important role in the inflammatory loop causing airway hyper-reactivity in respiratory diseases like asthma. The aim of this study was to investigate in vitro the effects of a 1-hour incubation with budesonide at 2.5 x 10(-7), 5 x 10(-7), 1 x 10(-6), 2 x 10(-6) and 4 x 10(-6) mol/l on O(2)(*-), NO, and peroxynitrite production during the respiratory burst of human neutrophils stimulated by N-formyl-methionyl-leucyl-phenylalanine (fMLP, 5 x 10(-7) mol/l) or phorbol 12-myristate 13-acetate (PMA, 2 x 10(-6) mol/l), as documented by luminol-amplified chemiluminescence (LACL). In absence of L-arginine, budesonide (5 x 10(-7) to 4 x 10(-6) mol/l) dose-dependently reduced both fMLP- and PMA-induced LACL (18.3-50.6%). In the presence of L-arginine (100 microg/ml), a NO donor increasing peroxynitrite production, LACL increased 3-5 times compared with baseline, but budesonide dose-dependently reduced LACL (25.5-59.6%). Mifepristone (4 x 10(-6) mol/l), a glucocorticoid receptor antagonist, inhibited the effect of budesonide on LACL, thus confirming that budesonide reacts with glucocorticoid receptors to exert an antioxidant activity. These results suggest that budesonide target rapidly human neutrophils leading to a fast reduction in both NO and peroxynitrite production, and are consistent with decrease in exhaled NO levels after treatment with budesonide in patients with asthma.


Case Series: Cariprazine for treatment of methamphetamine use disorder.
Methamphetamine use is a major source of morbidity and mortality but has no reliably effective interventions. We identified cariprazine as an option for treatment of methamphetamine use disorder (MUD) and present two cases. Two patients with MUD and psychotic disorders were treated with cariprazine. Abstinence and cravings were assessed using urine drug screens and the Brief Substance Craving Scale, respectively. Both patients reported global functional improvement, reduction in methamphetamine cravings and use with cariprazine, confirmed with negative urine drug screens. Cariprazine's unique pharmacodynamic profile conveys potential efficacy for MUD. It would be a novel treatment that targets multiple psychiatric symptoms seen in MUD.


Purification and properties of a plasminogen activator from pig heart.
An improved procedure is described for the purification of plasminogen activator from pig heart. The initial purification steps were similar to these described previously (Bachmann, F., Fletcher, A. P., Alkjaersig, N., and Sherry, S. (1964) Biochemistry 3, 1578--1585). Use of a novel extraction medium containing EDTA, cysteine, and 2,3-dimercaptopropanol-1 facilitated the removal of large amounts of inert proteins prior to gel filtration on Bio-Gel P-150. The final product had a specific activity of 120,000 to 160,000 CTA units/mg of protein (CTA, Committee on Thrombolytic Agents of the National Heart Institute). Total purification over pig heart was 25,000 to 30,000-fold, average recovery compared to the initial extract was 6 to 8%. Polyacrylamide gel electrophoresis revealed a major and two minor components. The molecular weight of the activator determined by gel filtration was 51,500 +/- 3,400 for the major activity component and 48,000 for a minor component which was partially separated from the major peak in eight of nine chromatography runs. A gamma-globulin fraction of antiserum against purified activator neutralized the biological activity of the activator on fibrin plates. Immunoelectrophoresis of gel-filtered activator revealed only one anodic component.


[Microsporidiosis of Sakhalin Salmonidae: the incidence and dynamics of the infection].
Four-year summer observations have shown that G. takedai distribution in Salmonidae of Sakhalin is limited by the rivers entering the Aniva Bay. Maximum infection of pink salmon (Oncorhynchus gorbuscha) amounts to 70-100%, that of masu salmon (Oncorhynchus masou) to 9.0-45.6% and was recorded in September. Dynamics and possible ways of infection are discussed.


Asymptomatic COVID-19 presenting with features of mixed pattern acute liver injury in a young healthy female, a case report.
COVID-19 associated severe acute liver injury in a young healthy patient has not been reported much in the literature. And currently, there are no standard management guidelines. We want to report a case of acute liver injury of mixed pattern in a young healthy female with asymptomatic COVID-19 infection. She presented with abdominal pain, nausea, vomiting and yellowish discoloration of her skin. Further laboratory investigations revealed mixed pattern liver injury with highly raised liver enzymes. She was managed with N-acetyl cysteine protocol and monitoring of her liver enzymes. Other causes of acute liver injury were ruled out. She remained stable during her hospital stay and follow up. Our aim is to highlight the significance of acute liver injury in COVID 19 patients that may lead to fatal outcomes if not managed and monitored accordingly.


