Ocular torsion produced by unilateral chemical inactivation of the interstitial nucleus of Cajal in chronically labyrinthectomized cats.
Unilateral lesions of the rostral midbrain involving the interstitial nucleus of Cajal (INC) have been known to produce ocular torsion in alert animals including humans, which has been assumed to be the result of an impaired otolith-ocular reflex. We examined the effects of chemical deactivation of the INC using a gamma-aminobutyric acid (GABA) agonist (muscimol) in cats that had received bilateral labyrinthectomy, and compared the results with those in normal cats. Ocular torsion with a magnitude similar to that observed in normal cats appeared in chronically labyrinthectomized cats after unilateral muscimol infusion into the INC, indicating that ocular torsion following unilateral INC deactivation can be produced by a mechanism independent of the otolith-ocular reflex.


Modeling sulfate removal by inhibited mesophilic mixed anaerobic communities using a statistical approach.
Optimizing sulfate removal by a mixed anaerobic mesophilic culture fed glucose, linoleic acid (LA) and sulfate under several pH conditions was performed using a three factor three level Box-Behnken design (BBD). Based on the BBD approach, a statistical model was developed to predict the residual sulfate concentration. The LA concentration, initial pH and the COD/SO4(2-) ratio were the three experimental factors under consideration. Increasing the COD/SO4(2-) ratio increased the quantity of sulfate removed. The COD/SO4(2-) ratio showed the largest effect on reducing the sulfate level. Significant interactions between the three experimental factors were confirmed by the surface plots, interaction plot and ANOVA. An analysis of residuals verified accuracy of the model. Acetate and H2 production was dominant in cultures with the pH set at 6.0 and 6.75 and fed LA. After 168 h, butyrate and H2S were associated with the largest quantity of sulfate removed. At a D-optimality value of 1.0, a minimum response (residual sulfate concentration) of 36.2 mg L(-1) was recorded at 1500 mg L(-1) LA with a COD/SO4(2-) ratio of 2.18 and a pH set at 6.0. Based on the conditions under consideration, the model provided a useful approach for predicting the residual sulfate concentration in inhibited mixed anaerobic cultures.


The calcium binding protein S100A9 is essential for pancreatic leukocyte infiltration and induces disruption of cell-cell contacts.
Leukocyte infiltration is an early and critical event in the development of acute pancreatitis. However, the mechanism of leukocyte transmigration into the pancreas and the function of leukocytes in initiating acute pancreatitis are still poorly understood. Here, we studied the role of S100A9 (MRP14), a calcium binding protein specifically released by polymorph nuclear leukocytes (PMN), in the course of acute experimental pancreatitis. Acute pancreatitis was induced by repeated supramaximal caerulein injections in S100A9 deficient or S100A9 wild-type mice. We then determined S100A9 expression, trypsinogen activation peptide (TAP) levels, serum amylase and lipase activities, and tissue myeloperoxidase (MPO) activity. Cell-cell contact dissociation was analyzed in vitro with biovolume measurements of isolated acini after incubation with purified S100A8/A9 heterodimers, and in vivo as measurement of Evans Blue extravasation after intravenous application of S100A8/A9. Pancreatitis induced increased levels of S100A9 in the pancreas. However, infiltration of leukocytes and MPO activity in the lungs and pancreas during acute pancreatitis was decreased in S100A9-deficient mice and associated with significantly lower serum amylase and lipase activities as well as reduced intrapancreatic TAP-levels. Incubation of isolated pancreatic acini with purified S100A8/A9-heterodimers resulted in a rapid dissociation of acinar cell-cell contacts which was highly calcium-dependent. Consistent with these findings, in vivo application of S100A8/A9 in mice was in itself sufficient to induce pancreatic cell-cell contract dissociation as indicated by Evans Blue extravasation. These data show that the degree of intrapancreatic trypsinogen activation is influenced by the extent of leukocyte infiltration into the pancreas which, in turn, depends on the presence of S100A9 that is secreted from PMN. S100A9 directly affects leukocyte tissue invasion and mediates cell contact dissociation via its calcium binding properties.


Ziconotide, an intrathecally administered N-type calcium channel antagonist for the treatment of chronic pain.
Ziconotide is a novel peptide that blocks the entry of calcium into neuronal N-type voltage-sensitive calcium channels, preventing the conduction of nerve signals. N-type calcium channels are present in the superficial laminae of the dorsal horn of the spinal cord. In various animal models of pain, intrathecal administration of ziconotide blocked nerve transmission and nociception. The United States Food and Drug Administration recently approved ziconotide intrathecal infusion for the management of severe chronic pain in patients who require intrathecal therapy and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. The drug has a narrow therapeutic window and a lag time for the onset and offset of analgesia and adverse events. In early clinical trials, frequent and severe psychiatric and central nervous system adverse effects were associated with rapid intrathecal infusion (0.4 microg/hr) and frequent up-titration (every 12 hrs). Therefore, patients with psychiatric symptoms are not candidates for this drug. Drug trials of external intrathecal catheters and microinfusion devices demonstrated a 3% risk of meningitis. A low initial infusion rate of 0.1 microg/hour and limiting infusion rate increases to 2-3 times/week are now recommended. Patients responsive to intrathecal ziconotide require an implanted infusion system to receive long-term therapy.


Subtle fluctuations in psychotic phenomena as functional states of abnormal dopamine reactivity in individuals at risk.
Subjects at increased risk for psychosis experience continuous variation in the intensity of subtle psychotic experiences in response to minor stressors. It was investigated whether this psychotic reactivity in individuals at risk for psychosis is the exophenotypic expression of an underlying endophenotype characterized by a hyperreactive dopamine (DA) system. First-degree relatives (n = 47) and control subjects (n = 49) were studied with the Experience Sampling Method (ESM), a structured diary technique assessing current context and psychopathology in daily life, to assess psychotic experiences in response to stress. A metabolic perturbation paradigm (administration of 2-deoxy-D-glucose inducing a mild state of glucoprivation) causing plasma elevation of homovanillic acid (HVA) was used as a proxy of DA reactivity. Multilevel regression analyses revealed that the interaction between HVA reactivity and daily stress in their effect on psychotic experiences differed according to underlying vulnerability. In the first-degree relatives, underlying HVA reactivity modified the psychotic experiences to daily stress, whereas no such effect was found in control subjects. These results suggest that psychotic experiences in response to minor stresses in the flow of daily life may be functional states of an underlying abnormal DA reactivity in subjects at risk to develop psychosis. The results add credence to the suggestion that abnormal DA reactivity may be part of the substrate that increases risk for psychotic symptoms in individuals at risk.


A Comparative Study of Treatment-Emergent Adverse Events Following Use of Common Bowel Preparations Among a Colonoscopy Screening Population: Results from a Post-Marketing Observational Study.
Colonoscopy may be one of the most frequent elective procedures in older adults and is associated with a low occurrence of complications. However, reduction of risks attributable to the bowel preparation may be achieved with the use of effective and safer products. The aim of this study was to examine the incidence of treatment-emergent adverse events (TEAEs) associated with SUPREP(®) [oral sulfate solution (OSS)] and other common prescription bowel preparations (non-OSS). This real-world, observational study used de-identified health insurance claims and laboratory results to identify TEAEs in the 3 months following screening colonoscopy in adults with a prescription for a bowel preparation in the prior 60 days. The unadjusted and adjusted (controlling for patient risk factors) cumulative incidences of TEAEs were estimated using Kaplan-Meier and Poisson regression, respectively. Among patients ≥45 years, the overall cumulative incidence was significantly lower (p < 0.001) in the OSS cohort than in the non-OSS cohort (unadjusted: 2.31 vs. 2.89 %; adjusted: 1.61 vs. 1.95 %), with significantly lower acute cardiac conditions (1.56 vs. 1.90 %; p < 0.001), renal failure/other serious renal diseases (OSS: 0.21 %, non-OSS: 0.32 %; p < 0.001), and serum electrolyte abnormalities (OSS: 0.39 %, non-OSS: 0.49 %; p = 0.017). There were no significant differences between cohorts in death, seizure disorders, aggravation of gout, and ischemic colitis. Results were similar in the adjusted cumulative incidences. In actual use, the overall cumulative incidence of TEAEs was significantly lower in the OSS cohort, demonstrating that OSS is as safe as, or possibly safer than, non-OSS prescription bowel preparations.


Delayed recovery of normal hematopoiesis in arsenic trioxide treatment of acute promyelocytic leukemia: a comparison to all-trans retinoic acid treatment.
To examine laboratory data including total blood cell count, leukocyte morphology and coagulation parameters during treatment for acute promyelocytic leukemia (APL) at a single institute, and compare the precise differences between all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) treatment. Sixteen patients with APL who were treated with ATRA or As2O3 alone and achieved complete remission (CR) were analyzed. ATRA 45 mg/m2/day was given orally until CR. As2O3 0.15 mg/kg/day was given intravenously until leukemic blasts and promyelocytes were eliminated from the bone marrow. All 7 patients in the ATRA-treated group were primary cases and all 9 patients in the As2O3-treated group were relapsed cases after the achievement of CR with the ATRA. There was no difference in the data before treatment between these two groups. The duration of leukocytopenia and neutropenia during As2O3 treatment was significantly longer than those of ATRA treatment. The nadir of leukocyte and neutrophil counts was observed later in the As2O3-treated group. Terminal neutrophil differentiation was observed more obviously in the ATRA-treated group. The red blood cell count and hemoglobin concentration decreased significantly at the end of As2O3 treatment and were lower than those of ATRA treatment. Platelets recovered earlier in the ATRA-treated group. Coagulation parameters were not significantly changed between the two groups. In comparison with ATRA treatment, the recovery of several components in the peripheral blood cells was delayed in As2O3 treatment. Therefore we should pay more and longer attention in As2O3 treatment.


