Chemoimmunotherapy of acute leukemia in children.
Comparative results of chemo- and chemoimmunotherapy with Soviet strain of BCG vaccine in children with acute leukemia are presented. The immunotherapeutical regimen includes 20 intracutaneous injections of 0.1 mg BCG vaccine given weekly during 5--6 months with subsequent 5--6 months intervals simultaneously with maintenance chemotherapy. In the control group children were only given conventional chemotherapy. The median duration of remission and survival in patients who had received BCG chemoimmunotherapy was 25.2 +/- 1.5 and 32.3 +/- 1.2 months respectively. In the group of patients with chemotherapy alone--13.2 +/- 0.9 and 21.8 +/- 1.1 months respectively (p less than 0.01). The best results were obtained in children who had received before BCG immunotherapy neuroleukemia prophylactic treatment.


Bicarbonate Recycling by HIF-1-Dependent Carbonic Anhydrase Isoforms 9 and 12 Is Critical in Maintaining Intracellular pH and Viability of Nucleus Pulposus Cells.
Intervertebral disc degeneration is a ubiquitous condition closely linked to chronic low-back pain. The health of the avascular nucleus pulposus (NP) plays a crucial role in the development of this pathology. We tested the hypothesis that a network comprising HIF-1α, carbonic anhydrase (CA) 9 and 12 isoforms, and sodium-coupled bicarbonate cotransporters (NBCs) buffer intracellular pH through coordinated bicarbonate recycling. Contrary to the current understanding of NP cell metabolism, analysis of metabolic-flux data from Seahorse XF analyzer showed that CO2 hydration contributes a significant source of extracellular proton production in NP cells, with a smaller input from glycolysis. Because enzymatic hydration of CO2 is catalyzed by plasma membrane-associated CAs we measured their expression and function in NP tissue. NP cells robustly expressed isoforms CA9/12, which were hypoxia-inducible. In addition to increased mRNA stability under hypoxia, we observed binding of HIF-1α to select hypoxia-responsive elements on CA9/12 promoters using genomic chromatin immunoprecipitation. Importantly, in vitro loss of function studies and analysis of discs from NP-specific HIF-1α null mice confirmed the dependency of CA9/12 expression on HIF-1α. As expected, inhibition of CA activity decreased extracellular acidification rate independent of changes in HIF activity or lactate/H+ efflux. Surprisingly, CA inhibition resulted in a concomitant decrease in intracellular pH that was mirrored by inhibition of sodium-bicarbonate importers. These results suggested that extracellular bicarbonate generated by CA9/12 is recycled to buffer cytosolic pH fluctuations. Importantly, long-term intracellular acidification from CA inhibition lead to compromised cell viability, suggesting that plasma-membrane proton extrusion pathways alone are not sufficient to maintain homeostatic pH in NP cells. Taken together, our studies show for the first time that bicarbonate buffering through the HIF-1α-CA axis is critical for NP cell survival in the hypoxic niche of the intervertebral disc. © 2017 American Society for Bone and Mineral Research.


Functional Gastrointestinal Disorders in Children: A Survey on Clinical Approach in the Mediterranean Area.
Childhood functional gastrointestinal disorders (FGIDs) are common conditions associated with significant morbidity and high healthcare costs. This multicenter study aimed at assessing the clinical approach to infants (0-6 months) and children/adolescents (4-18 years) with suspected FGIDs by pediatricians from the Mediterranean Area. A survey evaluating the diagnostic approach, including the use of Rome II and III criteria, and the therapeutic management of some of the most prevalent FGIDs, such as irritable bowel syndrome (IBS), functional constipation (FC), and functional regurgitation (FR), was distributed to a sample of pediatricians. We collected 278 questionnaires from 9 countries (Croatia, Greece, Israel, Italy, Lebanon, Montenegro, Serbia, Slovenia, and Spain). Rome III criteria are used to diagnose FC by 28.8%. Treatment of FC is based on dietary modifications (97.5%) and osmotic laxatives (93.5%). Rome III criteria are used to diagnose FR by 22.3% of the responders, in contrast to 79.5% who rely on personal experience for diagnosis. Reported treatments mainly consist of reassurance (96.8%) and thickened feedings (77.3%). Nevertheless, 21.2% prescribe proton pump inhibitors or H2-blockers to infants with FR. Rome III criteria are used to diagnose IBS by only 25.9%. Moreover, 86% of the pediatricians base IBS therapy on the predominant symptom. The most prescribed treatments are analgesics (36.6%) for pain control, dietary advice (41.5%) for diarrhea-predominant IBS, and dietary advice (47.8%) for constipation-predominant IBS. Our data show that the use of Rome III diagnostic criteria is not sufficiently widespread among pediatricians, and that large variability remains in the management of FGIDs within the different Mediterranean countries surveyed.


Biological control of chestnut blight.
After 77 years of being attacked by the chestnut blight fungus, American chestnut trees continue to sprout from gradually declining root systems. The blight fungus in Italy is now associated with virus-like agents that limit its pathogenicity, and attempts have been made to introduce these controlling agents into the blight fungus in the United States. If a way can be found to help the spread here of strains of the fungus with controlling agents, it may be possible to save the American chestnut trees in our eastern forests.


Smoking history predicts for increased risk of second primary lung cancer: a comprehensive analysis.
Tobacco use is the most important risk factor for the development of lung cancer. The objective of the current study was to determine the effect of smoking on the development of second primary lung cancers (SPLCs) and other clinical outcomes after surgery for non-small cell lung cancer (NSCLC). All patients who underwent surgery for NSCLC at the study institution from 1995 through 2008 were identified. Rates of SPLC were analyzed based on smoking status and pack-year exposure. Multivariate analysis was performed to determine risk factors for SPLC. Overall survival, local control, distant metastases, and postoperative mortality were also examined. A total of 1484 patients were identified, including 98 never-smokers. The incidence of SPLC at 3 years, 5 years, and 8 years was 5%, 8%, and 16%, respectively. Only 1 never-smoker developed an SPLC. On multivariate analysis, which was restricted to ever-smokers with pack-years as a continuous variable, smoking history was found to be the only independent risk factor for SPLC (hazard ratio, 1.08; 95% confidence interval, 1.02-1.16 [P = .031]), corresponding to an 8% increased risk per 10 pack-year exposure. There were no differences in rates of local control or distant metastases based on smoking status. There was a trend toward lower postoperative mortality in never-smokers compared with ever-smokers (0% vs 3.3%; P = .069). Overall survival was found to be significantly worse for current smokers compared with former and never-smokers. SPLCs are rare in never-smokers. Increasing tobacco exposure is associated with a higher risk of SPLC in patients with a history of smoking. Current smokers have an increased risk of mortality whereas former and never-smokers have comparable survival.


Family Outcomes After the Pediatric Intensive Care Unit: A Scoping Review.
Intensivists are increasingly attuned to the postdischarge outcomes experienced by families because patient recovery and family outcomes are interdependent after childhood critical illness. In this scoping review of international contemporary literature, we describe the evidence of family effects and functioning postpediatric intensive care unit (PICU) as well as outcome measures used to identify strengths and weaknesses in the literature. We reviewed all articles published between 1970 and 2017 in PubMed, Embase, PsycINFO, Cumulative Index of Nursing and Allied Health Literature (CINAHL), or the Cochrane Controlled Trials Registry. Our search used a combination of terms for the concept of "critical care/illness" combined with additional terms for the prespecified domains of social, cognitive, emotional, physical, health-related quality of life (HRQL), and family functioning. We identified 71 articles reporting on the postPICU experience of more than 2400 parents and 3600 families of PICU survivors in 8 countries. These articles used 101 different metrics to assess the various aspects of family outcomes; 34 articles also included open-ended interviews. Overall, most families experienced significant disruption in at least five out of six of our family outcomes subdomains, with themes of decline in mental health, physical health, family cohesion, and family finances identified. Almost all articles represented relatively small, single-center, or disease-specific observational studies. There was a disproportionate representation of families of higher socioeconomic status (SES) and Caucasian race, and there was much more data about mothers compared to fathers. There was also very limited information regarding outcomes for siblings and extended family members after a child's PICU stay. Significant opportunities remain for research exploring family functioning after PICU discharge. We recommend that future work include more diverse populations with respect to the critically ill child as well as family characteristics, include more intervention studies, and enrich existing knowledge about outcomes for siblings and extended family.


The laboratory diagnosis of megaloblastic anemias.
The diagnostic approach to megaloblastic anemia involves four usually sequential steps. The first step, recognition of megaloblastosis, requires attention to altered blood cell size and morphology. These changes may sometimes be subtle or masked. The cornerstone of the second step, identification of the specific vitamin deficiency, is assay of serum vitamin B(12) and folic acid levels, although they may occasionally be misleading. The third step, identification of the specific disease entity responsible for the vitamin deficiency, generally revolves around tests of absorption and gastric function. The fourth step, reevaluation after replacement therapy, is often not thought of as a diagnostic step but carries important diagnostic implications and is sometimes the only way in which coexisting abnormalities can be unmasked and identified.


Ribonucleic acid from aerobically and anaerobically grown Rhodopseudomonas spheroides: comparison by hybridization to chromosomal and satellite deoxyribonucleic acid.
Ribonucleic acid (RNA) species from aerobically and anaerobically grown Rhodopseudomonas spheroides were compared via hybridization to deoxyribonucleic acid (DNA). Both long-labeled and stable RNA bound to chromosomal DNA to the same extent, regardless of derivation. About 4% of the chromosomal DNA hybridized with total cell RNA and about 0.08% with stable RNA. About 4% of the mixed satellite DNA could be hybridized to total cell RNA from aerobic or anaerobic cultures, whereas essentially no stable RNA formed a hybrid with this DNA. Hybridization competition experiments with aerobic and anaerobic pulse-labeled RNA and chromosomal or satellite DNA demonstrated that no qualitative differences existed between the RNA species. It is concluded that identical species of RNA in the same relative amounts are synthesized by R. spheroides during aerobic or anaerobic growth on the same medium.