Removal of Ni(II), Zn(II) and Cr(VI) from aqueous solution by Alternanthera philoxeroides biomass.
Alternanthera philoxeroides biomass, a type of freshwater macrophyte, was used for the sorptive removal of Ni(II), Zn(II) and Cr(VI) from aqueous solutions. Variables of the batch experiments include solution pH, contact time, particle size and temperature. The biosorption capacities are significantly affected by solution pH. Higher pH favors higher Ni(II), Zn(II) removal, whereas higher uptake of Cr(VI) is observed as the pH is decreased. A two-stage kinetic behavior is observed in the biosorption of Ni(II), Zn(II) and Cr(VI): very rapid initial biosorption in a few minutes, followed by a long period of a slower uptake. It is noted that an increase in temperature results in a higher Ni(II), Zn(II) and Cr(VI) loading per unit weight of the sorbent. Decreasing the particle sizes of the Alternanthera philoxeroides biomass leads to an increase in the Ni(II), Zn(II) and Cr(VI) uptake per unit weight of the sorbent. All isothermal data are fairly well fitted with Langmuir equations. The thermodynamic parameter, DeltaG degrees, were calculated. The negative DeltaG degrees values of Cr(VI), Ni(II) and Zn(II) at various temperatures confirm the adsorption processes are spontaneous.


Revisiting MET: Clinical Characteristics and Treatment Outcomes of Patients with Locally Advanced or Metastatic, MET-Amplified Esophagogastric Cancers.
Metastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches. Patients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non-MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group. We identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and <25 MET copy number) compared with highly amplified tumors (≥25 MET copy number). MET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes. This article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice.


Progesterone modulation of inflammatory cytokine production in a fetoplacental artery explant model.
The purpose of this study was to determine if progesterone has an effect on fetoplacental artery production of inflammatory cytokines. Chorionic plate arteries were dissected from 5 placentas obtained from normal pregnancies after delivery at term. Arteries were incubated in Dulbecco's modified Eagle's medium (DMEM) alone, DMEM and lipopolysaccharide (LPS), DMEM with progesterone (P4), and DMEM with P4 and LPS. Samples of the tissue culture media were collected and evaluated for interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10) by immunoassay. There was a significant decrease in the production of IL-6 in P4-exposed fetoplacental arteries after LPS stimulation (P < .001). IL-10 and TNF-alpha levels were similar in control and treatment groups after LPS exposure. Pretreating fetoplacental arteries with P4 significantly decreased the production of IL-6 after LPS stimulation without altering the production of TNF-alpha or IL-10.


Induction of innate immunity in lungs with virus-like nanoparticles leads to protection against influenza and Streptococcus pneumoniae challenge.
Nanoparticles composed of the coat protein of a plant virus (papaya mosaic virus; PapMV) and a single-stranded RNA (ssRNA) trigger a strong innate immune stimulation in the lungs of the animals a few hours following instillation. A rapid recruitment of neutrophils, monocytes/macrophages and lymphocytes follows. This treatment was able to provide protection to an influenza challenge that lasts at least 5 days. Protection could be recalled for longer periods by repeating the instillations once per week for more than 10 weeks. The treatment also conferred protection to a lethal challenge with Streptococcus pneumoniae--the major cause of bacterial pneumonia. Finally, we also showed that the nanoparticles could be used to treat mice infected with influenza and significantly decrease morbidity. These data strengthen the potential for using PapMV nanoparticles as non-specific inducers of the innate immune response in lungs during viral pandemics or to combat bioterrorist attack. In this study, virus-like nanoparticles were utilized to induce innate immune responses in a mouse model. They were also demonstrated to provide enhanced immune responses during actual pneumonia and ongoing viral infection. Strategies like this may become very helpful in human applications, including bioterrorism countermeasures.


Effect of island area on Drosophila population densities.
Species of the Drosophila affinis subgroup show a positive correlation between population density and island area on islands in the vicinity of Deer Isle, Maine. The low density of flies on small islands may be due to inbreeding depression, exposure to salt spray, desiccation, or decimation by violent storms. Mushroom-feeding species of Drosophila show great year to year fluctuations in abundance on these islands, probably due to changes in the level of their resource supply. Population fluctuations and non-linear correlations between island area and population size may have complicating effects on the probability of extinction of species on different sized islands.