Systemic Therapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma- A Systematic Review and Meta-Analysis.
The most effective regimen is unclear for patients with recurrent or metastatic head and neck squamous cell carcinomas (R/M HNSCC). We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating only systemic therapy for R/M HNSCC. This systematic review followed PRISMA and the Cochrane Collaboration Handbook for Systematic Reviews of Interventions. Endpoints included overall survival (OS), progression-free survival (PFS) and overall response rates (ORR). 55 RCTs from 1990-November 2019 qualified for review (n=12132). Only PD-1/PDL-1 inhibitors increased OS in R/M HNSCC platinum-resistant disease against their control (HR = 0·79, 95%CI 0·70-0.90, p<0·001), especially for PD-L1 ≥ 1% expressing tumours (HR = 0·72, 95%CI 0·60-0·86, p<0·001). PFS was prolonged for anti-EGFR agents against methotrexate when used in a second line setting (HR = 0·74, 95 %CI 0·62-0·87, p=0·001), and when cetuximab (HR = 0·60, 95%CI 0·49-0·72, p<0·0001) and panitumumab (HR = 0·76, 95%CI 0·65-0·89, p=0·001) were introduced to platinum-based regimens for first-line treatment. PD-1/PD-L1 inhibitors may represent the future of R/M HNSCC treatment. However, EGFR inhibitors may still play improve clinical outcomes.


COVID-19 and the epistemology of epidemiological models at the dawn of AI.
The models used to estimate disease transmission, susceptibility and severity determine what epidemiology can (and cannot tell) us about COVID-19. These include: 'model organisms' chosen for their phylogenetic/aetiological similarities; multivariable statistical models to estimate the strength/direction of (potentially causal) relationships between variables (through 'causal inference'), and the (past/future) value of unmeasured variables (through 'classification/prediction'); and a range of modelling techniques to predict beyond the available data (through 'extrapolation'), compare different hypothetical scenarios (through 'simulation'), and estimate key features of dynamic processes (through 'projection'). Each of these models: address different questions using different techniques; involve assumptions that require careful assessment; and are vulnerable to generic and specific biases that can undermine the validity and interpretation of their findings. It is therefore necessary that the models used: can actually address the questions posed; and have been competently applied. In this regard, it is important to stress that extrapolation, simulation and projection cannot offer accurate predictions of future events when the underlying mechanisms (and the contexts involved) are poorly understood and subject to change. Given the importance of understanding such mechanisms/contexts, and the limited opportunity for experimentation during outbreaks of novel diseases, the use of multivariable statistical models to estimate the strength/direction of potentially causal relationships between two variables (and the biases incurred through their misapplication/misinterpretation) warrant particular attention. Such models must be carefully designed to address: 'selection-collider bias', 'unadjusted confounding bias' and 'inferential mediator adjustment bias' - all of which can introduce effects capable of enhancing, masking or reversing the estimated (true) causal relationship between the two variables examined.1 Selection-collider bias occurs when these two variables independently cause a third (the 'collider'), and when this collider determines/reflects the basis for selection in the analysis. It is likely to affect all incompletely representative samples, although its effects will be most pronounced wherever selection is constrained (e.g. analyses focusing on infected/hospitalised individuals). Unadjusted confounding bias disrupts the estimated (true) causal relationship between two variables when: these share one (or more) common cause(s); and when the effects of these causes have not been adjusted for in the analyses (e.g. whenever confounders are unknown/unmeasured). Inferentially similar biases can occur when: one (or more) variable(s) (or 'mediators') fall on the causal path between the two variables examined (i.e. when such mediators are caused by one of the variables and are causes of the other); and when these mediators are adjusted for in the analysis. Such adjustment is commonplace when: mediators are mistaken for confounders; prediction models are mistakenly repurposed for causal inference; or mediator adjustment is used to estimate direct and indirect causal relationships (in a mistaken attempt at 'mediation analysis'). These three biases are central to ongoing and unresolved epistemological tensions within epidemiology. All have substantive implications for our understanding of COVID-19, and the future application of artificial intelligence to 'data-driven' modelling of similar phenomena. Nonetheless, competently applied and carefully interpreted, multivariable statistical models may yet provide sufficient insight into mechanisms and contexts to permit more accurate projections of future disease outbreaks.


Dataset of temperature, heat flux and infrared emission from flat premixed laminar methane-air flames.
To enable the use of flat flame burners in the context of fire resistance testing, we present a data set covering temperature, infrared emission and heat 15 mm above the burner. A laminar premixed methane-air flame is characterized for eleven different fuel/air ratios, ranging from lean (0.9) to rich (1.45), extending an existing a widely used reference [1]. We provide complementing flame temperature readings from thermocouple measurements that can be used for calibration. In addition, broadband flame optical emissions are acquired in the visual (VIS) and the infrared (IR) spectral region. Chemiluminescence measurements reveal the spatial distribution of the OH* radicals. Heat flux density measurements with a water-cooled gauge are also provided. Finally, the expected species concentration, velocity, temperature are obtained from chemical kinetics calculations. Ambient conditions and burner control parameters are presented as supplementary data.


Novel compact device for clinically measuring extraocular muscle (EOM) tension.
Accurate knowledge of extraocular muscle (EOM) tension is important for the diagnosis of and surgical planning for strabismus, such as choosing which eye to operate or determining the amount of muscle displacement. Previous evaluations of passive EOM tension have relied extensively on the experience and skill of ophthalmic surgeons, who generally perform such evaluations by gripping the eyeball and then pushing and pulling it. This methodology, named the forced duction test, has the significant limitation that the tension is felt subjectively via the forceps, with the results therefore not being quantifiable. Previous quantitative analyses have utilized several different types of equipment with implanted force transducers or have involved connecting the muscle tendon to a strain gauge. However, the associated equipment setups and recording systems are highly complex and rarely used outside research settings. This situation prompted the present study to develop a novel compact, quantifiable and clinically applicable device for measuring the passive tension in human EOMs for use in clinical practice. The device employs locking forceps and a tilting sensor to rule out effects of the gripping force and to compensate for changes in the force due to tilting, which improves the measurement accuracy. The performance of the device was investigated in 60 eyes of 30 consecutive anaesthetized patients immediately prior to ophthalmic surgery. The results showed that the measured EOM tension in each rectus muscles agreed with previous findings: 48.3 ± 14.5 g (0.82 ± 0.28 g/deg, mean ± SD) for the lateral rectus, 45.6 ± 13.2 g (0.82 ± 0.23 g/deg) for the medial rectus, 48.6 ± 14.7 g (0.71 ± 0.21 g/deg) for the inferior rectus and 53.4 ± 13.7 g (0.77 ± 0.25 g/deg) for the superior rectus.


Expression of cyclooxygenase isoforms in the rat spinal cord and their regulation during adjuvant-induced arthritis.
Spinal regulation of cyclooxygenase (COX) isoforms was investigated in the animal model of peripheral inflammation induced by injection of complete Freund's-type adjuvant (CFA) in the rat hindpaw. Peripheral inflammation was induced by intraplantar injection of CFA in one hind footpad of male Sprague Dawley rats (n = 3 per time point). Spinal cord was removed after different times (3 h to 22 d). mRNA and protein were isolated and analyzed by comparative reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. Under the acute inflammatory stimulus 6h after CFA application, RT-PCR revealed a twofold increase in COX-2 mRNA that reached baseline again at day 3. This transient increase occurred in the lumbar spinal cord, but changes in COX-2 mRNA expression were also registered in RNA preparations from cervical sections, spinal COX-2 induction thus not being a spatially confirmed phenomenon. Western blot analysis of spinal membrane preparations reflected the transient COX-2 mRNA induction at protein levels. During the chronic phase of arthritis at day 22, COX-2 levels were again raised significantly (1.6 fold) over baseline. Spinal levels of COX-1 were not altered at any time point of the peripheral inflammation. These data imply a regulatory role for COX-2 but not COX-1 in the spinal modulation under acute and chronic peripheral inflammation.


Unusual Disappearance of Inferior Q Waves in an Elderly Man.
In a patient with an old inferior myocardial infarct, the Q waves disappear when he develops left anterior fascicular block.


The ring of Soemmerring in man: an ultrastructural study.
The ultrastructure of lens remnants is described and illustrated after extracapsular cataract extraction in 11 pseudophakic human eyes, using scanning and transmission electron microscopy. The retained lens material formed a ringlike structure that was enclosed by the posterior and anterior capsule, as described extensively in the literature, and was found to contain dividing and differentiating epithelium. Both normal and degenerating subcapsular lenticular fibers and a central cataractous region were found. The sealing of the anterior capsular flap to the posterior capsule, although rather tight, had failed to prevent epithelial cells from escaping the ring in 9 out of 11 cases. Inflammatory cells near this sealing place and in the ring were found in all three specimens examined by transmission electron microscopy.