Higher-order splitting algorithms for solving the nonlinear Schrödinger equation and their instabilities.
Since the kinetic and potential energy terms of the real-time nonlinear Schrödinger equation can each be solved exactly, the entire equation can be solved to any order via splitting algorithms. We verified the fourth-order convergence of some well-known algorithms by solving the Gross-Pitaevskii equation numerically. All such splitting algorithms suffer from a latent numerical instability even when the total energy is very well conserved. A detail error analysis reveals that the noise, or elementary excitations of the nonlinear Schrödinger equation, obeys the Bogoliubov spectrum and the instability is due to the exponential growth of high-wave-number noises caused by the splitting process. For a continuum wave function, this instability is unavoidable no matter how small the time step. For a discrete wave function, the instability can be avoided only for Deltatkmax2 < or =2pi, where kmax=pi/Deltax.


Association of CD94/NKG2A, CD94/NKG2C, and its ligand HLA-E polymorphisms with Behcet's disease.
Inhibitory CD94/NKG2A and activating CD94/NKG2C receptors are expressed on natural killer, CD4, and CD8 T cells and recognize human leukocyte antigen (HLA)-E, resulting in the modulation of cytotoxic activity and cytokine production. An imbalance in cytotoxic activity and cytokine production has been implicated in Behcet's disease (BD). The results of this study showed that the NKG2A c.-4258*C, c.338-90*G, and CD94 c.-134*T alleles (P= 0.015, OR = 0.8; P < 0.0001, OR = 0.5; and P= 0.034, OR = 0.8, respectively) were associated with decreased risk and that NKG2A c.284-67_-62del, c.1077*C, and the activating receptor, NKG2C c.305*T were not associated with 345 patients with BD. But a significant difference in NKG2C c.305*T was detected among BD patients with ocular lesions and arthritis (P < 0.0001, OR = 2.1 and P= 0.0001, OR = 1.8, respectively). We already showed in our previous research that HLA-E*0101 also appears to contribute to a reduction in risk through the inhibitory CD94/NKG2A-mediated immune response. This result led us to the analyses of the combined risk of the HLA-E and the NKG2A for BD. Individuals harboring HLA-E*0101, NKG2A c.-4258*C, and c.338-90*G evidenced a reduced risk of BD compared with healthy controls (21.1% vs 40.1%, P < 0.0001, OR = 0.4). By way of contrast, individuals without the HLA-E*0101, NKG2A c.-4258*C, and c.338-90*G alleles evidenced a twofold increased risk of BD (P= 0.014, OR = 2.0). Individuals without HLA-E*0101, NKG2A c.-4258*G/*G, and c.338-90*G evidenced a 4.8-fold increase in BD risk (P= 0.0002, OR = 4.8). Although the effects of these single nucleotide polymorphisms (SNPs) remain unclear, our results indicate that the SNPs of the inhibitory receptor CD94/NKG2A and its haplotypes, as well as its ligand HLA-E, are associated with BD immune systems.


Building the vector in: construction practices and the invasion and persistence of Anopheles stephensi in Jigjiga, Ethiopia.
Anopheles stephensi is a major vector of malaria in Asia and the Arabian Peninsula, and its recent invasion into Africa poses a major threat to malaria control and elimination efforts on the continent. The mosquito is well adapted to urban environments, and its presence in Africa could potentially lead to an increase in malaria transmission in cities. Most of the knowledge about An stephensi ecology in Africa has been generated from studies conducted during the rainy season, when vectors are most abundant. Here, we provide evidence from the peak of the dry season in the city of Jigjiga in Ethiopia, and report An stephensi immature stages infesting predominantly in water reservoirs made to support construction operations (ie, in construction sites or associated with brick-manufacturing businesses). Political and economic changes in Ethiopia (particularly the Somali Region) have fuelled an unprecedented construction boom since 2018 that, in our opinion, has been instrumental in the establishment, persistence, and propagation of An stephensi via the year-round availability of perennial larval habitats associated with construction. We argue that larval source management during the dry season might provide a unique opportunity for focused control of An stephensi in Jigjiga and similar areas.


LightCycler technology in molecular diagnostics.
LightCycler technology combines rapid-cycle polymerase chain reaction with real-time fluorescent monitoring and melting curve analysis. Since its introduction in 1997, it is now used in many areas of molecular pathology, including oncology (solid tumors and hematopathology), inherited disease, and infectious disease. By monitoring product accumulation during rapid amplification, quantitative polymerase chain reaction in a closed-tube system is possible in 15 to 30 minutes. Furthermore, melting curve analysis of probes and/or amplicons provides genotyping and even haplotyping. Novel mutations are identified by unexpected melting temperature or curve shape changes. Melting probe designs include adjacent hybridization probes, single labeled probes, unlabeled probes, and snapback primers. High-resolution melting allows mutation scanning by detecting all heterozygous changes. This review describes the major advances throughout the last 15 years regarding LightCycler technology and its application in clinical laboratories.


The effect of system-level access factors on receipt of reconstruction among Latina and white women with DCIS.
Treatment decisions associated with ductal carcinoma in situ (DCIS), including the decision to undergo breast reconstruction, may be more problematic for Latinas due to access and language issues. To help understand the factors that influence patients' receipt of reconstruction following mastectomy for DCIS, we conducted a population-based study of English- and Spanish-speaking Latina and non-Latina white women from 35 California counties. The objectives of this study were to identify the role of ethnicity and language in the receipt of reconstruction, the relationship between system-level factors and the receipt of reconstruction, and women's reasons for not undergoing reconstruction. Women aged 18 and older, who self-identified as Latina or non-Latino white and were diagnosed with DCIS between 2002 and 2005 were selected from eight California Cancer Registry (CCR) regions encompassing 35 counties. Approximately 24 months after diagnosis, they were surveyed about their DCIS treatment decisions. Survey data were merged with CCR records to obtain tumor and treatment data. The survey was successfully completed by 745 women, 239 of whom had a mastectomy and represent the sample included in this study. Whites had a higher completion rate than Latinas (67 and 55%, respectively). Analysis included descriptive statistics and logistic regression modeling. Mean age was 54 years. A greater proportion of whites had reconstruction (72%) compared to English-speaking Latinas (69%) and Spanish-speaking Latinas (40%). Multivariate analysis showed that women who were aged 65 and older, unemployed, and had a lower ratio of plastic surgeons in their county were less likely to have reconstructive surgery after mastectomy. The most frequent reasons mentioned not to receive reconstruction included lack of importance and desire to avoid additional surgery. Although ethnic/language differences in treatment selection were observed, multivariable analysis suggests that these differences could be explained by differential employment levels and geographic availability of plastic surgeons.


Evidence for RNA-mediated toxicity in the fragile X-associated tremor/ataxia syndrome.
Fragile X premutation carriers are at risk for developing a late-onset, progressive neurodegenerative disorder termed fragile X-associated tremor/ataxia syndrome (FXTAS). A growing body of evidence suggests the characteristic excess CGG repeat containing FMR1 mRNA observed in premutation carriers is pathogenic and leads to clinical features of FXTAS. The current model suggests premutation mRNA transcripts can induce the formation of intranuclear inclusions by the sequestration of RNA-binding proteins and other proteins. The sequestered proteins are prevented from performing their normal functions, which is thought to lead to the neuropathology-observed FXTAS. This paper discusses the existing evidence that microsatellite expansions at the level of RNA play a role in the disease pathogenesis of FXTAS and some of the approaches that may uncover downstream effects of expanded riboCGG expression.


Age-dependent changes in the ability to encode a novel elementary motor memory.
In healthy individuals, motor training elicits cortical plasticity that encodes the kinematic details of the practiced movements and is thought to underlie recovery of function after stroke. The influence of age on this form of plasticity is incompletely understood. We studied 55 healthy subjects and identified a substantial decrease in training-dependent plasticity as a function of age in the absence of differences in training kinematics. These results suggest that the ability of the healthy aging motor cortex to reorganize in response to training decreases with age.


Resting metabolism of mouse papillary muscle.
The aims of this study were to measure the resting metabolic rate of isolated mouse papillary muscles and to determine whether diffusive O2 supply is adequate to support the resting metabolism. Resting metabolism of left ventricular papillary muscles was measured in vitro (27 degrees C) using the myothermic technique. The rate of resting metabolism declined exponentially with time towards a steady value, with a time constant of 18+/-2 min (n=13). There was no alteration in isometric force output during this time. The magnitude of the resting metabolism, which depended inversely on muscle mass, more than doubled following a change in substrate from glucose to pyruvate and was increased 2.5-fold when the osmolarity of the bathing solution was increased by addition of 300 mM sucrose. Addition of 30 mM 2, 3-butanedione monoxime affected neither the time course of the decline in metabolic rate nor the eventual steady value. Analysis of the diffusive oxygen supply to the isolated preparation indicated that small papillary muscles (mass <1 mg), which have a very high resting metabolic rate early in an experiment, are unlikely to be adequately oxygenated.


Financial impact of alternative approaches to reduce bacterial contamination of platelet transfusions.
Bacterial contamination of platelets remains the leading infectious risk from blood transfusion. Pathogen reduction (PR), point-of-release testing (PORt), and secondary bacterial culture (SBC) have been proposed as alternative risk control strategies, but a comprehensive financial comparison has not been conducted. A Markov-based decision tree was constructed to model the financial and clinical impact of PR, PORt, and SBC, as well as a baseline strategy involving routine testing only. Hospitals were assumed to acquire leukoreduced apheresis platelets on Day 3 after collection, and, in the base case analysis, expiration would occur at the end of Day 5 (PR and SBC) or 7 (PORt). Monte Carlo simulations assessed the direct medical costs for platelet acquisition, testing, transfusion, and possible complications. Input parameters, including test sensitivity and specificity, were drawn from existing literature, and costs (2018 US dollars) were based on a hospital perspective. The total costs per unit acquired by the hospital under the baseline strategy, PR, PORt, and SBC were $651.45, $827.82, $686.33, and $668.50, respectively. All risk-reduction strategies decreased septic transfusion reactions and associated expenses, with the greatest reductions from PR. PR would add $191.09 in per-unit acquisition costs, whereas PORt and SBC would increase per-unit testing costs by $31.79 and $17.26, respectively. Financial outcomes were sensitive to platelet dating; allowing 7-day storage with SBC would lead to a cost savings of $12.41 per transfused unit. Results remained robust in probabilistic sensitivity analyses. All three strategies are viable approaches to reducing bacterially contaminated platelet transfusions, although SBC is likely to be the cheapest overall.