GCPII modulates oxidative stress and prostate cancer susceptibility through changes in methylation of RASSF1, BNIP3, GSTP1 and Ec-SOD.
Glutamate carboxypeptidase II (GCPII) haplotypes were found to influence susceptibility to prostate cancer. In the current study, we have elucidated the impact of these haplotypes on the expression of PSMA, BNIP3, Ec-SOD, GSTP1 and RASSF1 genes to understand the epigenetic basis of oxidative stress and prostate cancer risk. Expression analysis was carried out by RT-PCR. Bisulphite treated DNA was subjected to MS-PCR and COBRA for epigenetic studies. Plasma MDA and glutathione levels were measured. In prostate cancer, upregulation of BNIP3 (204.4 ± 23.77 vs. 143.9 ± 16.42 %, p = 0.03); and downregulation of Ec-SOD (105.8 ± 13.69 vs. 176.3 ± 21.1 %, p = 0.027) and RASSF1A (16.67 ± 16.0 vs. 90.8 ± 8.5 %, p = 0.0048) was observed. Hypomethylation of BNIP3 (31.25 ± 16.19 vs. 45.70 ± 2.42 %, p < 0.0001), hypermethylation of Ec-SOD (71.4 ± 6.75 vs. 10.0 ± 3.78 %, p < 0.0001) and RASSF1 (76.25 ± 12.53 vs. 30.0 ± 8.82 %, p = 0.0077) was observed in prostate cancer. The gene expression signature of PSMA, BNIP3, Ec-SOD, GSTP1, clearly demarcated cases and controls (AUC = 0.89 in the ROC curve). D191V variant of GCPII showed positive association with oxidative stress and inverse association with Ec-SOD expression. H475Y variant showed positive association with Ec-SOD expression and inverse association with oxidative stress. R190W variant was found to reduce oxidative stress by increasing glutathione levels. GCPII genetic variants contribute to increased oxidative stress and prostate cancer risk by modulating the CpG island methylation of Ec-SOD.


Appetitive and Metabolic Responses to an Exercise versus Dietary Intervention in Adults with Obesity.
Dietary restriction (DIET) and aerobic exercise (AEX) interventions may impact energy balance differently. Our aim was to describe the effects of weight loss interventions via DIET or AEX on measures of energy balance. Adults with overweight or obesity were randomized to 12 weeks of DIET or AEX with similar calorie deficit goals. A study day was conducted before and after the intervention to assess subjective and hormonal (ghrelin, peptide-YY, glucagon-like peptide-1) appetite responses to a control meal, ad libitum energy intake (EI) at a single meal, and over three days of free-living conditions and eating behavior traits. Resting metabolic rate (RMR) was measured with indirect calorimetry and adjusted for body composition measured by dual X-ray absorptiometry. Non-exercise activity was measured using accelerometers. Forty-four individuals were included (age: 37 ± 9 years, body mass index: 30.6 ± 3.1 kg/m2). Both interventions resulted in weight and fat mass loss. The DIET group lost fat-free mass, although differences between groups were not significant (DIET: -1.2 ± 1.7 kg, p<0.001; AEX: 0.4 ± 1.5 kg, p=0.186; p=0.095 interaction). There were no differences in RMR after body composition adjustment. Both interventions were associated with an increase in dietary restraint (DIET: 4.9 ± 1.2, AEX: 2.8 ± 0.7; p<0.001 in both groups). Hunger decreased with DIET (-1.4 ± 0.5, p=0.003), and disinhibition decreased with AEX (-1.5 ± 0.5, p<0.001), although these changes were not different between groups (i.e., no group × time interaction). No other differences in appetite, EI, or non-exercise physical activity were observed within or between groups. AEX did not result in compensatory alterations in appetite, ad libitum EI, or physical activity, despite assumed increased energy expenditure. Modest evidence also suggested that disinhibition and hunger may be differentially impacted by weight loss modality.


Studies on the serological cross-reaction between Marek's disease virus and herpesvirus of turkeys using monoclonal antibodies to major virus-specific polypeptides. Brief report.
A major virus-specific polypeptide antigenically cross-reactive between Marek's disease virus (MDV) and herpesvirus of turkeys (HVT) was characterized by two monoclonal antibodies against MDV. The antigenic determinant recognized by one monoclonal antibody was present only in the MDV polypeptide but not in the HVT polypeptide, whereas the antigenic determinant recognized by the other antibody was present in both MDV and HVT polypeptides. Peptide mapping showed the difference in the amino acid sequence of the two polypeptides.


The Efficacy of Arthroscopic Simulation Training on Clinical Ability: A Systematic Review.
To examine the effect of arthroscopic simulator training on technical performance in a human model. A systematic review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Literature searches of PubMed, Embase, and Cochrane Library were conducted using combinations of the terms virtual, digital, computer, reality, simulation, arthroscopy, training, learning, and education. Studies were considered for inclusion if they tested the effect of arthroscopic simulator training in a randomized controlled fashion, performed testing in a cadaver or live patient, and used explicit outcome measures of technical skill. Data from studies were extracted and study characteristics and outcomes were reviewed. The primary outcome measure was the number of studies in which the simulation trained group had significantly improved performance results relative to the control group in ≥50% of all measured outcomes. Risk of bias was assessed with Cochrane's Collaboration Tool. Twelve studies, including 340 total study participants, were included for review. Eight studies showed improved performance of the simulation trained group relative to the control group in ≥50% of assessed outcomes. Six of ten studies reporting completion time, three of six studies reporting task checklist completion, 3 of 7 studies reporting global rating scales, and 1 of 4 studies reporting Arthroscopic Surgical Skill Evaluation Tool scores showed improved performance of the simulation group relative to the control group for the respective outcome measures. The literature is limited due to heterogeneity, both in type and merit, of the outcome measures that have been used to assess the transfer validity of arthroscopic simulator training to clinical performance. Despite the limitations of the literature, this review demonstrates that arthroscopic simulator training has potential to improve clinical performance. II, systematic review of Level II studies.