Catheter inversion to achieve complete isthmus block in patients with typical atrial flutter.
Endocardial catheter ablation is now considered as the therapy of first choice in highly symptomatic patients with recurrent atrial flutter. Despite of primary success rates between 90 and 100% complete isthmus block is sometimes hard to achieve. We present ablation results of 100 consecutive patients suffering from typical right atrial flutter. After a mean of 18 energy applications persistent bidirectional isthmus block could not be achieved in 16 patients and right atrial angiography was performed in all of them. In 9 patients a large Eustachian valve was detected and considered responsible for failure of endocardial catheter ablation of atrial flutter. Catheter manipulation targeting the anterior region of the Eustachian ridge was successful in all patients after looping the ablation catheter within the right atrium. With a mean of 3 additional RF applications, 6 of the 9 affected patients could be successfully ablated. Large Eustachian ridges are not a rare finding in patients undergoing ablation of typical right atrial flutter. Inversion of the ablation catheter within the right atrium is a simple technique providing excellent tissue contact of the ablation electrode with the anterior region of the Eustachian Ridge. Using this approach, the creation of bidirectional isthmus block is possible in the majority of the respective patients.


CT findings in gastrointestinal perforation by ingested fish bones.
Preoperative diagnosis of complications due to foreign bodies in the gastrointestinal tract is uncommon by conventional radiographic methods. We present two cases of gastric and duodenal perforation secondary to fish bone ingestion, diagnosed preoperatively by CT.


A Randomized, Double-Blind, Controlled Phase III Clinical Trial to Evaluate the Immunogenicity and Safety of a Lyophilized Human Rabies Vaccine (Vero Cells) in Healthy Participants Aged 10-60 Years Following Essen and Zagreb Vaccination Procedures.
In this paper, we aim to show that the immunogenicity of the lyophilized human rabies vaccine (Vero cells) (investigational vaccine) developed by Dalian Aleph Biomedical Co., Ltd. in healthy participants aged 10-60 years old is non-inferior to the lyophilized PVRV (positive control) manufactured by Liaoning Chengda Biotechnology Co., Ltd. (Shenyang, China), and that its safety is clinically acceptable. A total of 2776 participants were enrolled in this study and divided into four groups: a five-dose test group, a five-dose control group, a four-dose test group, and a four-dose control group. The patients in the four-dose groups (Zagreb) were vaccinated on Days 0 (two doses), 7 (one dose), and 21 (one dose), and those in the five-dose groups (Essen) were vaccinated on Days 0, 3, 7, 14, and 28 (one dose each). The rabies-virus-neutralizing antibody assay with the RFFIT was used to assess the immunogenicity, and the adverse events (AEs) and serious adverse events (SAEs) were identified and collated. The positive seroconversion rate was up to 100% on Days 14 and 35/42 after vaccination following any procedures in pre-immunization antibody-negative participants, and the positive seroconversion rate and geometric mean concentration (GMC) of the test groups (Zagreb and Essen vaccination procedures) was not inferior to that of the control groups. On Day 7 after vaccination, the immunogenicity of the Zagreb procedure with two doses of the vaccine on Day 0 was superior to the Essen procedure with one dose of vaccine, that is, the former had a higher seroconversion rate and RVNA titer. The non-inferiority criterion of immunogenicity was met for the whole population, the population aged 10-18 years and ≥18 years, and the pre-immunization antibody-positive population. The incidences of all AEs, solicited AEs, and unsolicited AEs in both groups were not statistically significant, and no vaccination-related SAEs were observed. The investigated vaccine is safe, its immunogenicity is non-inferior to that of the control vaccine, and the efficacy of the Zagreb procedure is superior to that of the Essen procedure 7 days after the first dose.


Hemodynamics of different configurations of the left subclavian artery parallel stent graft for thoracic endovascular aortic repair.
Parallel (chimney and periscope) graft technique is an effective approach for left subclavian artery (LSA) reconstruction in patients treated by thoracic endovascular aortic repair (TEVAR) for the inadequate landing zone. However, certain stent graft (SG) configurations may promote thrombosis and reduce distal blood flow, increasing risks of cerebral infarction and reintervention. In this paper, we first attempt to systematically evaluate the hemodynamic performances of different parallel graft techniques as potential determinants of complication risks. Based on the patient-specific 3D aortic geometry undergoing parallel graft technique, fifteen models in total for five kinds of LSA branched SG configurations (Forward, Backward, Extended, Elliptical and Periscopic) were designed virtually, and the hemodynamic discrepancies between them were analyzed by computational fluid dynamics. Results show that flow rate of patients undergoing periscope technique reduces by half compared with chimney technique, suggesting that periscope SG may cause more serious flow obstruction to LSA, leading to stroke. For chimney stent structure, the extension length 0has little influence on energy loss and other parameters. Conversely, hemodynamic differences between the retrograde curvature and the antegrade curvature are significant (time average WSS: 47.07%), so the retrograde curvature might prompt SG displacement. Furthermore, the flatter chimney SG induces more aggressive hemodynamic forces, among which the difference of the maximum WSS between the flatter SG and nearly round SG reaches 65.56%, leading to the greater risk of vascular wall damage. Results obtained might provide suggestions for physicians to formulate appropriate parallel graft technique schemes in TEVAR.


Clinical and histopathological considerations for the diagnosis and treatment of verrucous carcinoma of the larynx.
Verrucous carcinoma of the larynx is quite distinct from well-differentiated squamous cell carcinoma has a characteristic morphology and specific clinical behavior. It accounts for approximately 1%-2% of all laryngeal carcinomas. However, difficulties are encountered clinically in separating verrucous carcinomas from keratoses, verruca vulgaris and squamous cell carcinomas with a verrucous appearance. Between 1962 and 1982, 1504 patients with squamous cell carcinomas of the larynx were diagnosed and treated by staff physicians in the Department of Otolaryngology--Head and Neck Surgery, Washington University in St. Louis. Fifteen of these patients (1%) had verrucous carcinomas. These cases were studied in order to clarify any diagnostic problems, trace the biologic behavior of the tumors and report the results of the treatment used. Of these 15 patients, we were able to follow up 8. The latter had been treated only with surgery and none of them had received radiotherapy. One death occurred, but the patient died of other causes and remained free of cancer. Reports in the literature describe a high rate of recurrence of verrucous carcinomas following radiotherapy with occasional anaplastic transformation of tumors. No patients in our series developed a metastasis in the neck, indicating that neck dissection is not justified for patients with these neoplasms even though clinically enlarged neck nodes may be present.


[Primary non-specific ureteritis].
To better understand primary non-specific ureteritis. The etiological, clinical, and pathological manifestations, diagnosis, and treatment of 3 cases of primary non-specific ureteritis were discussed. Preoperative diagnosis failed. Uretero-ureterostomy was performed in 2 cases, and ureteroneocystostomy in one. The patients were free from hydronephrosis and ureteral dilatation. Diagnosis depends on pathological manifestations, differentiation from secondary non-specific ureteritis, ureteral tuberculosis, negative X-ray of ureteral stone and ureteral carcinoma. Surgical intervention is effective with good prognosis.


Composition and predicted functions of the bacterial community in spouting pool sediments from the El Tatio Geyser field in Chile.
The El Tatio Geyser Field (ETGF), located in Northern Chile, is the main geyser field in the southern hemisphere. Despite this, details of its microbial ecology are still unknown. Here, we briefly report on the composition and predicted functions of the bacterial community in spouting pool sediments from the ETGF as revealed by high-throughput sequencing of 16S rRNA genes. Results of this analysis showed that while there were differences in richness and diversity between samples, bacterial communities were primarily dominated by the phyla Proteobacteria, followed Firmicutes, Bacteroidetes, Acidobacteria, and Chloroflexi. Analyses of predicted functional activity indicated that the functions were mostly attributed to chemoheterotrophy and aerobic chemoheterotrophy, followed by sulfur (respiration of sulfur compounds and sulfate) and nitrogen (nitrate reduction, respiration of nitrogen and nitrate) cycling. Taken together, our results suggest a high diversity in taxonomy and predictive functions of bacterial communities in sediments from spouting pools. This study provides fundamentally important information on the structure and function predictive functions of microbiota communities in spouting pools. Moreover, since the ETGF is intensively visited and impacted by tens of thousands of tourists every year, our results can be used to help guide the design of sustainable conservation strategies.


Initial combination therapy versus step-up therapy in treatment to the target of remission in daily clinical practice in early rheumatoid arthritis patients: results from the DREAM registry.
Treat to target (T2T) is widely accepted as the standard of care for patients with rheumatoid arthritis (RA) and has been shown to be more effective than traditional routine care. The objective of this study was to compare the effectiveness of two T2T strategies in patients with early RA: a step-up approach starting with methotrexate (MTX) monotherapy (cohort I) versus an initial disease-modifying antirheumatic drug combination approach (cohort II). A total of 128 patients from cohort II were case-control-matched with 128 patients from cohort I on gender, age, and baseline disease activity. Twelve-month follow-up data were available for 121 patients in both cohorts. The primary outcome was the proportion of patients having reached at least one 28-joint Disease Activity Score (DAS28) score <2.6 (remission) during 12 months of follow-up. Secondary outcomes were time until remission was achieved and mean DAS28 scores at 6- and 12-month follow-up. After 12 months of follow-up, remission was reached at least once in 77.3 % of the patients in cohort II versus 71.9 % in cohort I (P = 0.31). Median time until first remission was 17 weeks in cohort II versus 27 weeks in cohort I (P = 0.04). A significant time by strategy interaction was found in mean DAS28 scores. Post hoc analysis revealed a significant difference in mean DAS28 scores between both cohorts at 6 months (P = 0.04), but not at 12 months (P = 0.36). The initial combination strategy resulted in a comparable remission rate after 1 year but a significantly shorter time until remission. At 6 months, mean DAS28 scores were lower in patients with initial combination treatment than in those with step-up therapy. At 12 months, no significant differences remained in mean DAS28 scores or the proportion of patients in remission.