An Exploratory Assessment of Sociocultural Attitudes and Appearance Comparison Among Athletes With Physical Disabilities.
This study aimed to assess the internalization of sociocultural attitudes and appearance comparison among U.S. athletes with physical disabilities. Female (n = 19) and male (n = 25) athletes between the ages of 18 and 73 years completed a quantitative survey along with two exploratory open-ended questions related to body appearance and influencers. Results showed significant correlations between internalization of the thin and low-body-fat ideal and appearance comparison (r = .55, p < .05) and internalization of the muscular ideal and appearance comparison (r = .76, p < .05) among women. For men, results showed a significant association between internalization of the muscular ideal and appearance comparison (r = .52, p < .05). The findings prompt further investigation of whether appearance comparison and internalization influence body dissatisfaction and disordered eating among athletes with physical disabilities.


Efficacy and safety of one anastomosis gastric bypass versus Roux-en-Y gastric bypass for type 2 diabetes remission (ORDER): protocol of a multicentre, randomised controlled, open-label, superiority trial.
Previous studies have demonstrated that one anastomosis gastric bypass (OAGB) is not inferior to Roux-en-Y gastric bypass (RYGB) in treating obesity. However, high level evidence comparing the efficacy and safety of both procedures in type 2 diabetes (T2D) treatment is still lacking, which is another main aim of bariatric surgery. The presented trial has been designed to aim at investigating the superiority of OAGB over the reference procedure RYGB in treating T2D as primary endpoint. And diabetes-related microvascular and macrovascular complications, cardiovascular comorbidities, weight loss, postoperative nutritional status, quality of life and overall complications will be followed up for 5 years as secondary endpoints. This prospective, multicentre, randomised superiority open-label trial will be conducted in patients of Asian descent. A total of 248 patients (BMI≥27.5 kg/m2) who are diagnosed with T2D will be randomly assigned (1:1) to OAGB or RYGB with blocks of four. The primary endpoint is the complete diabetes remission rate defined as HbA1c≤6.0% and fasting plasma glucose≤5.6 mmol/L without any antidiabetic medications at 1 year after surgery. All secondary endpoints will be measured at different follow-up visit points, which will start at least 3 months after enrolment, with a continuous annual follow-up for five postoperative years in order to provide solid evidence on the efficacy and safety of OAGB in patients with T2D. The study has been approved by the ethics committee of leading centre (Beijing Friendship Hospital, Capital Medical University, no. 2021-P2-037-03). The results generated from this work will be disseminated to academic audiences and the public via publications in international peer-reviewed journals and conferences. The data presented will be imported into a national data registry. Findings are expected to be available in 2025, which will facilitate clinical decision-making in the field. NCT05015283.


PROphylaxis for ThromboEmbolism in Critical Care Trial protocol and analysis plan.
This article reports the preparatory studies as well as the design, implementation, and a priori analysis plans of PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) before dissemination of results. PROphylaxis for ThromboEmbolism in Critical Care Trial (NCT00182143) is a randomized, stratified, concealed international trial comparing subcutaneous injection of unfractionated heparin (UFH) 5000 IU or the low-molecular weight heparin (LMWH) dalteparin 5000 IU once daily plus once-daily placebo for the duration of the intensive care unit stay. The objective of PROTECT is to examine, among medical-surgical critically ill patients, the effect of the LMWH vs heparin on the primary outcome of proximal leg deep vein thrombosis (DVT) and the following secondary outcomes: DVT elsewhere, pulmonary embolism, any venous thromboembolism (DVT or pulmonary embolism), the composite of venous thromboembolism or death, bleeding, and heparin-induced thrombocytopenia. Patients are followed up to death or hospital discharge. Venous thromboembolism events were included after intensive care unit discharge. All patients, families, clinicians, research personnel, and the trial biostatistician are blind to allocation. We describe the pilot work, large trial methodology, implementation methods, and the analytic plan. Patient recruitment is complete, but 2 patients remain in the hospital. The rigorous design of PROTECT suggests that the risk of systematic error will be low. The sample size suggests that the risk of random error will be low. PROTECT will be the largest investigator-initiated peer-review funded thromboprophylaxis trial in critical care in the world. If PROTECT shows that LMWH is more effective than UFH, this trial will change practice in that LMWH may be the anticoagulant thromboprophylaxis of choice for this population. If the results show that UFH is as effective or more effective than LMWH, intensivists in many parts of the world may continue to use UFH, whereas those currently using LMWH may reconsider and change to use UFH. Unfavorable consequences such as major bleeding, ease of use, and the costs of complications will also factor into such decisions.


Structure-activity relationship of drug conjugated polymeric materials against uropathogenic bacteria colonization under in vitro and in vivo settings.
The human world has been plagued with different kinds of bacterial infections from time immemorial. The increased development of resistance towards commercial antibiotics has made these bacterial infections an even more critical challenge. Bacteria have modified their mode of interactions with different types of commercial drugs by bringing changes to the receptor proteins or by other resisting mechanisms like drug efflux. Various chemical approaches have been made to date to fight against these smart adapting species. Towards this, we hypothesize chemically modifying the commercial antibacterial drugs in order to deceive the bacteria and destroy the bacterial biomass. In this study, different molecular weight polyethyleneimines are taken and conjugated with some well-known commercial drugs like penicillin and chloramphenicol to explore their antibacterial properties against some of the laboratory and uro-pathogenic strains of Gram-positive and Gram-negative bacteria. A detailed structure-activity relationship of these polymeric prodrug-like materials has been evaluated to determine the optimum formulation. The standardized system not only shows significant ∼90% bacterial killing in liquid broth culture, but also demonstrates promising bacterial inhibition towards biofilm formation for the pathogenic strains on inanimate surfaces like urinary catheters and on an in vivo mouse skin abrasion model. The reported bioactive polymeric materials can be successfully used for widespread therapeutic applications with promising medical relevance.


[Brain abscess as a complication of Osler's disease with lung involvement].
Eight months after sustaining a reversible left motor hemisyndrome, predominantly of the arm, a 47-year-old man known to have hereditary haemorrhagic telangiectasia (Osler's disease) again developed neurological symptoms (headache, vertigo, unsteady gait) with fever (up to 38.5 degrees C). Clinical features and findings on computed tomography indicated a cerebellar abscess. This was resected because it continued to enlarge despite antibiotic treatment with daily 2 g ceftriaxone and twice daily 0.5 g ornidazole. As another manifestation of Osler's disease further tests revealed an arteriovenous malformation (2.5 x 2.0 cm) in the right upper lobe of the lung, presumably the cause of the cerebral abscess. After wedge resection of the anterior upper lobe segment the further course was without complications.


Increased expression of TLR7 in CD8(+) T cells leads to TLR7-mediated activation and accessory cell-dependent IFN-gamma production in HIV type 1 infection.
It has recently been demonstrated that toll-like receptors (TLRs) can recognize structural conserved motifs carried by circulating microbial products and lead to systemic immune responses in individuals infected with HIV-1. TLRs have been detected in CD8(+) T cells at either a protein or RNA level. The role of TLRs on CD8(+) T cells involved in the host's immune responses during HIV-1 infection has not been well characterized. In this study, we analyzed expression of TLR4, TLR5, TLR7, and TLR8 in CD8(+) T cells in HIV-1 infection. All these four TLRs could be detected in CD8(+) T cells, but only TLR7 in CD8(+) T cells from HIV-1-infected individuals showed a higher expression level compared with that from healthy individuals (p < 0.05). The function of TLR7 in CD8(+) T cells was then investigated. We found that TLR7 ligand responsiveness significantly increased the expression of immune activation markers on purified CD8(+) T cells in HIV-1-infected individuals compared with healthy controls. And the levels of these markers were equivalent to those achieved by CD8(+) T cells from peripheral blood mononuclear cells (PBMCs). However, we also observed that TLR7 ligand stimulated significant IFN-gamma production by CD8(+) T cells in an accessory cell-dependent manner. Therefore, although CD8(+) T cells can be directly activated by TLR7, accessory cells must play an essential role in the activation of effective functions such as IFN-gamma production. These findings suggest that the abnormal expression of TLR7 in CD8(+) T cells from HIV-1-infected individuals may contribute to the abnormal immune activation in HIV-1 infection and play an important role in HIV-1 pathogenesis.


From Mollusks to Medicine: A Venomics Approach for the Discovery and Characterization of Therapeutics from Terebridae Peptide Toxins.
Animal venoms comprise a diversity of peptide toxins that manipulate molecular targets such as ion channels and receptors, making venom peptides attractive candidates for the development of therapeutics to benefit human health. However, identifying bioactive venom peptides remains a significant challenge. In this review we describe our particular venomics strategy for the discovery, characterization, and optimization of Terebridae venom peptides, teretoxins. Our strategy reflects the scientific path from mollusks to medicine in an integrative sequential approach with the following steps: (1) delimitation of venomous Terebridae lineages through taxonomic and phylogenetic analyses; (2) identification and classification of putative teretoxins through omics methodologies, including genomics, transcriptomics, and proteomics; (3) chemical and recombinant synthesis of promising peptide toxins; (4) structural characterization through experimental and computational methods; (5) determination of teretoxin bioactivity and molecular function through biological assays and computational modeling; (6) optimization of peptide toxin affinity and selectivity to molecular target; and (7) development of strategies for effective delivery of venom peptide therapeutics. While our research focuses on terebrids, the venomics approach outlined here can be applied to the discovery and characterization of peptide toxins from any venomous taxa.