Predictors of Chronic Pain in Elderly Patients Undergoing Total Knee and Hip Arthroplasty: A Prospective Observational Study.
Chronic postsurgical pain (CPSP) after total knee arthroplasty and total hip arthroplasty (TKA and THA) is an important clinical problem in which many factors play a role. The risk factors for CPSP in elderly individuals are currently unknown. Therefore, our aim was to predict the risk factors for CPSP after TKA and THA and to provide help regarding early screening and interventions for elderly individuals at risk. In this prospective observational study, we collected and analyzed 177 TKA patients and 80 THA patients. Based on pain results at the 3-month follow-up, they were divided into the no chronic postsurgical pain and CPSP groups, respectively. The preoperative baseline conditions, including pain intensity (Numerical Rating Scale) and sleep quality (Pittsburgh Sleep Quality Index), as well as intraoperative and postoperative factors, were compared. Factors with P < .05 were included in binary regression analyses to establish prediction models for CPSP after TKA and THA. The prevalence of CPSP was 20.9% after TKA and 7.5% after THA. The preoperative sleep disorders were an independent risk factor of CPSP after TKA, but no risk factors of CPSP after THA were identified. This study indicated that the prevalence of CPSP after TKA was significantly higher than after THA, and that preoperative sleep disorders were an independent risk factor for CPSP after TKA, which may aid clinicians in screening people at risk for CPSP for primary prevention.


Complete structural model of Escherichia coli RNA polymerase from a hybrid approach.
The Escherichia coli transcription system is the best characterized from a biochemical and genetic point of view and has served as a model system. Nevertheless, a molecular understanding of the details of E. coli transcription and its regulation, and therefore its full exploitation as a model system, has been hampered by the absence of high-resolution structural information on E. coli RNA polymerase (RNAP). We use a combination of approaches, including high-resolution X-ray crystallography, ab initio structural prediction, homology modeling, and single-particle cryo-electron microscopy, to generate complete atomic models of E. coli core RNAP and an E. coli RNAP ternary elongation complex. The detailed and comprehensive structural descriptions can be used to help interpret previous biochemical and genetic data in a new light and provide a structural framework for designing experiments to understand the function of the E. coli lineage-specific insertions and their role in the E. coli transcription program.


Use of a modified Tenax GC column packing for the direct gas chromatographic analysis of phenols in water at the ppm level.
Dilute solutions of phenols in water at the ppm level may be analysed gas chromatographically by direct injection onto a column with a packing similar to that used in the Viking 1975 spacecraft: Tenax GC (2,6-diphenyl-p-phenylene oxide polymer) modified with polymetaphenyl ether liquid phase to eradicate irreversible adsorption. Symmetrical peaks were observed for injections of less than 1 ng of phenol and some of its alkylated derivatives. Chromatographic properties of modified Tenax GC columns are reported along with their application to the analysis of some industrial effluents with previous work-up.


A randomized controlled trial of early oral analgesia in gynecologic oncology patients undergoing intra-abdominal surgery.
To evaluate the safety and efficacy of early oral analgesia after intra-abdominal surgery in gynecologic oncology patients. Over a 2.5-year period, 227 gynecologic oncology patients undergoing intra-abdominal surgery were enrolled in a randomized controlled trial of early oral versus traditional parenteral analgesia. All patients initially received parenteral morphine via a patient-controlled analgesia (PCA) pump with a basal dose of 0.5 mg/h and a PCA dose of 1 mg with a 10-minute lockout. On the first postoperative day, all patients began a clear liquid diet, which was advanced as tolerated. Patients allocated to early oral analgesia were switched from parenteral to oral morphine. They received a scheduled dose of 20 mg every 4 hours with an additional dose of 10 mg every 2 hours as needed for breakthrough pain. Patients allocated to traditional parenteral analgesia continued to receive parenteral morphine via a PCA pump with basal and PCA doses. On the second postoperative day, the scheduled oral and basal parenteral doses were discontinued. The oral and parenteral PCA doses were continued until 24 hours before discharge, at which time the patient was switched to oxycodone 5 mg/acetaminophen 325 mg. There were no significant differences among the groups in any demographic or clinical indices, including age, case distribution, surgery length, blood loss, time to return of bowel function, length of hospital stay, pain, sedation, and satisfaction scores, and incidence of nausea, vomiting, or major postoperative complications. Early oral analgesia in gynecologic oncology patients undergoing intra-abdominal surgery is safe and efficacious.