Relationship between Body Mass Index and Bone Turnover Markers in Girls with Idiopathic Central Precocious Puberty.
This study aimed to determine the effect of body mass index (BMI) on bone turnover markers in girls with idiopathic central precocious puberty (ICPP) according to weight status at diagnosis. Two hundred and eleven girls with ICPP were divided according to their weight status at diagnosis into three groups: normal weight, overweight, and obese. The serum levels of total procollagen type 1 N-terminal propeptide (P1NP), N-terminal midfragment of osteocalcin, β-C-terminal telopeptide of type 1 collagen, and some biochemical indicators were measured. Associations between variables were evaluated by multiple regression analysis. Serum P1NP concentrations were significantly different among groups (p < 0.001). No other significant differences were noted in N-terminal midfragment of osteocalcin and β-C-terminal telopeptide of type 1 collagen. BMI was associated with estradiol (r = 0.155, p < 0.05) and inversely associated with P1NP (r = -0.251, p < 0.01), luteinizing hormone peak (r = -0.334, p < 0.01), follicle-stimulating hormone peak (r = -0.215, p < 0.01), and luteinizing hormone/follicle-stimulating hormone peak (r = -0.284, p < 0.01). Multiple regression analysis of factors associated with BMI showed that it was correlated with P1NP, follicle-stimulating hormone base, and luteinizing hormone peak in the overweight group and the obese group. Our findings showed that BMI was associated with P1NP, revealing the reduction of bone formation in overweight and obese girls with ICPP. During the diagnosis and treatment of girls with ICPP, attention should be paid to body weight and bone metabolism.


Exploration of Extracellular Vesicle miRNAs, Targeted mRNAs and Pathways in Prostate Cancer: Relation to Disease Status and Progression.
Prostate cancer (PCa) lacks non-invasive specific biomarkers for aggressive disease. We studied the potential of urinary extracellular vesicles (uEV) as a liquid PCa biopsy by focusing on the micro RNA (miRNA) cargo, target messenger RNA (mRNA) and pathway analysis. We subjected uEV samples from 31 PCa patients (pre-prostatectomy) to miRNA sequencing and matched uEV and plasma EV (pEV) from three PCa patients to mRNA sequencing. EV quality control was performed by electron microscopy, Western blotting and particle and RNA analysis. We compared miRNA expression based on PCa status (Gleason Score) and progression (post-prostatectomy follow-up) and confirmed selected miRNAs by quantitative PCR. Expression of target mRNAs was mapped in matched EV. Quality control showed typical small uEV, pEV, RNA and EV-protein marker enriched samples. Comparisons between PCa groups revealed mostly unique differentially expressed miRNAs. However, they targeted comprehensive and largely overlapping sets of cancer and progression-associated signalling, resistance, hormonal and immune pathways. Quantitative PCR confirmed changes in miR-892a (Gleason Score 7 vs. ≥8), miR-223-3p (progression vs. no progression) and miR-146a-5p (both comparisons). Their target mRNAs were expressed widely in PCa EV. PCa status and progression-linked RNAs in uEV are worth exploration in large personalized medicine trials.


Mapping of superficial extremity veins: normal diameters and trends in a vascular patient-population.
Ultrasonic measurement of superficial extremity veins is a common procedure. To establish normal values for vein-size in a population of vascular patients and to assess if measurements remain unchanged over time, we analyzed a database with results of 28,130 measurements in 2420 separate saphenous and 3206 cephalic veins. Mean size of the great saphenous vein ranges from 2.3 mm to 4.4 mm but did not follow a tapering pattern as is often assumed. The distal calf segment is smaller than the ankle segment. The mean cephalic vein size in the upper arm (2.4 mm) was smaller than at the antecubital level (2.7 mm). A decrease in vein diameter over time was noted in many locations and this reached statistical significance (p < 0.005 for the thigh segment). The clinical significance of this is a need to repeat ultrasonic vein-mapping if more than a year elapses between ultrasound and surgical vein harvest.


Projections of the superior colliculus to the supraspinal nucleus and the cervical spinal cord gray of the cat.
Anterograde transport experiments reveal two novel findings regarding the distribution of descending tectofugal axons. First, such axons project to the supraspinal nucleus of the caudal medulla; this nucleus is known to project to the upper cervical spinal cord gray. Second, some tectospinal axons ramify within Rexed's lamina IX of the first 5 cervical spinal cord segments. This zone contains motoneurons which innervate neck musculature. Retrograde data reveal that tectospinal neurons occur in clusters within the intermediate and deep gray layers. A close relationship between the clusters of tectospinal neurons and a modular type of connectional organization of the intermediate and deep gray layers is suggested.


Ipsilateral foot and contralateral hand anomalies in a patient with Poland-Moebius syndrome.
This report describes a patient who had bilateral facial nerve paralysis, external ophthalmoplegia, absence of pectoralis major muscle at right side, ipsilateral hand and foot, and contralateral hand anomalies. To our knowledge, this is the first patient with Poland syndrome reported in combination with Moebius syndrome, presenting with contralateral hand and ipsilateral foot anomalies.


Modeling placental development and disease using human pluripotent stem cells.
Our current knowledge of the cellular and molecular mechanisms of placental epithelial cells, trophoblast, primarily came from the use of mouse trophoblast stem cells and tumor-derived or immortalized human trophoblast cell lines. This was mainly due to the difficulties in maintaining primary trophoblast in culture and establishing human trophoblast stem cell (hTSC) lines. However, in-depth characterization of these cellular models and in vivo human trophoblast have revealed significant discrepancies. For the past two decades, multiple groups have shown that human pluripotent stem cells (hPSCs) can be differentiated into trophoblast, and thus could be used as a model for normal and disease trophoblast differentiation. During this time, trophoblast differentiation protocols have evolved, enabling researchers to study cellular characteristics at trophectoderm (TE), trophoblast stem cells (TSC), syncytiotrophoblast (STB), and extravillous trophoblast (EVT) stages. Recently, several groups reported methods to derive hTSC from pre-implantation blastocyst or early gestation placenta, and trophoblast organoids from early gestation placenta, drastically changing the landscape of trophoblast research. These culture conditions have been rapidly applied to generate hPSC-derived TSC and trophoblast organoids. As a result of these technological advancements, the field's capacity to better understand trophoblast differentiation and their involvement in pregnancy related disease has greatly expanded. Here, we present in vitro models of human trophoblast differentiation, describing both primary and hPSC-derived TSC, maintained as monolayers and 3-dimensional trophoblast organoids, as a tool to study early placental development and disease in multiple settings.


Management of Pregnancy-and Lactation-Related Osteoporosis: Case Series.
To share the experience regarding management and follow-up of patients with Pregnancy- and lactation-related osteoporosis (PLRO) who were effectively treated. This case series presented 10 patients diagnosed with PLRO and treated from January 2010 to December 2019. Visual analog scale and laboratory findings were evaluated. Spinal and extremity magnetic resonance imaging was obtained for patients with spinal and extremity pains. Dual energy X-ray absorptiometry was used for the measurement of bone mineral density. Values assessed on dual energy X-ray absorptiometry were L1?L4 T score, L2?L4 T score, and femoral neck T score. In the first-month follow-ups, all patients had meaningful pain relief and symptom resolution. The mean duration of pain control during the treatment period was 2.4 months. Two patients who continued breast-feeding were also the patients whose pain control was achieved at the latest. One patient required vertebroplasty. Patients with PLRO should be promptly treated and followed up. Discontinuation of breast-feeding will provide rapid advantage and should be the first step of the management. Early diagnosis and treatment of calcium and vitamin D with conservative procedures with spinal braces are very important for the treatment of PLRO patients. Additionally, bisphosphonates or teriparatide can improve the bone mineral density in patients with PLRO.


SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation.
Infection of SARS-CoV-2 may cause acute respiratory syndrome. It has been reported that SARS-CoV-2 nucleocapsid protein (N-protein) presents early in body fluids during infection. The direct involvement of N-protein in lung injury is poorly understood. Recombinant N-protein was pretreated with polymyxin B, a lipopolysaccharide (LPS)-neutralizing agent. C57BL/6, C3H/HeJ (resistant to LPS), and C3H/HeN (control for C3H/HeJ) mice were exposed to N-protein via intratracheal administration to examine acute lung injury. In vitro, bone marrow-derived macrophages (BMDMs) were cultured with N-protein to study phosphorylation of nuclear factor kappa B (NF-ĸB) p65, macrophage polarization, and expression of proinflammatory cytokines. N-protein produced acute lung injury in C57BL/6 mice, with elevated protein permeability, total cell count, neutrophil infiltration, and proinflammatory cytokines in the bronchioalveolar lavage. N-protein also induced lung injury in both C3H/HeJ and C3H/HeN mice, indicating that the effect could not be attributed to the LPS contamination. N-protein triggered phosphorylation of NF-ĸB p65 in vitro, which was abolished by both N-protein denaturation and treatment with an antibody for N-protein, demonstrating that the effect is N-protein specific. In addition, N-protein promoted M1 macrophage polarization and the expression of proinflammatory cytokines, which was also blocked by N-protein denaturation and antibody for N-protein. Furthermore, N-protein induced NF-ĸB p65 phosphorylation in the lung, while pyrrolidine dithiocarbamate, an NF-ĸB inhibitor, alleviated the effect of N-protein on acute lung injury. SARS-CoV-2 N-protein itself is toxic and induces acute lung injury in mice. Both N-protein and NF-ĸB pathway may be therapeutic targets for treating multi-organ injuries in Coronavirus disease 2019 (COVID-19).