Study of Latest Trend on Acupuncture for Obesity Treatment.
The aim of this review was to appraise Korean studies published between 2010 and 2021 which examined the role of acupuncture in the treatment of obesity. We performed a search of the NDSL, KISS, RISS, OASIS, PubMed, EMBASE electronic databases for relevant animal researches, case reports, and clinical trials, using the following search terms 'obesity', 'acupuncture', 'electroacupuncture', and 'pharmacopuncture'. We excluded previous reviews and meta-analyses, studies not related to obesity or acupuncture treatment, as well as studies conducted in countries other than Korea. We also excluded studies where relevant information on acupuncture treatment in obesity could not be obtained. Most studies were conducted in animals, followed by case reports and clinical trials. In animal researches and case reports, pharmacopuncture was the most used intervention. In case studies, electroacupuncture, thread-embedding therapy, manual acupuncture, acupotomy, and auricular acupuncture were also used. In animal researches, pharmacopuncture treatment was associated with improvement in obesity indices. In the case of local obesity, specific acupuncture techniques such as thread-embedding therapy and pharmacopuncture were associated with significant improvements in local obesity, even when diet and exercise were not controlled for. Acupuncture treatment showed significant benefit in the treatment of obesity, with a local effect evident for certain approaches, such thread-embedding therapy and acupotomy.


Fully digital workflow for the rehabilitation of a total nasal defect with a prosthesis.
For a patient with a total nasal defect, an esthetic prosthesis remains the optimal choice for enhancing quality of life. This technique describes a fully digital workflow for designing virtual patterns and negative molds for a nasal prosthesis. This fully digital workflow facilitated the provision of an esthetic prosthesis.


Approximate Bayesian computation.
Approximate Bayesian computation (ABC) constitutes a class of computational methods rooted in Bayesian statistics. In all model-based statistical inference, the likelihood function is of central importance, since it expresses the probability of the observed data under a particular statistical model, and thus quantifies the support data lend to particular values of parameters and to choices among different models. For simple models, an analytical formula for the likelihood function can typically be derived. However, for more complex models, an analytical formula might be elusive or the likelihood function might be computationally very costly to evaluate. ABC methods bypass the evaluation of the likelihood function. In this way, ABC methods widen the realm of models for which statistical inference can be considered. ABC methods are mathematically well-founded, but they inevitably make assumptions and approximations whose impact needs to be carefully assessed. Furthermore, the wider application domain of ABC exacerbates the challenges of parameter estimation and model selection. ABC has rapidly gained popularity over the last years and in particular for the analysis of complex problems arising in biological sciences (e.g., in population genetics, ecology, epidemiology, and systems biology).


Prevalence of an unusual hypoplastic defect of the permanent maxillary lateral incisor in great apes.
In this article, I describe a previously unreported maxillary lateral incisor defect (MLID) of the enamel in great apes and evaluate potential general causes (genetic, systemic stress, or localized disturbance), as well as examine differences in prevalence among the represented taxa. This defect occurred only on the labial surface of the maxillary lateral incisor and extended from the cervical-mesial quarter of the crown to the mesial edge of the cementoenamel junction (CEJ). The study sample consisted of 136 great ape specimens, including 41 gorillas, 25 chimpanzees, and 70 orangutans from the Smithsonian's National Museum of Natural History great ape collection. I used logistic regression to assess the prevalence of this defect in the sample and a binomial probability test for bilaterality. This defect of the maxillary lateral incisor is the second most common defect I observed in the study sample (30.1% of individuals affected), and was more likely to occur in individuals with linear enamel hypoplasia (LEH) and pit defects than those without these defects. Among specimens with both maxillary lateral incisors present, the defect was mostly bilateral. Pan and Pongo were significantly more likely to exhibit the defect than Gorilla. Between Pongo species, Pongo pygmaeus was significantly more likely to exhibit the defect than Pongo abelii. Between subspecies of Gorilla, although Gorilla gorilla gorilla exhibited the defect and Gorilla gorilla beringei did not, the difference was not significant. No sex differences were evident in this sample. The prevalence of this defect indicates it is not hereditary. The bilateral trend indicates a systemic cause, although the high inter-tooth specificity suggests a local disturbance and a combination of both is possible.


Response to Hepatitis A Vaccination in Immunocompromised Travelers.
Hepatitis A vaccines are highly immunogenic in healthy patients, but there is uncertainty about their immunogenicity in immunocompromised patients. Our study included immunocompromised patients who received 1 or 2 hepatitis A vaccinations between January 2011 and June 2013. We assessed factors that influenced the serologic response to vaccination. We performed a literature review of previous studies on hepatitis A vaccination in immunocompromised patients. Of 85 immunocompromised patients, 65 used immunosuppressive drugs, 13 had received stem cell transplants, and 7 were infected with human immunodeficiency virus. After vaccination, 65 of 85 (76.5%) developed antibodies. Tumor necrosis factor α blocker use was associated with better serologic responses than other immunosuppressive drugs. Female patients were more compliant than male patients with postvaccination antibody titer measurements. In 11 relevant studies, antibody responses after the first and second vaccination averaged 37% and 82%, respectively. Factors that negatively influenced serologic response rates were high doses of immunosuppressive drugs, fewer hepatitis A vaccinations, and a short interval between vaccination and antibody measurement. Immunocompromised patients showed moderate to good serologic responses to hepatitis A vaccination, but may need more time to develop immunity. Tumor necrosis factor α blocker use was associated with better antibody responses than other drugs. Specifically, male patients should be motivated to return for antibody titer measurements.


Morphological recovery in the reattached retina of the toad Bufo marinus: a new experimental model of retinal detachment.
The retinal pigment epithelium (RPE) of the toad (Bufo marinus) has been used in many studies as a model for understanding its role and interaction with the neural retina. The toad's retina has been used to establish a new in vitro model of experimental retinal detachment (RD) and replacement . It has been shown that the electrophysiological measures of retinal function recovered following complete RD. The toad was chosen because its RPE is similar to the mammalian RPE . In this report, light microscopy was used to characterize the morphologic changes that occur in the RPE and neural retina following RD/replacement and to correlate these findings with recovery of electrophysiologic function. Retinas from Bufo marinus were studied in vitro. The neural retina completely detached from the RPE and then replaced. At various times after replacement, neural retina-RPE tissues were processed for light microscopy. At 30 min after replacement, the subretinal space was greatly expanded, and the apical processes that normally ensheath the rod outer segments were short and no longer contacted the rod outer segments. The RPE was swollen, contained many vacuoles and the apical surface was rounded. By 2 h after replacement, the subretinal space was significantly resorbed and contained many shredded rod outer segments; RPE cells were still swollen, although less. During the next 5-10 h, the number of phagosomes in the RPE cytoplasm increased and the number of shredded rod outer segments in the subretinal space decreased. RPE cells regained their normal size and interdigitation of apical processes and rod outer segments were observed. These results demonstrate the re-establishment of morphological interactions between the RPE and neural retina within hours following RD/replacement. Morphological recovery coincides with recovery of electrophysiologic parameters. This is a good model to investigate the retinal pigment epithelium (RPE) and neural retina mechanisms involved in retinal adhesion and recovery from retinal detachment.


The impact of sevoflurane anesthesia on postoperative renal function: a systematic review and meta-analysis of randomized-controlled trials.
Renal damage secondary to fluoride ions and compound A (CpdA) after sevoflurane anesthesia remains unclear. For safety reasons, some countries still recommend minimum fresh-gas flows (FGFs) with sevoflurane. We review the evidence regarding the intraoperative use of sevoflurane for anesthesia maintenance and postoperative renal function compared with other anesthetic agents used for anesthetic maintenance. Secondarily, we examine the effects of peak plasma fluoride and CpdA levels and the effect of FGF and duration of anesthesia on these parameters. The databases of MEDLINE (OVID and Pubmed), EMBASE, the Cochrane Library, Health Technology Assessment Database, CINAHL, and Web of Science were searched from inception until 23 April 2020 to identify randomized-controlled trials (RCTs) in humans utilizing sevoflurane or an alternative anesthetic for anesthesia maintenance with subsequent measurements of renal function. Two different paired reviewers independently selected the studies and extracted data. The quality of the evidence was appraised using GRADE recommendations. Of 3,766 publications screened, 41 RCTs in human patients were identified. There was no difference between creatinine at 24 hr (21 studies; n = 1,529), or creatinine clearance (CCR) at 24 hr (12 studies; n = 728) in the sevoflurane vs alternative anesthetic groups. Peak fluoride and fluoride measured at 24 hr were higher with sevoflurane compared with other inhaled anesthetics. Subgroup analyses for sevoflurane usage in various contexts showed no significant difference between sevoflurane and alternative anesthetics for creatinine or CCR at 24 hr at varying FGF, duration of exposure, baseline renal function, or absorbent use. We did not find any association between the use of sevoflurane and postoperative renal impairment compared with other agents used for anesthesia maintenance. The scientific basis for recommending higher FGF with the use of sevoflurane needs to be revisited.


Increased insulin-like growth factor I receptor expression and signaling are components of androgen-independent progression in a lineage-derived prostate cancer progression model.
Apoptosis and inhibition of mitosis are primary mechanisms mediating androgen ablation therapy-induced regression of prostate cancer (PCa). However, PCa readily becomes androgen independent, leading to fatal disease. Up-regulated growth and survival signaling is implicated in development of resistance to androgen ablation therapy. We are testing the hypothesis that insulin-like growth factor (IGF) responsiveness is required for androgen-independent (AI) progression. Using the LNCaP human PCa progression model, we have determined that IGF-I-mediated protection from apoptotic stress and enhanced mitotic activity is androgen dependent in LNCaP cells but is androgen independent in lineage-derived C4-2 cells. Both cell lines exhibit androgen-responsive patterns of IGF-I receptor (IGF-IR) expression, activation, and signaling to insulin receptor substrate-2 and AKT. However, C4-2 cells express higher levels of IGF-IR mRNA and protein and exhibit enhanced IGF-I-mediated phosphorylation and downstream signaling under androgen-deprived conditions. In comparisons of naive and AI metastatic human PCa specimens, we have confirmed that IGF-IR levels are elevated in advanced disease. Together with our LNCaP/C4-2 AI progression model data, these results indicate that increased IGF-IR expression is associated with AI antiapoptotic and promitotic IGF signaling in PCa disease progression.