Population data of nine STR loci, D3S1358, vWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317 and D7S820, in Bangladeshis and Indonesians.
Allele frequencies of nine short tandem repeat (STR) loci, D3S1358, vWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317 and D7S820, were determined for 127 unrelated Bangladeshi individuals and 105 unrelated Indonesian individuals using the AmpFLSTR Profiler Kit. The genotype frequency distributions of the nine STR loci were in the Hardy-Weinberg equilibrium for both populations.


Should all endometrioid uterine cancer patients undergo systemic lymphadenectomy?
To evaluate the potential benefits of systemic pelvic and para-aortic lymphadenectomy in endometrioid uterine cancer patients. We conducted a retrospective study on 244 cases of endometrioid uterine cancer that involved surgery in the Center of Gynecologic Oncology, Peking University People's Hospital, Beijing, from January 2000 to May 2008. We conducted staging for each case to ensure accordance with FIGO 2009 surgical staging criteria. Clinical data, including histology, age at diagnosis, surgical procedure, adjuvant therapy, date of death or last follow-up, and date and sites of recurrence were collected for each patient. Among 244 endometrioid uterine cancer patients, 207 cases (84.8%) underwent systemic pelvic lymphadenectomy. Among these cases, pelvic lymph nodes in 17 cases (8.2%) exhibited tumor metastasis. Systemic aortic lymphadenectomy was performed in 127 cases (52.0%) among 244 total patients. Five cases (3.9%) exhibited positive aortic lymph nodes, of which four exhibited positive pelvic lymph nodes. We investigated the impact of positive retroperitoneal lymph nodes on staging: 4 (4/161, 2.5%), 6 (6/29, 20.7%), 6 (6/35, 17.1%), 1 (1/8) and 1 (1/6) case changed to stage IIIc from stage Ia, Ib, II, IIIa, and IIIb, respectively. Tumor-free and overall survival did not differ between patients who underwent pelvic lymphadenectomy or not (P > 0.05). Tumor-free survival improved in stage Ib pelvic lymphadenectomy patients (P = 0.040); para-aortic lymphadenectomy did not improve patient survival in all stages (P > 0.05). Systemic lymphadenectomy is not warranted in stage Ia endometrioid uterine cancer.


Oncology nursing workforce: challenges, solutions, and future strategies.
The global oncology nursing workforce is essential to achieving Sustainable Development Goals 3.4 (reduce non-communicable disease morbidity by a third by 2030) and 3.8 (universal health coverage). Unfortunately, challenges to a robust oncology nursing workforce include nursing shortages, recruitment barriers (eg, perceptions of a demanding specialty with complex care and hazardous work environments), and burnout. Innovative recruitment strategies, onboarding and continuing education programmes, occupational safety measures, and burnout prevention interventions are documented solutions. The long-term effect of COVID-19 on oncology care worldwide is unknown, but immediate therapy interruptions, workforce consequences, and threats to standard oncology nursing practice are addressed here. Retention of experienced oncology nurses is crucial for future cancer control in all countries and must be addressed, particularly in resource-constrained countries with few oncology nursing staff and continuing out-migration of nurses to resource-rich countries. As the cancer burden worldwide increases, the future of the oncology nursing workforce is reflected in the call from the International Council of Nurses, Nursing Now, and WHO for nurses to move to higher levels of leadership, advocacy, and policy making (ie, national cancer control planning) and assume responsibility for their key role in achieving global goals for cancer control.


Age and gender in gerontechnology development : Emphasizing the need for an intersectional approach.
The challenges of the digital divide emerge with new technologies being created to address the needs of the increasing older population. This divide is influenced by the social dimensions of age and gender, often resulting in impaired participation of the affected demographic groups. Gerontechnological designs in which inadequate attention is paid to gender and old age easily run the risk of reproducing gender-specific and age-specific stereotypes. An approach to counteracting the digital exclusion of technology users is the introduction of co-creative methods of participatory design (PD). As there are diverse challenges when putting these methods into practice regarding their claim to be more socially inclusive and democratizing technology development, it is necessary to investigate the effect that age and gender could play when considering PD in gerontechnology. This article aims to shed light on the intersection of age and gender as dimensions of horizontal inequalities in gerontechnology development to support the further development of co-creation practices. The PD approaches can be regarded as suitable methodologies to descript age and gender in technology development as long as they are enhanced by a critical awareness of gendered and ageist patterns in society and technology development. The intersectional approach can contribute to further understanding of how current gerontechnology development practices promote the reinforcement and challenging of dominant discourses on old age and gender.