No evidence of male-biased sexual selection in a snake with conventional Darwinian sex roles.
Decades of research on sexual selection have demonstrated that 'conventional' Darwinian sex roles are common in species with anisogamous gametes, with those species often exhibiting male-biased sexual selection. Yet, mating system characteristics such as long-term sperm storage and polyandry have the capacity to disrupt this pattern. Here, these ideas were explored by quantifying sexual selection metrics for the western diamond-backed rattlesnake (Crotalus atrox). A significant standardized sexual selection gradient was not found for males (β SS = 0.588, p = 0.199) or females (β SS = 0.151, p = 0.664), and opportunities for sexual selection (Is ) and selection (I) did not differ between males (Is = 0.069, I = 0.360) and females (Is = 0.284, I = 0.424; both p > 0.05). Furthermore, the sexes did not differ in the maximum intensity of precopulatory sexual selection (males: s' max = 0.155, females: s' max = 0.080; p > 0.05). Finally, there was no evidence that male snout-vent length, a trait associated with mating advantage, is a target of sexual selection (p > 0.05). These results suggest a lack of male-biased sexual selection in this population. Mating system characteristics that could erode male-biased sexual selection, despite the presence of conventional Darwinian sex roles, are discussed.


Genome-wide analysis of Nilaparvata lugens nymphal responses to high-density and low-quality rice hosts.
The brown planthopper (BPH) Nilaparvata lugens is an economically important pest on rice plants. In this study, the higher population density and yellow-ripe stage of rice plants were used to construct adverse survival conditions (ASC) against BPH nymphs. Simultaneously, the low population density and tillering stage of rice plants were used to establish a suitable survival condition (SSC) as a control. Solexa/Illumina sequencing was used to identify genes of BPH nymphs responding to ASC. Significantly longer duration development of BPH nymphs and significantly lower brachypterous ratio of BPH adults were observed by ASC compared with SSC. A total of 2 544 differentially expressed genes (DEGs) were obtained and analyzed by BLASTx, Gene Ontology and KEGG Orthology. Gene ontology analysis revealed that the DEGs were mainly involved in categories of cell, cell part, cellular process, binding, catalytic, organelle and metabolic processes. 1 138 DEGs having enzyme commission numbers were assigned to different metabolic pathways. The largest clusters were neurodegenerative diseases (137, 12.0%), followed by carbohydrate metabolism (113, 9.9%), amino acid metabolism (94, 8.3%), nucleotide metabolism (76, 6.7%), energy metabolism (64, 5.6%), translation (60, 5.3%), lipid metabolism (58, 5.1%), and folding, sorting and degradation (52, 4.6%). Expressing profile of 11 DEGs during eight nymphal developmental stages of BPH were analyzed by quantitative real-time polymerase chain reaction. The 11 genes exhibited differential expression between ASC and SSC during at least one developmental stage. The DEGs identified in this study provide molecular proof of how BPH reconfigures its gene expression profile to adapt to overcrowding and low-quality hosts.


Interaction of intrathecally infused morphine and lidocaine in rats (part I): synergistic antinociceptive effects.
Synergistic antinociception of opioids and local anesthetics has been established in bolus injections but not in long-term use. The somatic and visceral antinociceptive effects of intrathecally infused morphine or lidocaine were characterized, and the nature of the interaction of those agents in rats was evaluated. Intrathecal catheters were implanted in rats. Morphine (0.3 to 10 microg x kg(-1) x h(-1)), lidocaine (30-1,000 microg x kg(-1) x h(-1)), a combination of those, or saline was infused intrathecally at a constant rate of 1 microl/h for 6 days. The tail flick and colorectal distension tests were used to measure the somatic and visceral antinociceptive effects, respectively. Nociceptive tests and motor function tests were repeated on days 1, 2, 3, 4, and 6. Isobolographic analysis was performed on the results of the tail flick test to determine the magnitude of the interaction. Intrathecally infused morphine produced dose-dependent antinociceptive effects in both the tail flick and the colorectal distension tests. Morphine showed a lower peak percentage maximum possible effect (%MPE) in the colorectal distension test than in the tail flick test. Intrathecal lidocaine also produced dose-dependent antinociceptive effects. Lidocaine infusion at 1,000 microg x kg(-1) x h(-1) caused motor impairment. Coinfusion of morphine 0.3 microg x kg(-1) x h(-1) and lidocaine 200 microg x kg(-1) x h(-1), which had no effects by themselves, significantly increased the percentage maximum possible effects (P < 0.01). Coinfused lidocaine potentiated the duration and the magnitude of morphine antinociception. Isobolographic analysis of the tail flick test on day 1 showed a synergistic interaction between morphine and lidocaine. Morphine and lidocaine intrathecally coadministered synergistically potentiated the antinociceptive effects of each other. That coinfusion dramatically potentiated visceral antinociception, whereas the infusion of morphine alone showed little visceral antinociception.


Posttraumatic stress as a contributor to behavioral health outcomes and healthcare utilization in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.
To examine the association between posttraumatic stress symptoms (PTSS), neurocognitive and psychosocial late-effects, health behaviors, and healthcare utilization in long-term survivors of childhood cancer. Participants included individuals (N = 6844; 52.5% female; mean [SD] age at diagnosis = 7.6 [5.8], at follow-up = 34.9 [7.5]) in the Childhood Cancer Survivor Study (CCSS). Follow-up included the Posttraumatic Stress Scale, Brief Symptom Inventory-18, Short-form 36 Health-related quality of life (HRQOL) survey, CCSS Neurocognitive Questionnaire, and questions about sociodemographics, physical health, health behaviors, and healthcare utilization. Modified Poisson regression and multinomial logistic regression models examined associations between posttraumatic stress symptoms (PTSS) and neurocognitive, HRQOL, health behavior, and healthcare outcomes when adjusting for sociodemographics, disease, and treatment. Long-term survivors with PTSS (N = 995, 14.5%) reported more impairment in mental (relative risk [RR] 3.42, 95% confidence interval [CI] 3.05-3.85), and physical (RR = 2.26, CI = 1.96-2.61) HRQOL. PTSS was also associated with increased impairment in task efficiency (RR = 3.09, CI = 2.72-3.51), working memory (RR = 2.55, CI = 2.30-2.83), organization (RR = 2.11, CI = 1.78-2.50), and emotional regulation (RR = 3.67, CI = 3.30-4.09). Survivors with PTSS were significantly more likely to attend cancer-specific health visits in the past 2 years (OR = 1.89, CI = 1.50-2.39), and showed greater likelihood of either high frequency (OR = 1.89, CI = 1.50-2.39) or complete lack of (OR = 1.63, CI = 1.32-2.01) primary care visits compared to survivors without PTSS. Survivors with PTSS reported significantly more psychosocial and neurocognitive late effects, and were more likely to engage in variable use of healthcare. PTSS is associated with additional challenges for a population vulnerable to adverse late effects. Inclusion of integrative services during follow-up visits may benefit functional outcomes.


Changes of neuropeptide concentrations in the brain following experimentally induced mononeuropathy in Wistar Kyoto and spontaneously hypertensive rats.
The effect of unilateral, experimentally induced, mononeuropathy on concentrations of neuropeptide Y (NPY), neurokinin A (NKA), substance P (SP), calcitonin gene-related peptide CGRP) and galanin- (GAL-) like immunoreactivities (-LI) was studied in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rat brains. Two weeks following ligation of the sciatic nerve, significantly higher concentrations of NPY-LI were found in the hippocampus, striatum and occipital cortex of both rat strains. CGRP-LI and GAL-LI were increased in the hippocampus of WKY rats. NKA-LI and SP-LI were decreased to different degrees in the pituitary of the WKY and SHR rats, indicating that the changes of the tachykinins, CGRP and GAL were selectively associated with the basal level of sympathetic tone. The increased concentrations of NPY-LI in the brain, not influenced by sympathetic tone, may be part of a general defense reaction in response to trauma.


Tamoxifen decreases the estradiol induced progesterone receptors by interfering with nuclear estrogen receptor accumulation.
The retention time of the estrogen receptor in the nucleus of target cells after antiestrogen treatment has been shown to be longer than after estradiol. This paper describes the accumulation of nuclear estrogen receptors and the obtention of estrogenic responses (i.e. synthesis of cytosolic progesterone receptors and DNA) in the rat uterus after tamoxifen treatment in the presence or absence of estradiol. One-week ovariectomized adult rats were implanted with a silicone elastomer capsule containing corn oil or 25 micrograms estradiol/capsule (0 h). 48 h after implantation rats were injected with corn oil or 2 mg tamoxifen/kg and decapitated at 72, 96 or 120 h after implantation. In parallel experiments the implants were removed just before the injections of tamoxifen or oil. Tamoxifen injected into rats implanted with oil increased both the occupied nuclear receptors and the progesterone receptors at 96 h. In rats implanted with estradiol, tamoxifen did not increase the occupied nuclear receptors and decreased the levels of progesterone receptor and DNA at 96 h. In rats whose estradiol implants were removed at 48 h tamoxifen did not change the level of occupied nuclear receptors at 72 h but it increased them abruptly at 96 and 120 h. In these rats progesterone receptors decreased at 72 h but they increased at 96 and 120 h, and DNA decreased at 120 h to a lower level than before implantation. The results suggest that when estradiol is acting, tamoxifen is not able to increase the level of occupied estrogen receptor and it acts as an antiestrogen by decreasing the high level of progesterone receptors previously induced by estradiol. When estradiol is not acting tamoxifen behaves as a partial estrogen agonist by inducing progesterone receptors. However, the antiestrogenic action of tamoxifen on the rat uterus DNA does not seem to be affected by estradiol.


Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia.
Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed patients with AML treated at the Memorial Sloan Kettering Cancer Center, we show that ontogeny assignments based on the database registry lack accuracy. MR gene mutations are frequently observed in de novo AML. Among the MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in the univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also helped stratify the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny, and questions the current classification and risk stratification of AML with MR gene mutations.


A novel time-dimension and circadian rhythm-dependent strategy for pharmacodynamic evaluation of Uncaria in the regulation of neurotransmitter circadian metabolic homeostasis in spontaneously hypertensive rats.
In the present study, we aimed to use metabolomics platforms to examine circadian-regulated neurotransmitters across a 24-h day and the effects of Uncaria administration on daily rhythmicity in order to establish a strategy for evaluating the spatiotemporal efficacy evaluation strategy of Uncaria. By using targeted ultrahigh performance liquid chromatography-mass spectrometry metabolomics, we quantified 32 neurotransmitter metabolites every 4 h over 24 h. To assess 24-h metabolite rhythmicity, we performed cosinor analysis. The expression of hypothalamic rhythm genes was detected by reverse transcription polymerase chain reaction (RT-PCR). Data revealed circadian loss of many neurotransmitters during the entire circadian cycle in the serum of group M, indicating that hypertension causes circadian rhythm disorders. Cosinor analysis of the rhythmic oscillations of the levels of 32 neurotransmitters in the three groups showed that the metabolite rhythms peaked at approximately the same time of day (ZT4 and ZT16). Moreover, the amplitudes of the metabolite rhythms were altered. After treatment with Uncaria, the amplitudes of 13 neurotransmitters reverted to normal. The change trends in the hypothalamic rhythm genes confirmed the rhythm changes in neurotransmitters. Collectively, a novel pharmacodynamic evaluation strategy was established to dynamically observe the holistic effects of Uncaria on 32 circulating neurotransmitters within 24 h from the perspective of time dimension.


Fe/Mn- and P-modified drinking water treatment residuals reduced Cu and Pb phytoavailability and uptake in a mining soil.
Management of industrial hazardous waste is of great concern. Recently, aluminum rich drinking water treatment residuals (Al-WTR) received considerable attention as a low-cost immobilizing agent for toxic elements in soils. However, the suitability and effectiveness of modified Al-WTR as stabilizing agent for toxic metals such as Cu and Pb in mining soil is not assessed yet. We examined the impact of different doses (0, 0.5, 1.5, and 2.5%) of raw and Fe/Mn- and P- modified Al-WTR on the bioavailability and uptake of Cu and Pb by ryegrass in Cu and Pb contaminated mining soil. The addition of Fe/Mn-and P- modified Al-WTR to the soil reduced significantly the concentrations of Pb (up to 60% by Fe/Mn-Al-WTR and 32% by P-Al-WTR) and Cu (up to 45% by Fe/Mn-Al-WTR and 18% by P-Al-WTR) in the shoots and roots of ryegrass as compared to raw Al-WTRs and untreated soil. Our results demonstrate that modification of the raw Al-WTR increased its pH, CEC, specific surface area, active functional groups (Fe-O and Mn-O), and thus increased its immobilization efficiency. Our results highlight the potential of the modified Al-WTR, particularly the Fe/Mn-Al-WTR, for the remediation of Cu and Pb contaminated soils and recommend field scale verification.


Regional variation of multiple sclerosis prevalence in Canada.
To describe the regional distribution of multiple sclerosis (MS) prevalence in Canada, controlling for age and sex. This study used data from the Canadian Community Health Survey, a large general health survey (n = 131,535) conducted in 2000/2001. Subjects aged 18 and over were included in the current analysis (n = 116,109). The presence of MS was determined by self-report. Prevalence was computed in five regions (Atlantic, Quebec, Ontario, Prairies and British Columbia). Logistic regression was used to compare regions and examine for confounding/interaction by age and sex. The overall Canadian MS prevalence was 240 per 100000 (95%CI: 210 280). Prevalence ranged from 180 (95%CI: 90-260) in Quebec to 350 (95%CI: 230-470) in Atlantic Canada. Logistic regression revealed no statistical difference between the odds of MS in Quebec, Ontario and British Columbia adjusted for age and sex. The adjusted odds of MS in the Prairies and Atlantic regions were significantly higher than in the other regions combined, with odds ratios of 1.7 (95%CI: 1.1-2.4, P <0.01) and 1.6 (95%CI: 1.1-2.4, P <0.05) respectively. Sensitivity analysis demonstrated similar prevalence in the nonaboriginal/nonimmigrant group (n = 96219). Results suggest that Canadian MS prevalence differs by region. If validated, these regional differences may facilitate investigation of environmental influences.


Designing fisetin nanocrystals for enhanced in cellulo anti-angiogenic and anticancer efficacy.
We report the formulation, characterization, colloidal stability, and in vitro efficiency of Fisetin nanocrystals stabilized by poloxamer P407. Such nanocrystals present a nanometer scale (148.6 ± 1.1 nm) and a high homogeneity (polydispersity index of 0.17 ± 0.01), with a production yield of 97.0 ± 2.5%. The engineered formulations of nanocrystals suspension (pH of 7.4 ± 0.1), stabilized via steric repulsion, are stable for several days in aqueous environment (Milli Q water, NaCl 10 mM or mannitol 5% w/v), for few days in HEPES buffered saline (HBS) (20 / 150 mM) under sink conditions, and in culture medium. After freeze drying in 5% w/v mannitol, the nanocrystal formulations can be stored at -80 °C for at least 120 days. Drug release experiments displayed a 98.7 ± 5.1% cumulative release over 3 days in HBS. Compared to the free drug, the nanocrystal formulations showed an improved cytotoxicity highlighted by the decrease of the half maximal inhibitory concentration for both murine Lewis lung carcinoma (3LL) and human endothelial (EA.hy926) cell lines. In addition, after incubation with Fisetin nanosuspensions, significant changes in the cell morphology for both cell lines were observed, showing an improved anti-angiogenic effect of nanocrystals formulation compared to the free drug. Overall, Fisetin formulated as nanocrystals showed enhanced biopharmaceutical properties and in vitro activity, offering a wide range of indications for challenging applications in the clinic.


Unusual signals in a halo catheter: what is the mechanism?
In this "featured arrhythmia" article we present a set of unusual intracardiac electrode tracings that were recorded in a patient with typical clockwise flutter but a very dilated right atrium. The potential mechanism underlying this phenomenon is discussed with reference to the current literature.


Design of wavelet transform based electrocardiogram monitoring system.
The new age advancements in information technology due to materials and integrated circuit (IC) technologies and their applications in biomedical sciences have made the healthcare facilities more compact and affordable for the aging population. Market trends in healthcare and related devices indicate a sharp rise in their demand. Hence the researchers have converged the efforts on designing more smart and advanced medical devices using IC technology. Among these devices, cardiac pacemakers have become a recurrent biomedical device which is engrafted in the human body to detect and monitor a person's heart beating rate. The data thus generated is processed for various medical usages and devices via wireless methods. Cardiovascular diseases (CVDs) or diseases related to the heart are due to abnormalities or disorders of the heart and blood vessels. Till date, limited literature is available which focuses on a single technique that can perform all of the ECG signal denoising, ECG detection, lossless data compression and wireless transmission. In this work, a joint approach for denoising, detection, compression, and wireless transmission of ECG signal is proposed. The modified biorthogonal wavelet transform is used for denoising, detection and lossless compression of ECG signal. To reduce the circuit complexity, biorthogonal wavelet transform is realized using linear phase structure. Further, it is found in this work that the usage of modified biorthogonal wavelet transform increases the detection accuracy and CR of the proposed design. Also, in this work, the Wi-Fi-based wireless protocol is used for compressed data transmission. The proposed ECG detector achieves the highest sensitivity and positive predictivity of 99.95% and 99.92%, respectively, with the MIT-BIH arrhythmia database. The use of modified biorthogonal 3.1 wavelet transform and run-length encoding (RLE) for the compression of ECG data achieves a higher compression ratio (CR) of 6.271. To justify the effectiveness of the proposed algorithm, which uses modified biorthogonal wavelet 3.1transform, the results are compared with the existing methods, namely, Huffman coding/simple predictor, Huffman coding/adaptive, and slope predictor/fixed length packaging.


Combined fractures of the femoral and tibial shafts in the same limb.
This paper reports a study of ipsilateral fractures of the femoral and tibial shafts in 21 patients treated according to a detailed plan including shock treatment, prophylaxis against fat embolism, soft-tissue and fracture treatment. Death due to hypovalaemic shock was eliminated and the incidence of fat emboliism (9-5%) reduced in comparison with an earlier series. The tibial fracture was stabilized by plaster or internal fixation as soon as conditions allowed. In most cases the femoral fracture was treated by medullary mailing. Results have improved compared with earlier series. All fractures healed within 15 months, and functional end results have been excellent in the majority of the surviving patients (89%).