Combined influence of expertise and fatigue on riding strategy and horse–rider coupling during the time course of endurance races.
The relationship between the biomechanical horse–rider interaction and endurance race performance requires further investigation. To characterise, both quantitatively and qualitatively, elite and advanced horse–rider dyads on the basis of the biomechanical horse–rider interaction during endurance races. Five elite and 5 advanced horse–rider dyads were recorded during CEI*/CEI** endurance races using 2 synchronised triaxial accelerometers each placed close to horse and rider centres of mass. For each horse–rider dyad, analyses focused on the vertical displacements of horse and rider per stride. This allowed quantification of the proportional use of each gait and riding technique per loop. The quality of the biomechanical horse–rider interaction was examined through the relative phases (RP) of their respective vertical displacement minima. Instantaneous speed and rider heart rates were recorded using a global positioning system device/heart rate monitor. All dyads predominantly used 2 riding techniques per gait. The 2-point trot proportion was limited in both groups (11%). Throughout the race, the advanced horse–rider dyads showed a global stability in speed, in the proportion of 4 combinations of gait and riding techniques and in mean RP. However, the elite horse–rider dyads initially had higher mean RP values (P<0.01), and from mid-race to the end an increasing proportion of sitting canter, with associated increases in racing speed (P<0.001) and in mean heart rate (P<0.01). Intradyad RP variability in 2-point canter increased in both groups (P<0.01). Accelerometers are a valuable tool to follow the quantitative and qualitative trends of the biomechanical horse–rider interaction during international endurance races. The overall results emphasise the influence of the level of expertise on the adopted gait and riding techniques, thus influencing the racing speed. It remains to be established whether fatigue and/or strategy underlie our observations.


[Prolonged epidural analgesia induced by clopheline in combination with lidocaine in obstetric analgesia].
The study was carried out in 178 women without grave obstetrical or extragenital diseases. In group 1 labor pain was relieved by prolonged epidural anesthesia with 2% lidocaine solution (2-2.5 mg/kg), in group 2 prolonged epidural anesthesia with 1% lidocaine solution (1 mg/kg) and 0.01% clofelin (1 microgram/kg) was administered. Central hemodynamics, heart rhythm, external respiration function, uterine contractility, and fetal intrauterine status were assessed. The findings indicate that none of the methods had a negative impact on the vital parameters of women and newborns at any stage of anesthesia. However, a combination of epidural clofelin (1 microgram/kg) with lidocaine permits an appreciable decrease in the doses of both drugs without decreasing the efficacy of anesthesia. This method has a favorable effect on the course of labor: the mouth of the womb opens sooner at a lower uterine activity and there are no negative effects on the fetus and newborn.


Cognitive effects of very low nicotine content cigarettes, with and without nicotine replacement, in smokers with schizophrenia and controls.
Beneficial effects of nicotine on cognitive functioning may contribute to the markedly high rates of smoking among people with schizophrenia. A reduction in the nicotine content of cigarettes to non-addictive levels is being considered as a regulatory strategy for reducing tobacco dependence in the United States. We examined whether switching to very low nicotine content (VLNC) cigarettes impairs cognitive functioning in smokers with and without schizophrenia, andwhether nicotine replacement reverses these effects. Smokers with schizophrenia (SS, n = 29) and control smokers matched on smoking rate but without psychiatric illness (CS, n = 28) smoked usual-brand cigarettes, VLNC cigarettes while wearing 2 placebo patches (PLA), or VLNC cigarettes while wearing 2 nicotine patches totaling 42mg (NIC) for 5hr, and then completed computerized assessments of visual sustained attention, motor speed, visual working memory, processing speed, inhibitory control, and response variability. Across conditions, SS were slower than CS in tasks of motor speed and visual working memory, and had poorer target detectability on a visual sustained attention task. Across groups, functioning in domains of visual sustained attention, inhibitory control, processing speed, and response variability was impaired in the VLNC + PLA condition relative to the usual-brand and VLNC + NIC conditions. Dramatically reducing the nicotine content of cigarettes may impair cognitive functioning in heavy smokers with and without schizophrenia, but the use of nicotine replacement while smoking VLNC cigarettes may preserve cognitive functioning in these smokers.


Dosimetric impact of dental metallic crown on intensity-modulated radiotherapy and volumetric-modulated arc therapy for head and neck cancer.
Metal dental restoration materials cause dose enhancement upstream and dose disturbance downstream of the high-density inhomogeneous regions in which these materials are used. In this study, we evaluated the impact of a dental metallic crown (DMC) on intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) for head and neck cancer. Additionally, the possibility of sparing the oral mucosa from dose enhancement using an individual intraoral mouthpiece was evaluated. An experimental oral phantom was designed to verify the dosimetric impact of a DMC. We evaluated the effect on single beam, parallel opposing beam, arc beam, IMRT, and VMAT treatment plans. To evaluate the utility of a 3-mm-thick intraoral mouthpiece, the doses across the mouthpiece were measured. For single beam irradiation, the measured doses at the entrance and exit planes of the DMC were 51% higher and 21% lower than the calculated dose by the treatment planning system, respectively. The maximum dose enhancements were 22% and 46% for parallel opposing beams and the 90° arc rotation beam, respectively. For IMRT and VMAT, the measured doses adjacent to the DMC were 12.2% ± 6.3% (mean ± 1.96SD) and 12.7% ± 2.5% higher than the calculated doses, respectively. With regard to the performance of the intraoral mouthpiece for the IMRT and VMAT cases, the disagreement between measured and calculated doses at the outermost surface of the mouthpieces were -2.0%, and 2.0%, respectively. Dose enhancements caused by DMC-mediated radiation scattering occurred during IMRT and VMAT. Because it is difficult to accurately estimate the dose perturbations, careful consideration is necessary when planning head and neck cancer treatments in patients with DMCs. To spare the oral mucosa from dose enhancement, the use of an individual intraoral mouthpiece should be considered.


Metronidazole- and Amoxicillin-Loaded PLGA and PCL Nanofibers as Potential Drug Delivery Systems for the Treatment of Periodontitis: In Vitro and In Vivo Evaluations.
The purpose of this study was to prepare poly (D-L) lactide-co-glycolide (PLGA) and poly ε-caprolactone (PCL) nanofibers containing metronidazole and amoxicillin using an electrospinning process as intrapocket sustained-release drug delivery systems for the treatment of periodontal diseases. Scanning electron microscopy showed that the drug containing PLGA and PCL nanofibers produced from the electrospinning process was uniform and bead-free in morphology. The obtained nanofibers had a strong structure and resisted external tension according to the tensiometry results. The cytotoxicity results indicated acceptable cell viability (>80%). Quantification by high-performance liquid chromatography showed almost complete in vitro drug release between 7 and 9 days, whereas 14 days were required for complete drug release in vivo. No significant signs of irritation or inflammatory reaction were detected after three weeks of subcutaneous implantation of nanofibers in the animal models, thus indicating suitable compatibility. The results therefore suggest that the designed nanofibers can be used as potential commercial formulations in the treatment of periodontitis as controlled-release intrapocket drug delivery systems that can increase patient compliance. This is due to their ability to reduce the frequency of administration from three times daily in a systemic manner to once weekly as local delivery.


Survival Outcomes of Calcium Channel Blocker Therapy in Patients With Non-Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor Inhibitors: A Retrospective Study.
Non-cancer drugs are currently being repurposed for cancer treatment. Mounting evidence highlights the influence of calcium channels on tumorigenesis and progression. Hence, inhibition of calcium signaling may be a promising cancer treatment strategy. In this study, we aimed to examine whether calcium channel blockers (CCBs) affect the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). We conducted a retrospective analysis. In this study, conducted between January 2009 and June 2021, patients with NSCLC treated with erlotinib, or gefitinib for at least 1 week were enrolled and divided into 2 groups: CCBs-/EGFR-TKIs+ and CCBs+/EGFR-TKIs+, depending on whether they received CCB therapy. Progression-free survival (PFS) and overall survival (OS) were determined as the primary and secondary endpoints, respectively. : The estimated median PFS and OS for the CCBs-/EGFR-TKIs+group were 7.70 and 12.17 months, respectively, and they were significantly different from those of the CCBs+/EGFR-TKIs+ group (10.43 and 18.07 months, respectively). CCB use was associated with improved PFS (adjusted hazard ratios [HR] 0.77, 95% confidence interval [CI]: 0.61-0.98; P = .035) and OS (adjusted HR 0.66, 95% CI: 0.51-0.84; P < .001). Calcium channels have been implicated in cancer pathogenesis. Our findings revealed the potential additive anticancer effects of CCBs when used concomitantly with EGFR-TKIs. However, study limitations, including the retrospective nature and small number of patients, necessitate large-scale prospective studies on the therapeutic potential of CCB as an adjunctive therapy with EGFR-TKIs in patients with NSCLC.


Intestinal inflammation alters mucosal carbohydrate foraging and monosaccharide incorporation into microbial glycans.
Endogenous carbohydrates released from the intestinal mucus represent a constant source of nutrients to the intestinal microbiota. Mucus-derived carbohydrates can also be used as building blocks in the biosynthesis of bacterial cell wall components, thereby influencing host mucosal immunity. To assess the uptake of endogenous carbohydrates by gut microbes in healthy mice and during intestinal inflammation, we applied azido-monosaccharides that can be tracked on bacterial cell walls after conjugation with fluorophores. In interleukin-10 deficient mice, changes in the gut microbiota were accompanied by decreased carbohydrate hydrolase activities and increased lumenal concentrations of host glycan-derived monosaccharides. Tracking of the monosaccharide N-azidoacetylglucosamine (GlcNAz) in caecum bacteria revealed a preferential incorporation of this carbohydrate by Xanthomonadaceae in healthy mice and by Bacteroidaceae in interleukin-10 deficient mice. These GlcNAz-positive Bacteroidaceae fractions mainly belonged to the species B. acidifaciens and B. vulgatus. Growth of Bacteroides species in the presence of specific monosaccharides changed their stimulatory activity toward CD11c+ dendritic cells. Expression of activation markers and cytokine production was highest after stimulation of dendritic cells with B. vulgatus. The variable incorporation of monosaccharides by related Bacteroides species underline the necessity to investigate intestinal bacteria down to the species level when addressing microbiota-host interactions.


Association between perioperative low-molecular-weight heparin vs unfractionated heparin and clinical outcomes in patients with cancer undergoing surgery.
In patients with cancer undergoing surgery, what is the association between perioperative thromboprophylaxis with low-molecular-weight heparin (LMWH) or unfractionated heparin and mortality, pulmonary embolism, deep venous thrombosis, thrombocytopenia, and bleeding outcomes? When used for perioperative thromboprophylaxis, there are no differences in the association of LMWH vs unfractionated heparin for preventing mortality, pulmonary embolism, deep venous thrombosis, bleeding outcomes, or thrombocytopenia in patients with cancer.