Molecular mechanisms of antiestrogen action in breast cancer.
The success of antiestrogen therapy to treat all stages of breast cancer, and the evaluation of tamoxifen as a preventive for breast cancer in normal women, have focused attention on the molecular mechanisms of antiestrogen action and mechanisms of drug resistance. The overall goal of research is to enhance current therapies and to develop new approaches for breast cancer treatment and prevention. Recent studies show that tamoxifen and the new pure antiestrogens appear to have different mechanisms of action: tamoxifen and related compounds cause a change in the folding of the steroid binding domain that prevents gene activation whereas the pure antiestrogens cause a reduced interaction at response elements and cause a rapid loss of receptor complexes. Tamoxifen treatment produces changes in the cellular and circulating levels of growth factors that could influence both receptor negative or receptor positive tumor growth and the metastatic potential of a tumor. These events may explain the survival advantage observed with tamoxifen therapy. However, the current therapeutic challenge is to avoid drug resistance during long-term tamoxifen therapy. Numerous explanations for drug resistance to tamoxifen have been suggested, including elevated estrogen levels, increased tumor antiestrogen binding sites, receptor mutations, and impaired signal transduction. However, it is probable that multiple mechanisms evolve to facilitate tumor survival. Most importantly, current research is examining mechanisms responsible for the beneficial actions of tamoxifen on bones and lipids as well as the potentially deleterious effects of tamoxifen on liver and endometrial carcinogenesis and retinopathy. The urgent need to understand antiestrogenic drug mechanisms and toxicity is being facilitated by the application of the technology developed for basic molecular biology.


Ototoxicity monitoring through the eyes of the treating physician: Perspectives from pulmonology and medical oncology.
Integrating audiological management into the care pathways of clinical specialties that prescribe ototoxic medications for essential, often life-preserving medical care that is critical for early hearing loss identification and remediation. Research shows that successful implementation of a new health service or intervention requires alignment of goals among provider groups, institutional leadership and patients. Thoughtful consideration of the physician's viewpoints about ototoxicity and its implications for treatment planning is, therefore, important for the implementation and enduring success of an ototoxicity monitoring programme (OMP). This discussion paper uses qualitative methods to explore the perspectives of four physicians on OMP provision in their patient populations. Three pulmonologists and one oncologist completed the written survey or survey-based interview described in this report. Each physician indicated that (i) ototoxicity is a potential problem for their patients; (ii) monitoring hearing is important to ensure good quality of life among their patients and (iii) treatment modification would be considered if an alternative treatment option were available. The physicians differed in their approaches to ototoxicity monitoring, from routine referrals to audiology, to relying on patient self-referral. Physician provider input is needed to optimise monitoring schedules and OMP care coordination with audiology.


Use of antibiotics and risk of type 2 diabetes, overweight and obesity: the Cardiovascular Risk in Young Finns Study and the national FINRISK study.
To investigate whether exposure to systemic antibiotics influences the risk of developing type 2 diabetes and overweight/obesity. The study sample comprised 2209 (110 with incident diabetes) participants from the population-based Cardiovascular Risk in Young Finns Study (YFS) aged 24-39 years in 2001. The exposure was national linked register data on purchased antibiotic courses between 1993 and 2001. Clinical examinations including BMI were conducted in 2001, 2007 and 2011. Participants with prevalent diabetes in 2001 were excluded. Data on type 2 diabetes was also obtained from two national registers until 2017. Data from four population-based National FINRISK studies were used for replication (N = 24,674, 1866 with incident diabetes). Prior antibiotic exposure (> 5 versus 0-1 antibiotic courses) was associated with subsequent type 2 diabetes in both YFS (OR 2.29; 95%CI 1.33-3.96) and FINRISK (HR 1.73; 95%CI 1.51-1.99). An increased risk for type 2 diabetes was observed in YFS (OR 1.043; 95%CI 1.013-1.074) and FINRISK (HR 1.022; 95%CI 1.016-1.029) per course. Exposure to antibiotics increased the risk of overweight/obesity (BMI > 25 kg/m2) after a 10-year follow-up in YFS (OR 1.043; 95%CI 1.019-1.068) and in FINRISK (OR 1.023; 95%CI 1.018-1.029) at baseline per antibiotic course. Adjustments for confounders from early life in YFS and at baseline in FINRISK, including BMI, socioeconomic status, smoking, insulin, blood pressure, and physical activity, did not appreciably alter the findings. Our results show that exposure to antibiotics was associated with increased risk for future type 2 diabetes and overweight/obesity and support judicious antibiotic prescribing.