Pyrrolo[2,3-b]pyridine-3-one derivatives as novel fibroblast growth factor receptor 4 inhibitors for the treatment of hepatocellular carcinoma.
Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors, especially liver cancer. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR4 inhibitors. Currently, several selective irreversible inhibitors containing pyrrolo[2,3-b]pyridine-3-one and pyrrolo[2,3-d]pyrimidin-2-amine skeletons were designed and synthesized as FGFR4 inhibitors. Among the screened compounds, derivative 25 showed excellent enzymatic inhibitory activity (IC50, 51.6 nM) and antiproliferative potency of 0.1397 μM against Hep3B cell lines. Compound 25 exhibited good in vitro human liver microsomal stability with the half-life of 62.0 min, which was more stable than BLU9931 (46.7 min). But the in vivo pharmacokinetic results showed that the oral bioavailability was only 6.65%, which needs to be improved in the next work. These results showed that compound 25 might be an effective lead compound for further investigation to treat the hepatocellular carcinoma.


Canine spongiform leukoencephalomyelopathy is associated with a missense mutation in cytochrome b.
Two families of dogs (Australian cattle dogs and Shetland sheepdogs) with an inherited "spongiform leukoencephalomyelopathy" were identified, with widespread vacuolation of white matter of the brain and spinal cord. Affected dogs of both breeds developed tremors at 2-9 weeks of age followed by progressive neurological worsening with ataxia, paresis, paralysis, spasticity, and cranial nerve dysfunction. The modes of inheritance of both families were most likely maternal. The cerebrospinal fluid (CSF) analysis showed elevated ratio of 3-OH butyrate to acetoacetic acid. Mitochondrial DNA sequencing showed a G to A transition at 14,474 nt (G14474A, GenBank accession no. NC002008 ) that results in an amino acid change of valine-98 to methionine (V98M) of mitochondrial encoded cytochrome b. Western blot analysis showed increased levels of core I and core II but decreased level of cytochrome c1 of the complex III and cytochrome c oxidase of the complex IV of the respiratory chain.


SPARQL assist language-neutral query composer.
SPARQL query composition is difficult for the lay-person, and even the experienced bioinformatician in cases where the data model is unfamiliar. Moreover, established best-practices and internationalization concerns dictate that the identifiers for ontological terms should be opaque rather than human-readable, which further complicates the task of synthesizing queries manually. We present SPARQL Assist: a Web application that addresses these issues by providing context-sensitive type-ahead completion during SPARQL query construction. Ontological terms are suggested using their multi-lingual labels and descriptions, leveraging existing support for internationalization and language-neutrality. Moreover, the system utilizes the semantics embedded in ontologies, and within the query itself, to help prioritize the most likely suggestions. To ensure success, the Semantic Web must be easily available to all users, regardless of locale, training, or preferred language. By enhancing support for internationalization, and moreover by simplifying the manual construction of SPARQL queries through the use of controlled-natural-language interfaces, we believe we have made some early steps towards simplifying access to Semantic Web resources.


[The significance of the scientist Prof. Bernhard Heine (1800-1846) for his age, especially for German and French orthopedics].
The professor of Orthopaedics in Würzburg, Bernhard Heine (1800-1846) nephew and successor of Johann Georg Heine (1770-1838) at the Karolinen Institute in Würzburg, is not only of significance for the history of the university in Würzburg and for the development of his subject in the German-speaking area, as has mostly been represented up until now, but he should also be seen as one of the forerunners of international cooperation in the early 19th century! From his contacts to the Académie des sciences in Paris and his two Monthyon prizes, his influence on the technology of orthopaedics, the clinic and bone physiology should be indicated by means of his osteotome.


Sensitization of Bacillus subtilis spores to dry heat and desiccation by pretreatment with oxidizing agents.
To determine if pretreatment with oxidizing agents sensitizes Bacillus subtilis spores to dry heat or desiccation. Bacillus subtilis spores were killed approx. 90% by oxidizing agents, and the sensitivity of treated and untreated spores to dry heat and desiccation was determined. The effects of pyruvate on spore recovery after oxidizing agent pretreatment and then dry heat or desiccation were also determined. Spores pretreated with Oxone or hypochlorite were not sensitized to dry heat or freeze-drying. However, hydrogen peroxide or t-butylhydroperoxide pretreatment sensitized spores to dry heat or desiccation, and the desiccation caused mutagenesis in the survivors. Pyruvate increased recovery of spores treated with hydrogen peroxide alone or plus dry heat or desiccation, and with t-butylhydroperoxide and desiccation, but not with t-butylhydroperoxide alone or plus dry heat. Pretreatment with peroxides sensitizes bacterial spores to subsequent stress. This finding may suggest improved regimens for spore inactivation.


A cup of magic.
This reflective piece tells the story of an impactful patient interaction that shaped the practice of a medical student. The essay focuses on the power of shared time and the development of meaningful relationships as a form of adjunctive therapy for patients, regardless of diagnosis or prognosis. Fostering an appreciation for the present moment and savoring glimpses of human interaction are other themes that are touched upon in this piece.


The effects of the antioxidant α-tocopherol succinate on cisplatin-induced ototoxicity in HEI-OC1 auditory cells.
D-α-tocopherol succinate significantly reduced a cisplatin-induced hair cell loss in HEI-OC1 cell lines. These effects were mediated by its scavenging activity against reactive oxygen species (ROS) and inhibition of apoptosis. Alpha-tocopherol is a class of methylated phenols, known as fat-soluble antioxidants, and is a different form of vitamin E, which reduces free radicals and acts as an antioxidant. We hypothesized that the antioxidative effect of α-tocopherol could protect against cisplastin-induced cytotoxicity, and thus evaluated its effects on cisplatin-induced ototoxicity in HEI-OC1 auditory cells. HEI-OC1 cells were pretreated with D-α-tocopherol succinate at a concentration of 10 µM for 24 h, and then exposed to 15 µM cisplatin for 48 h. The cellular viability was measured by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The intracellular ROS level was measured by using a fluorescent dye, 2',7'-dichlorofluorescein diacetate (DCFH-DA). Both Annexin V-FITC and propidium iodide (PI) staining were performed to analyze the pattern of apoptosis. The enzymatic activity of caspase-3 was assayed with caspase3/CPP32 fluorometric assay kit. Also, it was assessed by immunoblotting technique of poly-ADP-ribose polymerase (PARP). Pretreatment with 10 µM D-α-tocopherol succinate protected HEI-OC1 auditory cells against cisplatin-induced cytotoxicity. D-α-tocopherol succinate significantly reduced the cisplatin-induced increase in ROS. D-α-tocopherol succinate treatment induced a 15% reduction of ROS and 50% decrease in necrosis and late apoptosis as compared to cisplatin treatment. D-α-tocopherol succinate also decreased the activation of caspase-3 and reduced levels of cleaved poly-ADP-ribose polymerase (PARP).


Bremazocine-induced urination in rats of different sizes.
The increased urine output after injection of the kappa agonist bremazocine was determined in rats of various body weights. Rats of all sizes were sensitive to the diuretic effect of bremazocine. The total diuretic effect was greater in heavier animals. The urine output plateaued between 4-5 ml/100 g body weight irrespective of body weight at the higher doses of bremazocine.


Transformed follicular lymphoma (tFL): consolidation therapy may improve survival.
Retrospective study to evaluate the outcome of patients with transformed follicular lymphoma (tFL) treated with rituximab-containing chemotherapy and consolidation. Patients diagnosed with tFL from 2003 to 2013 treated with consolidation therapy with last follow-up in December 2015 were identified from the institutional lymphoma database and included in this study. Data collected included age, gender, stage, interval to tFL diagnosis, R-IPI score, histological diagnosis and therapy. The treatment algorithm used was stratified for age, performance status (PS) and sibling donor availability using R-chemotherapy induction followed by consolidation with allogeneic stem cell transplant (SCT), autologous SCT, Zevalin or rituximab maintenance (RM). Patients with B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma (BCL-U), with FISH-proven t(14;18) and t(8;14) and their variants were excluded. Four hundred patients were diagnosed with FL of whom 26 (7%) developed histologically proven tFL. The group was predominantly male (73%) with a median age at transformation of 53 (range 27-72) years and 85% presented with stage III/IV disease. Thirteen (50%) patients presented with de novo tFL and the remainder had previously diagnosed FL, with a median time to transformation of 5.7 (range 1-15) years. The median follow-up time from tFL diagnosis to December 2015 is 8 (range 4-14) years. All patients received immuno-chemotherapy achieving an overall response rate (ORR) of 100%. Fourteen (54%), patients were transplant eligible and based on donor availability, six had an auto-SCT only, five had an allo-SCT only and three had a matched unrelated allo-SCT for a post-auto-SCT relapse. The 12 patients (46%) who were not transplant eligible were consolidated with rituximab maintenance (RM) in nine (35%) and Zevalin in three (11%) cases. The overall survival (OS) and progression-free survival (PFS) for the series at 5 years were, 92 and 73%, respectively. This consecutively treated series of 26 patients with tFL have had a better outcome than expected which may be due to the use of rituximab-chemotherapy and a consolidation strategy based on age, PS and availability of a sibling donor.


ZmEREB92 interacts with ZmMYC2 to activate maize terpenoid phytoalexin biosynthesis upon Fusarium graminearum infection through jasmonic acid/ethylene signaling.
Maize (Zea mays) terpenoid phytoalexins (MTPs) induced by multiple fungi display extensive antimicrobial activities, yet how maize precisely regulates MTP accumulation upon pathogen infection remains elusive. In this study, pretreatment with jasmonic acid (JA)/ethylene (ET)-related inhibitors significantly reduced Fusarium graminearum-induced MTP accumulation and resulted in enhanced susceptibility to F. graminearum, indicating the involvement of JA/ET in MTP regulatory network. ZmEREB92 positively regulated MTP biosynthetic gene (MBG) expression by correlation analysis. Knockout of ZmEREB92 significantly compromised maize resistance to F. graminearum with delayed induction of MBGs and attenuated MTP accumulation. The activation of ZmEREB92 on MBGs is dependent on the interaction with ZmMYC2, which directly binds to MBG promoters. ZmJAZ14 interacts both with ZmEREB92 and with ZmMYC2 in a competitive manner to negatively regulate MBG expression. Altogether, our findings illustrate the regulatory mechanism for JA/ET-mediated MTP accumulation upon F. graminearum infection with the involvement of ZmEREB92, ZmMYC2, and ZmJAZ14, which provides new insights into maize disease responses.