The Neurologic Manifestations of Coronavirus Disease 2019.
The coronavirus disease 2019 (COVID-19) is an ongoing global pandemic that has so far affected 216 countries and more than 5 million individuals worldwide. The infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While pulmonary manifestations are the most common, neurological features are increasingly being recognized as common manifestations of the COVID-19, especially in the cases of severe infection. These include acute cerebrovascular disease, encephalitis, and Guillain-Barre syndrome (GBS). Here, we review the neuropathogenesis of SARS-CoV-2 and the central and peripheral nervous system manifestations of COVID-19.


Wider view over bicycle crashes: Complementing and extending bicycle crash statistics in urban areas using surveys.
In pursuit of sustainability goals, many cities are introducing measures to increase the usage of bicycles as a means of transportation. City planners aim to ensure that this increase does not lead to an increase in crashes, but must make corresponding infrastructure decisions with limited information. Sufficient data to perform a statistical analysis of location-specific crash frequencies is rarely available. For example, only approximately 10% of all bicycle crashes are reported to the police (Shinar et al., 2018). Therefore, urban planners often rely on expert opinion, which may lead to suboptimal prioritization and realization of infrastructure improvements. This paper demonstrates how surveys on bicycle crashes can be used to aid urban planners in making infrastructure decisions. In addition to confirming the location and characteristics of reported crashes, surveys can uncover characteristics of crashes that are not reported to the police, situations in which a crash almost occurred, and locations perceived by cyclists to be dangerous. Surveys also allow urban planners to investigate non-infrastructure related causes of crashes, such as the frequency with which individual cyclists use other modes of transportation. The usefulness of surveys in the determination of urban cycling safety is demonstrated in this paper through analysis of survey results from the city of Zurich in 2018.


Adolescents' attrition from school-sponsored sports.
This study investigated reasons for adolescents' attrition from school-sponsored sports teams and the relationship between attrition and intention to participate in organized and nonorganized sports in the future. Of 674 high school student athletes, 26% dropped off at least one team in 1989-1990, and overall attrition increased to 29.8% when attrition from more than one sport was considered. Attrition was higher among black students, students reporting an athletic injury, those injured playing football, and those sustaining a knee injury. Injury was cited as the most frequent reason for attrition, followed by being cut from the team, "other reasons," needing to get a job, inconvenient game or practice schedule, and needing more time to study, although the main reason for attrition also varied by sport. When athletes were classified according to externally precipitated attrition, athlete-initiated attrition, or completion of the sports season, no differences were noted in the three groups' intent to engage in organized sports in the future. However, the group with externally precipitated attrition expressed a stronger intent to engage in nonorganized sports in the future than the other two groups.


Perineal extramammary Paget disease responsive to topical imiquimod.
Extramammary Paget disease (EMPD) is a rare neoplasm that arises in skin rich in apocrine glands, such as the axillae and anogenital region and usually affects the elderly. In most cases, EMPD is an apocrine carcinoma in situ, but it can be associated with internal malignancy spreading to overlying skin. Surgical excision with margin control is the generally accepted standard of care. A 74-year-old woman presented with a 1 year history of a pruritic eczematous eruption in perineum which on biopsy was diagnosed as EMPD. Because of the location and extent of the tumor, any surgical approach would have been problematic. Imiquimod 5 % cream applied three times weekly for 16 weeks induced complete resolution. Topical imiquimod appears to be a promising treatment option for EMPD, especially when surgery is a challenge, but only a few cases have been reported.


Prostacyclin analogue beraprost inhibits cardiac fibroblast proliferation depending on prostacyclin receptor activation through a TGF β-Smad signal pathway.
Previous studies showed that prostacyclin inhibited fibrosis. However, both receptors of prostacyclin, prostacyclin receptor (IP) and peroxisome proliferator-activated receptor (PPAR), are abundant in cardiac fibroblasts. Here we investigated which receptor was vital in the anti-fibrosis effect of prostacyclin. In addition, the possible mechanism involved in protective effects of prostacyclin against cardiac fibrosis was also studied. We found that beraprost, a prostacyclin analogue, inhibited angiotensin II (Ang II)-induced neonatal rat cardiac fibroblast proliferation in a concentration-dependent and time-dependent manner. Beraprost also suppressed Ang II-induced collagen I mRNA expression and protein synthesis in cardiac fibroblasts. After IP expression was knocked down by siRNA, Ang II-induced proliferation and collagen I synthesis could no longer be rescued by beraprost. However, treating cells with different specific inhibitors of PPAR subtypes prior to beraprost and Ang II stimulation, all of the above attenuating effects of beraprost were still available. Moreover, beraprost significantly blocked transforming growth factor β (TGF β) expression as well as Smad2 phosphorylation and reduced Smad-DNA binding activity. Beraprost also increased phosphorylation of cAMP response element binding protein (CREB) at Ser133 in the nucleus. Co-immunoprecipitation analysis revealed that beraprost increased CREB but decreased Smad2 binding to CREB-binding protein (CBP) in nucleus. In conclusion, beraprost inhibits cardiac fibroblast proliferation by activating IP and suppressing TGF β-Smad signal pathway.


Current issues on ageing in Japan: a comparison with Australia.
Japan's demography has changed dramatically, and with it, Japanese society and the circumstances of older people. These changes include shifts in family roles and functions, employment and social relations. Traditionally, families provided financial, physical and psychological support to their parents in the same household. While the proportion of older Japanese who live with adult children is still high in comparison to the rate in Western developed countries, patterns of care in Japan are gradually shifting towards the Western model. Public pensions supply financial support and the Long-Term Care Insurance System (LCIS) provides substantial physical care for frail older people. This paper focuses on current issues for older people in Japan, and provides a brief comparison with the situation in Australia. Japan's LCIS provides a simpler and more consistent basis for funding long-term care than Australia's system. On the other hand, Australia's pension system is comparatively robust.


Calibration of the LISST-VSF to derive the volume scattering functions in clear waters.
The recently commercialized LISST-VSF instrument measures the volume scattering function (VSF) from 0.1° to 15° with a traditional laser diffraction unit (LISST) and from 15° to 155° with an eyeball component. Between these two optical components, only the LISST unit is calibrated. The eyeball measurements are scaled using the VSFs at 15° that are measured by both components. As this relative calibration relies on a valid measurement at 15° by the LISST, it might fail in clear oceanic waters, where the forward scattering is relative weak either due to a lack of large particles or an overall low concentration of all particles. In this study, we calibrated the LISST-VSF eyeball component through a series of lab experiments using standard polystyrene beads. Validation with the beads of two different sizes showed a median difference of 11.1% between theoretical and calibrated values. Further evaluations with in situ data collected by the LISST-VSF and an ECO-BB3 meter indicated that the new calibration worked well in both turbid and clear waters, while the relative calibration method tended to overestimate VSFs in clear waters.


Antagonists, inhibitors and antisera in the evaluation of vascular renin activity. The role of local generation of angiotensin II.
It is well established that the arterial wall contains renin-like material. It is suggested that this renin generates significant quantities of angiotensin II (AII) which occupy vascular AII receptors. This is important in determining the pressor response to exogenous AII and in the maintenance of blood pressure. Four lines of evidence support this view. (a) Prevention of AII generation by nephrectomy or converting enzyme inhibition increases the pressor response to AII which then becomes independent of sodium balance. (b) AII antagonists are more effective in renin-mediated hypertension than AII antisera. (c) Changes in renin-mediated pressor responsive to AII after bilateral nephrectomy take a much longer time to occur than can be explained in terms of changes in circulating renin activity: these changes are also observed in isolated vessels. (d) The depressor response to antagonist and inhibitors is preserved after bilateral nephrectomy for much longer periods than can be accounted for by circulating levels of renin.


Effects of tacrine, velnacrine (HP029), suronacrine (HP128), and 3,4-diaminopyridine on skeletal neuromuscular transmission in vitro.
1. The effects of tacrine (9-amino-1,2,3,4-tetrahydroacridine), velnacrine (HP029, 9-amino-1,2,3,4-tetrahydroacridin-1-ol maleate), suronacrine (HP128, 9-benzylamino-1,2,3,4-tetrahydroacridin-1-ol maleate), and 3,4-diaminopyridine on neuromuscular transmission were compared on isolated nerve-muscle preparations. 2. Tacrine, HP029, and 3,4-diaminopyridine augmented responses of chick biventer cervicis preparations to nerve stimulation, with tacrine and HP029 increasing responses to exogenously applied acetylcholine. HP128 blocked responses to nerve stimulation and to carbachol, but increased responses to acetylcholine. 3. In mouse diaphragm preparations that were partially paralysed by tubocurarine or low calcium solutions, tacrine, HP029, and 3,4-diaminopyridine reversed the twitch block. HP128 deepened the block. 4. In mouse triangularis sterni preparations, tacrine and HP029 prolonged the decay phase of endplate potentials and miniature endplate potentials, but had no effect on quantal content at 36 degrees C; above 10 microM, they reduced endplate potential amplitude. 3,4-Diaminopyridine increased quantal content without affecting the time course of the endplate potentials. HP128 (1-10 microM) had no effect on amplitude or time course of endplate potentials, but reduced their amplitude at higher concentrations. 5. Extracellular recording of nerve terminal currents from triangularis sterni preparations revealed that 3,4-diaminopyridine and HP128 had a selective blocking action on the waveform associated with K+ currents, tacrine reduced and prolonged the K(+)-related waveform, and HP029 had nonselective blocking actions only seen at high concentrations. 6. Tacrine and HP029 behave predominantly as anticholinesterase agents, while HP128 has weaker anticholinesterase actions that are masked by cholinoceptor blockade. Tacrine and HP128, but not HP029, have some blocking actions on K+ currents of mouse motor nerve terminals.