Incidence and predictors of development of new onset hypertension post COVID-19 disease.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus) affects vital organs and causes vascular injury. There are concerns that this injury may have long-term consequences on the cardiovascular system after recovery from COVID-19. We investigated the incidence and predictors of new-onset hypertension at 1-year follow-up post-COVID-19 disease. In this prospective observational study, 393 patients hospitalised and diagnosed with COVID-19 disease at a tertiary cardiac care hospital during 27th March 2021 to 27th May 2021. Eligible 248 patients whose baseline characteristics, laboratory findings, treatment and outcome data were received systematically. Patients were followed up at 1 year of COVID-19 disease recovery. We found that 32.3% of the population had new onset of hypertension at 1 year follow-up post-COVID-19 disease recovery. More hypertensive patients had severe computed tomography (CT) score severity (28.7 vs 14.9%; P 0.02). More number of patients in the hypertensive group were treated with steroids (73.8% vs 39%; p < 0.0001) during hospital stay. In-hospital complications were higher (12.5 vs 4.2%; P 0.03) in the hypertensive group. Patients who developed new-onset hypertension had statistically significantly higher baseline values of serum ferritin and C-reactive protein (CRP) (P 0.02 and 0.03 respectively). Vascular age was found 12.5 ± 3.96 years more than chronological age in hypertensive patients. New onset of hypertension was detected in 32.3% of patients at one-year follow-up post-COVID-19 disease recovery. Severe inflammation at the time of admission and severe CT severity score were associated with the development of new onset of hypertension on follow-up.


[Clearance concept applied to pharmacokinetics: 1. Application for the study of tolamolol (beta-blocking agent) in healthy volunteers (author's transl)].
Pharmacokinetics is often performed using models derived from the properties of exponential equations in order to analyse the behaviour of drugs in normal and pathological situations. A new approach based on the clearance concept allows an interpretation of the experimental data with models incorporating some physiological parameters, such as hepatic blood flow. The present study shows how the clearance concept may be used for the treatment of the results obtained in healthy volunteers. In particular, it allows an estimation of the importance of hepatic first-pass metabolism and validates the model used for the analyses of the kinetics of tolamolol.


Etiology of sarcoplasmic reticulum calcium release channel lesions in doxorubicin-induced cardiomyopathy.
Alterations in the native function of the ryanodine-sensitive Ca2+ release channel complex of sarcoplasmic reticulum (SR) isolated from rat cardiac ventricles during acute and chronic exposure to doxorubicin are examined. Compared to control SR, actively loaded SR from animals exposed to a single intravenous dose of doxorubicin exhibit faster rates of doxorubicin-induced Ca2+ release and the occupancy of [3H]ryanodine is significantly enhanced with subsequent exposure of SR membranes to doxorubicin in vitro. One week after acute exposure to doxorubicin in vitro, the EC50 for activation of the binding of [3H]ryanodine by Ca2+ is not significantly different from control SR. However, the persistence of doxorubicin-sensitized SR channels appears to be latent since repeated exposure to doxorubicin in vitro significantly enhances receptor occupancy in SR obtained from the treated rats compared to control SR. Ryanodine receptors from rats chronically exposed to doxorubicin consistently exhibit a higher sensitivity to activation Ca2+ which persists at least 4 weeks following the last injection of drug. Chronic exposure produces a concomitant reduction in the capacity of [3H]ryanodine binding sites. The marked decrease in receptor density observed with SR from doxorubicin-treated rats coincides with significant reduction in body weight, suggesting a possible influence of nutrition. However, sodium dodecyl sulfate polyacrylamide electrophoresis indicates no significant loss of the high molecular weight subunit of the ryanodine receptor, suggesting that loss of [3H]ryanodine-binding capacity may be the result of progressive and permanent channel desensitization. Consistent with desensitized receptors, membrane vesicles prepared from rats chronically exposed to doxorubicin take up significantly more Ca2+ and exhibit significantly reduced rates of doxorubicin or Ca2+/ryanodine induced Ca2+ release. The data demonstrates (i) doxorubicin inflicts cumulative SR channel lesions in vivo, (ii) a persistent sensitization of the SR channel to activation by Ca2+ and (iii) a significant and apparently irreversible reduction in the number of functional channel complexes.


Interpretation of lesions of the cardiac conduction system in cocaine-related fatalities.
This study examines cases of chronic drug users who died suddenly after drug administration. Victims were young subjects, aged from 19 to 35 from Switzerland and known to the police as long-term drug users. The circumstances of death suggested the occurrence of a sudden, unexpected death. Some victims were undergoing methadone treatment. In each case, a forensic autopsy and toxicological analyses were performed at the Institute of Forensic Medicine in Lausanne in Switzerland between 2002 and 2004, including hair analysis as a means to establish chronic drug use in general, and cocaine use in particular. The conduction system was examined histologically and cases showing potentially lethal changes were chosen for this report. The most frequent lesions found were severe thickening of the atrioventricular node artery, intranodal and perinodal fibrosis, and microscopic foci of chronic inflammatory infiltration. The authors conclude that pathological lesions in the conduction tissue may play a role in the occurrence of death attributed to intoxication consecutive to cocaine ingestion.