Human motor corpus callosum: topography, somatotopy, and link between microstructure and function.
The corpus callosum (CC) is the principal white matter fiber bundle connecting neocortical areas of the two hemispheres. Although an object of extensive research, important details about the anatomical and functional organization of the human CC are still largely unknown. Here we focused on the callosal motor fibers (CMFs) that connect the primary motor cortices (M1) of the two hemispheres. Topography and somatotopy of CMFs were explored by using a combined functional magnetic resonance imaging/diffusion tensor imaging fiber-tracking procedure. CMF microstructure was assessed by fractional anisotropy (FA), and CMF functional connectivity between the hand areas of M1 was measured by interhemispheric inhibition using paired-pulse transcranial magnetic stimulation. CMFs mapped onto the posterior body and isthmus of the CC, with hand CMFs running significantly more anteriorly and ventrally than foot CMFs. FA of the hand CMFs but not FA of the foot CMFs correlated linearly with interhemispheric inhibition between the M1 hand areas. Findings demonstrate that CMFs connecting defined body representations of M1 map onto a circumscribed region in the CC in a somatotopically organized manner. The significant and topographically specific positive correlation between FA and interhemispheric inhibition strongly suggests that microstructure can be directly linked to functional connectivity. This provides a novel way of exploring human brain function that may allow prediction of functional connectivity from variability of microstructure in healthy individuals, and potentially, abnormality of functional connectivity in neurological or psychiatric patients.


A highly efficient organocatalyst for direct aldol reactions of ketones with aldehydes [corrected].
L-proline amides derived from various chiral beta-amino alcohols that bear substituents with various electron natures at their stereogenic centers are prepared and evaluated for catalyzing the direct Aldol reaction of 4-nitrobenzaldehyde with acetone. Catalysts with strong electron-withdrawing groups are found to exhibit higher catalytic activity and enantioselectivity than their analogues with electron-donating groups. The presence of 2 mol % catalyst 4g significantly catalyzes the direct Aldol reactions of a wide range of aldehydes with acetone and butanone, to give the beta-hydroxy ketones with very high enantioselectivities ranging from 96% to >99% ee. High diastereoselectivity of 95/5 was observed for the anti Aldol product from the reaction of cyclohexanone, and excellent enantioselectivity of 93% ee was provided for anti Aldol product from the reaction of cyclopentanone.


Indirect cost of maternal deaths in the WHO African Region in 2010.
An estimated 147,741 maternal deaths occurred in 2010 in 45 of the 47 countries in the African Region of the World Health Organization (WHO). The objective of this study was to estimate the indirect cost of maternal deaths in the Region to provide data for use in advocacy for increased domestic and external investment in multisectoral policy interventions to curb maternal mortality. This study used the cost-of-illness method to estimate the indirect cost of maternal mortality, i.e. the loss in non-health gross domestic product (GDP) attributable to maternal deaths. Estimates on maternal mortality for 2010 from Trends in maternal mortality: 1990 to 2010 published by WHO, UNICEF, UNFPA and the World Bank were used in these calculations. Values for future non-health GDP lost were converted into their present values by applying a 3% discount rate. One-way sensitivity analysis at 5% and 10% discount rates assessed the impact on non-health GDP loss. Indirect cost analysis was undertaken for the countries, categorized under three income groups. Group 1 consisted of nine high and upper middle income countries, Group 2 of 12 lower middle income countries, and Group 3 of 26 low income countries. Estimates for Seychelles in Group 1 and South Sudan in Group 3 were not provided in the source used. The 147,741 maternal deaths that occurred in 45 countries in the African Region in 2010 resulted in a total non-health GDP loss of Int$ 4.5 billion (PPP). About 24.5% of the loss was in Group 1 countries, 44.9% in Group 2 countries and 30.6% in Group 3 countries. This translated into losses in non-health GDP of Int$ 139,219, Int$ 35,440 and Int$ 16,397 per maternal death, respectively, for the three groups. Using discount rates of 5% and 10% reduced the total non-health GDP loss by 19.1% and 47.7%, respectively. Maternal mortality is responsible for a noteworthy level of non-health GDP loss among the countries in the African Region. There is urgent need, therefore, to increase domestic and external investment to scale up coverage of existing cost-effective, multisectoral women's health interventions to reduce maternal morbidity and mortality.


The endophyte Curtobacterium flaccumfaciens reduces symptoms caused by Xylella fastidiosa in Catharanthus roseus.
Citrus variegated chlorosis (CVC) is a disease of the sweet orange [Citrus sinensis (L.)], which is caused by Xylella fastidiosa subsp. pauca, a phytopathogenic bacterium that has been shown to infect all sweet orange cultivars. Sweet orange trees have been occasionally observed to be infected by Xylella fastidiosa without evidencing severe disease symptoms, whereas other trees in the same grove may exhibit severe disease symptoms. The principal endophytic bacterial species isolated from such CVC-asymptomatic citrus plants is Curtobacterium flaccumfaciens. The Madagascar periwinkle [Citrus sinensis (L.)] is a model plant which has been used to study X. fastidiosa in greenhouse environments. In order to characterize the interactions of X. fastidiosa and C. flaccumfaciens, periwinkle plants were inoculated separately with C. flaccumfaciens, X. fastidiosa, and both bacteria together. The number of flowers produced by the plants, the heights of the plants, and the exhibited disease symptoms were evaluated. PCR-primers for C. flaccumfaciens were designed in order to verify the presence of this endophytic bacterium in plant tissue, and to complement an existing assay for X. fastidiosa. These primers were capable of detecting C. flaccumfaciens in the periwinkle in the presence of X. fastidiosa. X. fastidiosa induced stunting and reduced the number of flowers produced by the periwinkle. When C. flaccumfaciens was inoculated together with X. fastidiosa, no stunting was observed. The number of flowers produced by our doubly- inoculated plants was an intermediate between the number produced by the plants inoculated with either of the bacteria separately. Our data indicate that C. flaccumfaciens interacted with X. fastidiosa in C. roseus, and reduced the severity of the disease symptoms induced by X. fastidiosa. Periwinkle is considered to be an excellent experimental system by which the interaction of C. flaccumfaciens and other endophytic bacteria with X. fastidiosa can be studied.


Evidence-based practice among Swedish medical social workers.
We have explored Swedish medical social workers' attitudes, beliefs, knowledge, and behavior concerning evidence-based practice (EBP) and investigated the properties of a questionnaire to measure EBP. One hundred seventy-four Swedish medical social workers within university hospital care and primary care participated in a cross-sectional survey. Our results showed positive attitudes toward EBP and the use of evidence to support clinical decision making. EBP was seen as necessary and something that needed to be implemented more often. The main barriers to implementing EBP were lack of time (78%), the perception that EBP does not take into account the limitations of the clinical practice setting (78%), and lack of knowledge about relevant research (46%).


Living kidney donation from people at risk of nephrolithiasis, with a focus on the genetic forms.
Deciding whether to accept a donor with nephrolithiasis is a multifaceted task because of the challenge of finding enough suitable donors while at the same time ensuring the safety of both donors and recipients. Until not long ago, donors with a history of renal stones or with stones emerging during screening on imaging were not considered ideal, but recent guidelines have adopted less stringent criteria for potential donors at risk of stones. This review goes through the problems that need to be approached to arrive at a wise clinical decision, balancing the safety of donors and recipients with the need to expand the organ pool. The risk of declining renal function and worsening stone formation is examined. Documents (consensus statements, guidelines, etc.) on this issue released by the most important medical societies and organizations are discussed and compared. Specific problems of living kidney donation associated with certain systemic (chronic hypercalcemia due to CYP24A1 gene mutations, primary hyperoxaluria, APRT deficiency) and renal (medullary sponge kidney, cystinuria, distal renal tubular acidosis, Dent's disease, Bartter syndrome, familial hypomagnesemia with hypercalciuria and nephrocalcinosis) Mendelian disorders that cause nephrolithiasis are also addressed.


Synthesis and characterization of Nafion((R))-115 nanowire arrays.
Aligned Nafion((R))-115 nanowire arrays have been synthesized by an extrusion method with anodic aluminium oxide (AAO) membranes templates in this work. A surface modification was carried out to improve the hydrophobicity of the AAO pore surface. The as-synthesized nanowires are about 85 nm in diameter and several to over ten micrometres in length. Near-IR Raman and IR spectrum studies show that the polymer nanowires are composed of pure Nafion((R))-115 only.


Product reformulation and nutritional improvements after new competitive food standards in schools.
In 2012, Massachusetts enacted school competitive food and beverage standards similar to national Smart Snacks. These standards aim to improve the nutritional quality of competitive snacks. It was previously demonstrated that a majority of foods and beverages were compliant with the standards, but it was unknown whether food manufacturers reformulated products in response to the standards. The present study assessed whether products were reformulated after standards were implemented; the availability of reformulated products outside schools; and whether compliance with the standards improved the nutrient composition of competitive snacks. An observational cohort study documenting all competitive snacks sold before (2012) and after (2013 and 2014) the standards were implemented. The sample included thirty-six school districts with both a middle and high school. After 2012, energy, saturated fat, Na and sugar decreased and fibre increased among all competitive foods. By 2013, 8 % of foods were reformulated, as were an additional 9 % by 2014. Nearly 15 % of reformulated foods were look-alike products that could not be purchased at supermarkets. Energy and Na in beverages decreased after 2012, in part facilitated by smaller package sizes. Massachusetts' law was effective in improving the nutritional content of snacks and product reformulation helped schools adhere to the law. This suggests fully implementing Smart Snacks standards may similarly improve the foods available in schools nationally. However, only some healthier reformulated foods were available outside schools.


An unusual etiology in cold injury: Liquefied petroleum gas.
Cold injury is a condition that causes reversible and irreversible damage when tissues are exposed to cold. This injury occurs due to various etiologies, and the most commonly observed ones include contact with liquefied petroleum gas (LPG) used in households, vehicles, and industry. LPG is a type of gas stored in liquid state under high pressure within cylinders. LPG contains a mixture of propane and butane gases. Direct contact of these gases with the tissues has the potential to cause metabolic, toxic, and respiratory damage. In this study, we present the cases of four patients with cold injury in the face and upper extremity caused by a pressurized jet stream of liquid gas that escaped out of the valves of the LPG cylinders. The patients had bullous lesions in the upper extremities and the face and second- and third-degree cold injuries with fibrotic and necrotic areas. The superficial defects secondarily healed with minimal scarring, while the necrotic finger had to be amputated. Cold injury on the skin caused by high-pressure jet streams of liquid gas as in our study is a rare occurrence. Our patients are important cases due to the rare etiology of cold injury.