Targeting neuroinflammation: The therapeutic potential of ω-3 PUFAs in substance abuse.
Substance abuse is a chronic relapsing disorder that results in serious health and socioeconomic issues worldwide. Addictive drugs induce long-lasting morphologic and functional changes in brain circuits and account for the formation of compulsive drug-seeking and drug-taking behaviors. Yet, there remains a lack of reliable therapy. In recent years, accumulating evidence indicated that neuroinflammation was implicated in the development of drug addiction. Findings from both our and other laboratories suggest that ω-3 polyunsaturated fatty acids (PUFAs) are effective in treating neuroinflammation-related mental diseases, and indicate that they could exert positive effects in treating drug addiction. Thus, in the present review, we summarized and evaluated recently published articles reporting the neuroinflammation mechanism in drug addiction and the immune regulatory ability of ω-3 PUFAs. We also sought to identify some of the challenges ahead in the translation of ω-3 PUFAs into addiction treatment.


Growth cone guidance by substrate-bound laminin pathways is correlated with neuron-to-pathway adhesivity.
Substrate-bound laminin pathways prepared by the method of Hammarback et al. [J.A. Hammarback, S.L. Palm, L.T. Furcht, and P.C. Letourneau (1985). J. Neurosci. Res. 13, 213-220] guided peripheral nervous system neurites (dissociated dorsal root ganglia and sympathetic ganglia) and central nervous system neurites (dissociated spinal cord and brain). Guidance of individual growth cones by 7- to 10-micron-wide laminin pathways was observed using time-lapse video microscopy. Fibronectin pathways, produced by the method used for laminin pathways, did not guide neurites. The guidance effect of laminin pathways was quantified and found to correlate with the concentration of laminin initially applied to the substratum. The concentration of laminin initially applied to the substratum also correlated with increased adhesivity of dorsal root ganglia (DRG) neurons to laminin constituting the pathways relative to uv-irradiated laminin that borders the pathways. The guidance effect of laminin pathways was blocked by anti-laminin antibodies or by laminin but not by anti-fibronectin antibodies. This study demonstrates that guidance of DRG neurites by laminin occurs at the growth cone in a manner consistent with the hypothesis of guidance by differential neuron-to-substratum adhesivity.


Quorum sensing and quenching in membrane bioreactors: Opportunities and challenges for biofouling control.
Membrane biofouling, due to biofilm growth after planktonic bacteria attachment to a membrane, is a major bottleneck limiting the energy-efficient operation and maintenance of membrane bioreactors (MBRs). Microbial communications, known as quorum sensing (QS), are responsible for this biofouling behavior. Novel strategies for stopping this communication, known as quorum quenching (QQ), appear to be successful for biofouling control in MBRs used for wastewater treatment. This review describes recent information regarding the signal molecules and mechanisms responsible for QS behaviors, promising approaches for QQ (enzymatic, bacterial, fungal, photocatalytic, mimicking, and biostimulating methods), and efficient fabrication and use of QQ media for MBR applications. We discuss the opportunities and challenges of QQ techniques for their further improvement and practical use in MBRs.


Loktanella aquimaris sp. nov., Isolated from Seawater.
Two novel bacterial strains, designated C5(T) and C9 were isolated from a fish cage at Tongyeong, South Korea and were characterized to determine their taxonomic position. The strains were Gram-negative, non-motile, strictly aerobic and short rod shaped. Growth occurred between 20 and 32 °C (optimum 30 °C) and at pH 6.0-9.0 (optimum pH 8.0) and at 0-10 % NaCl (optimum at 2 % NaCl). Based on the 16S rRNA gene sequence analysis, they were identified as a member of the genus Loktanella that belongs to the phylum Proteobacteria. Strains C5(T) and C9 were analyzed by a polyphasic approach, revealing variations in their phenotypic characters but reciprocal DNA-DNA hybridization values confirmed that they belong to the same species. Phylogenetic analysis of the 16S rRNA gene sequences of closely related species indicated their similarities were below 97 %. The predominant isoprenoid quinone is ubiquinone-10 (Q-10). The major cellular fatty acids were C16:0, and C18:1 ω7c. Major polar lipid contained phosphatidylglycerol (PG), phosphatidycholine (PC), diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), unidentified amino lipid (AL) and unidentified lipids (L1-3). Based on phylogenetic and phenotypic data, the isolated strains represent a novel species of the genus Loktanella, for which the name Loktanella aquimaris sp. nov. is proposed. The type strains were C5(T) (=KEMB 3-892(T) = JCM 30382(T)), and a second strain is C9 (=KEMB 3-893 = JCM 30383).