Combined morphological and molecular approach for identification of Stemphylium vesicarium inoculum in pear orchards.
Stemphylium vesicarium is the causal agent of brown spot of pear, an important disease reported in pear-growing areas of Europe. The pathogen is able to colonize pear leaf debris and dead tissues of herbaceous plants and produce abundant ascospores and conidia that are capable of infecting pear trees. Inoculum monitoring in pear orchards is mainly achieved through spore traps and species identification is based on conidial morphology, but the similarities on conidial traits among species of Stemphylium make correct identification difficult. In this work a total of thirty-seven Stemphylium isolates from pear orchards were characterized at the morphological, pathogenic, and molecular level. Correspondence among ITS and gpd sequences and morphological traits were evaluated. Species identification based exclusively on morphological data was not feasible. Combined morphological and molecular data were necessary for unambiguous identification of isolates in the S. vesicarium species group. Only isolates identified as S. vesicarium were pathogenic on pear. The study revealed that several species of Stemphylium coexist in pear orchards with S. vesicarium, the causal agent of BSP, and that combined morphological and molecular data are needed to differentiate them. Consequently, direct measurements of the airborne inoculum using volumetric spore traps may overestimate the actual pathogen population.


Microbiological characteristics of hypermucoviscous Klebsiella pneumoniae isolates from different body fluids.
Reports of hypermucoviscous Klebsiella pneumoniae (hvKP) isolated from fluids other than blood or abscess are rare. The aim of the study was to compare clinical and microbiological characteristics of hvKP found in blood or abscess fluid with those isolated from other loci. A total of 24 non-repetitive hvKP isolates were collected from January 2013 to June 2014 from patients with hvKP infections. There were 15 in Group 1 (fluid other than blood or abscess) and 9 in Group 2 (blood or abscess fluid). Medical records of all patients were reviewed. Capsular polysaccharide (CPS) typing, virulence factor determination, and multilocus sequence typing (MLST) of hvKP isolates were performed. Seventeen sequence types (STs) and 6 capsular serotypes were identified. Type K2CC65 was most commonly identified in Group 1 and type K2CC86 in Group 2. Deletion of pLVPK-derived loci were found in K2 and non-K1/K2 hvKP strains. Two virulent genes, fimH and ycfM, were identified more frequently in Group 2 than in Group 1. There was no difference in the frequency of other virulent genes or serotypes in the two groups. Two imipenem resistant hvKP isolates (cr-hvKP) were found in non-blood or abscess samples. hvKP isolated from different body fluids had similar clinical and microbiological characteristics. cr-hvKP identified in non-blood or abscess samples should raise our attention to the challenging situation and management of hvKP infection.


[Febrile cervicalgia revealing infectious epiduritis : a case report].
Infectious epiduritis and epidural abscesses are relatively rare pathologies but with important neurological consequences. A low incidence associated with an insidious clinical presentation leads to frequent delays in diagnosis, which worsen the prognosis of patients with the development of neurological deficits. While the evaluation of risk factors, a careful clinical examination and biological tests can guide to the diagnosis, the key examination remains magnetic resonance imaging (MRI) while lumbar puncture remains contraindicated. Although surgery (spinal decompression) has long been the treatment of choice, the current management of patients with infectious epiduritis is debated between surgery and conservative treatment with systemic antibiotic therapy.


Gain of distal chromosome arm 17q is not associated with poor prognosis in neuroblastoma.
In several studies, gain of the distal long arm of chromosome 17 was shown to be a frequent and prognostically relevant factor in neuroblastoma, in addition to MYCN amplification (MNA) or 1p deletion. We asked whether this observation could be confirmed in a German cohort. To evaluate the frequency and prognostic impact of 17q gain, we investigated tissue samples from 193 neuroblastoma patients by the use of fluorescence in situ hybridization. The DNA probe (MPO) was located in distal 17q in the region of interest as used by several groups. To analyze the association of patients' outcome with the breakpoint position within 17q, we used the more proximal DNA probe ERBB2 in 17q21 on a selected number of cases. Gain was defined as an excess of 17q material compared with the chromosome 17 centromere in at least 50% of the analyzed tumor cells. In addition, alterations in chromosomes 1p, 3p, and 11q, as well as MYCN status, were determined to describe the interrelationship between the different parameters and to evaluate an independent prognostic influence. Gain of 17q was found in 61% of the investigated tumors. An additional 23% displayed an excess of 17q in less than half of all cells. Gain correlated with stage 4 disease (P = 0.003) and with other chromosomal alterations, such as 1p (P < 0.001), 3p (P = 0.01), 11q (P = 0.001), and MNA (P = 0.016), as well as with increased patient age (P = 0.01). Outcome was not different between patients with 17q gain compared with those without, however. A prognostic influence could not be delineated in all stages or in localized or in stage 4 subgroups or in the MYCN nonamplified patient cohort. Outcome did not differ between patients with additional 17q material in <10% of the cells or in >70%. Patients showing a breakpoint in the more proximal part of 17q could not be described as having a more favorable outcome compared with patients with a more distal breakpoint. Prognosis was poor in patients with MNA and/or 11q loss either with or without 17q gain. A multivariate analysis including the chromosomal parameters 17q, 11q, and MYCN status, as well as stage, showed MYCN and 11q status (P < 0.001), but not 17q or stage as significant prognostic factors. Although the most frequent aberration in neuroblastoma to date, we found no association between 17q gain and an inferior prognosis in our cohort; the status of MYCN and 11q, however, allowed reliable prediction of patients' outcomes.


Structure and physiology of developing neuromuscular synapses in culture.
The structure and function of developing neuromuscular synapses in culture have been investigated. We used neuromuscular junctions formed by coculturing dissociated muscle cells and dissociated neurons obtained from Xenopus embryos. After recording nerve-evoked endplate potentials (e.p.p.s) and spontaneously occurring miniature endplate potentials (m.e.p.p.s) from a given junction, the same specimen was investigated for electron-microscopic histology. We surveyed almost the total area of the junctional region by making serial sections. Even in preparations cocultured for only a short time (4-11 hr), both e.p.p.s and m.e.p.p.s could be obtained. The junctional region of these early synapses revealed a simple structure. The presynaptic terminals contained smooth-surfaced clear vesicles, but there were no presynaptic specializations such as active zones. The width of the synaptic cleft was variable, with predominance of narrow regions (10-30 nm), and there was no basal lamina inside the cleft. When the coculture time was 1 d or longer, the junctional area started to show structural features resembling a mature neuromuscular synapse. In the presynaptic terminal there were active zones, consisting of the presynaptic density and an accumulation of vesicles near the density. In many junctions, the postsynaptic membrane showed densities and thickenings, with a widened synaptic cleft, that contained basal lamina. It is known that growth cones, prior to making neuromuscular junctions, can release the transmitter substance with a very long latency if stimulated repetitively. In contrast, e.p.p.s with short latencies can be evoked by single stimuli soon after the growth cones attach to muscle cells. However, our data did not reveal any structural changes to account for such functional changes.(ABSTRACT TRUNCATED AT 250 WORDS)


Hindbrain Adrenergic/Noradrenergic Control of Integrated Endocrine and Autonomic Stress Responses.
Hindbrain adrenergic/noradrenergic nuclei facilitate endocrine and autonomic responses to physical and psychological challenges. Neurons that synthesize adrenaline and noradrenaline target hypothalamic structures to modulate endocrine responses while descending spinal projections regulate sympathetic function. Furthermore, these neurons respond to diverse stress-related metabolic, autonomic, and psychosocial challenges. Accordingly, adrenergic and noradrenergic nuclei are integrative hubs that promote physiological adaptation to maintain homeostasis. However, the precise mechanisms through which adrenaline- and noradrenaline-synthesizing neurons sense interoceptive and exteroceptive cues to coordinate physiological responses have yet to be fully elucidated. Additionally, the regulatory role of these cells in the context of chronic stress has received limited attention. This mini-review consolidates reports from preclinical rodent studies on the organization and function of brainstem adrenaline and noradrenaline cells to provide a framework for how these nuclei coordinate endocrine and autonomic physiology. This includes identification of hindbrain adrenaline- and noradrenaline-producing cell groups and their role in stress responding through neurosecretory and autonomic engagement. Although temporally and mechanistically distinct, the endocrine and autonomic stress axes are complementary and interconnected. Therefore, the interplay between brainstem adrenergic/noradrenergic nuclei and peripheral physiological systems is necessary for integrated stress responses and organismal survival.


Subjective and Objective Quantification of the Effect of Distraction on Physician's Workload and Performance During Simulated Laparoscopic Surgery.
BACKGROUND Distracting interference cognitive tasks place undeniable pressure on the minds of people who need high precision and attention during the tasks, such as those tasks performed during surgery; these tasks might affect current surgical procedures. We measured the effect of additional cognitive tasks on the mental load of the physician by measuring the mean change in pupil size, blink rate, and subjective assessment during surgery. MATERIAL AND METHODS We recruited 24 participants with different levels of laparoscopic surgery to perform a complete appendectomy using a standardized virtual reality laparoscopic surgery simulator. The participants then performed the cognitive task (arithmetic problem), after that they performed an appendectomy surgery task while completing the cognitive task on the simulator. All participants wore trackers to monitor pupil size and blink rate during surgery and the cognitive task. The National Aeronautics and Space Administration (NASA) Task Load Index (TLX) score also recorded performance parameters during the surgical mission. RESULTS The double-task pupil size and the blink rate were significantly increased compared to the single-task observation, and the associated increase in psychological load might have been affected by surgical performance, and the performance parameters were also statistically significant. However, for the aforementioned parameters, experienced surgeons had some differences compared with inexperienced surgeons, but these differences did not reach statistical significance. CONCLUSIONS Distracted cognitive task stimulation in the operating room can increase the surgeon's psychological burden while also affecting their operational skills, thereby threatening patient safety; reduced cognitive costs might be obtained by improving or managing cognitive deficits.