[Determination of plasma ethambutol with liquid chromatography and ultraviolet spectrophotometry].
The method presented here is based on the ability of ethambutol to give chelates with divalent cationic metals. With copper salts, the chelate presents a characteristic ultraviolet absorbance at 270 nm, making it possible to titrate ethambutol extracted from plasma with chloroform in alkaline medium. The column which was used contained silica (LiChrosorb Si 60, 5 microns) and the mobile phase was a mixture of equal parts of water and acetonitrile, containing copper sulphate and ammonia. The internal standard was a lower homologue of ethambutol with the same chelating ability. The detection limit was 0.15 mg/l. No interference with other antitubercular agents was observed.


Alzheimer's disease and other dementing conditions.
Dementia is a common and growing problem, with 20% of those over 80 years of age suffering from this disorder. The prospect of more effective treatments has caused an increasing demand for a more accurate and earlier diagnosis of different dementia syndromes. Neuroimaging techniques may have an important role in the clinical evaluation of dementia for early diagnosis, differential diagnosis and may help in the prediction of conversion to dementia in individuals at a higher risk of developing the disorder. Moreover, new MRI techniques might not only further broaden our understanding of the pathophysiology but also accelerate treatment discovery. This review will focus on the use of conventional and non-conventional MRI techniques to investigate dementias.


Disposable, sheathed, flexible sigmoidoscopy: a prospective, multicenter, randomized trial. The Disposable Endoscope Study Group.
A new fiberoptic sigmoidoscopic system has been developed that utilizes a disposable sheath to cover and protect all working surfaces of the endoscope from contamination. The reusable part of the endoscope has no air, water, or suction/biopsy channels. These are incorporated in the disposable sheath, which is easily removed after use to provide each patient with a contamination-free endoscope. A prospective, randomized, controlled trial was performed to compare the disposable, sheathed, flexible sigmoidoscope with standard sigmoidoscopes. Clinical evaluations of the new sigmoidoscope system were performed at 15 facilities. Visual analog rating scales were used to record evaluations of endoscope performance and reprocessing by endoscopists and reprocessing personnel. The time to perform procedures, depth of insertion, and total instrument downtime were also recorded. One hundred forty-three procedures (70 standard, 73 sheathed) were performed. No significant difference was found for overall depth of insertion (50 versus 48 cm), although fewer sheathed endoscopes reached to 60 cm than did standard endoscopes (51% versus 30%). The sheathed system had a slightly longer mean procedure time than the standard (5.6 versus 6.7 minutes), but a significantly shortened overall downtime (32.8 vs 8.1 minutes). The standard system was preferred by the endoscopists. Reprocessing personnel preferred the disposable system. The disposable sigmoidoscope system has important advantages of decreased instrument turn-around time and potentially increased staff and patient safety, and future models should be improved to meet physicians' concerns.


Molecular characterization of Staphylococcus aureus isolates causing skin and soft tissue infections in patients from Malakand, Pakistan.
Comparatively few studies have been published describing Staphylococcus aureus/MRSA epidemiology in Central Asia including Pakistan. Here, we report the genotyping of Staphylococcus aureus strains (that include both methicillin-susceptible and methicillin-resistant Staphylococcus aureus) from community- and hospital-acquired skin and soft-tissue infections in a tertiary care hospital in the Malakand district of the Khyber Pakhtunkhwa Province of Pakistan. Forty-five isolates of Staphylococcus aureus were characterized by microarray hybridization. Twenty isolates (44 %) were MRSA, whereas 22 (49 %) were PVL-positive. Fourteen isolates (31 %) harboured both mecA and PVL genes. The dominant clones were CC121-MSSA (n = 15, 33 %) and the PVL-positive "Bengal Bay Clone" (ST772-MRSA-V; n = 13, 29 %). The PVL-positive CC8-MRSA-IV strain "USA300" was found once. The pandemic ST239-MRSA-III strain was absent, although it has previously been observed in Pakistan. These observations require a re-assessment of schemes for initial antibiotic therapy to cover MRSA and they emphasise the need for a rapid and non-molecular test for PVL.


Endoscopic intracranial surgery enhanced by electromagnetic-guided neuronavigation in children.
Navigated intracranial endoscopy with conventional technique usually requires sharp head fixation. In children, especially in those younger than 1 year of age and in older children with thin skulls due to chronic hydrocephalus, sharp head fixation is not possible. Here, we studied the feasibility, safety, and accuracy of electromagnetic (EM)-navigated endoscopy in a series of children, obviating the need of sharp head fixation. Seventeen children (ten boys, seven girls) between 12 days and 16.8 years (mean age 4.3 years; median 14 months) underwent EM-navigated intracranial endoscopic surgery based on 3D MR imaging of the head. Inclusion criteria for the study were intraventricular cysts, arachnoid cysts, aqueduct stenosis for endoscopic third ventriculostomy (ETV) with distorted ventricular anatomy, the need of biopsy in intraventricular tumors, and multiloculated hydrocephalus. A total of 22 endoscopic procedures were performed. Patients were registered for navigation by surface rendering in the supine position. After confirming accuracy, they were repositioned for endoscopic surgery with the head fixed slightly on a horseshoe headholder. EM navigation was performed using a flexible stylet introduced into the working channel of a rigid endoscope. Neuronavigation accuracy was checked for deviations measured in millimeters on screenshots after the referencing procedure and during surgery in the coronal (z = vertical), axial (x = mediolateral), and sagittal (y = anteroposterior) planes. EM-navigated endoscopy was feasible and safe. In all 17 patients, the aim of endoscopic surgery was achieved, except in one case in which a hemorrhage occurred, blurring visibility, and we proceeded with open surgery without complications for the patient. Navigation accuracy for extracranial markers such as the tragus, bregma, and nasion ranged between 1 and 2.5 mm. Accuracy for fixed anatomical structures like the optic nerve or the carotid artery varied between 2 and 4 mm, while there was a broader variance of accuracy at the target point of the cyst itself ranging between 2 and 9 mm. EM-navigated endoscopy in children is a safe and useful technique enhancing endoscopic intracranial surgery and obviating the need of sharp head fixation. It is a good alternative to the common opto-electric navigation system in this age group.


Outcomes of Patients Undergoing Interfacility Extracorporeal Membrane Oxygenation Transfer Based on Cannulation Location and Mode of Transport.
As the use of extracorporeal membrane oxygenation (ECMO) expands, so has the need for interfacility transfer to ECMO centers. However, the impact of these transfers has not been fully studied. This study evaluates complications and inhospital mortality in adult patients treated with venovenous (V-V) ECMO based on institutional location of cannulation and mode of transport. Retrospective cohort study. Large midwestern ECMO center. Adult patients receiving VV-ECMO. Need for transfer to ECMO center following VV-ECMO cannulation. The study included 102 adult patients, 57% of which were cannulated at an outside institution prior to transfer. Of these, 60% were transported by ground, and the remainder were transported by air. Risk-adjusted logistic regression did not reveal any significant increase in odds for any complication or inhospital mortality between the groups based on location of cannulation or mode of transport. This study supports the practice of interfacility ECMO transfer with no difference in outcomes or inhospital mortality based on institutional location of cannulation or mode of transport.


Alterations in serum electrolytes, antioxidative enzymes and haematological parameters of Labeo rohita on short-term exposure to sublethal dose of nitrite.
An experiment was conducted to study the effects of short-term exposure to sublethal levels of nitrite on electrolyte regulation, antioxidative enzymes and haematological parameters in Labeo rohita juveniles. The fishes were exposed to graded levels of nitrite (0-15 mg l(-1)) for different duration (0, 12, 24, 48 and 96 h). The 96-h LC(50) value for L. rohita (avg. wt, 66.5 ± 0.5 g) was found to be 11.28 mg l(-1). Activities of antioxidative enzymes (catalase and superoxide dismutase), acetylcholine esterase (AChE) and methaemoglobin reductase, serum electrolytes (sodium, potassium and chloride), haematological parameters and blood glucose level significantly varied (P < 0.05) in a dose-dependent manner. With increasing nitrite concentration and exposure period, a progressive reduction in the total erythrocyte count and haemoglobin were observed. With increase in nitrite concentration, a significant (P < 0.05) increase in activities was evidenced in catalase and superoxide dismutase in liver as well as gill, methaemoglobin reductase in blood, while progressive decline in AChE activity in brain was recorded. The serum sodium and chloride content showed a progressive decline, while potassium showed an increasing trend upon increase in nitrite concentration. The serum K(+) and Cl(-) after 96-h exposure demonstrated a linear relationship (Y = 0.221x + 2.542, R (2) = 0.938, P < 0.01 and Y = -5.760x + 129.5, R (2) = 0.952, P < 0.01, respectively) with nitrite concentrations. This study revealed that nitrite exposure causes alteration in all measured tissue enzymes, serum electrolytes and haematological parameters.


Bonding strengths to porcelain: An in vitro study of ultrasonic and conventional tooth preparation and etching.
To compare the bond strength of porcelain to enamel and dentin preparations finished with either ultrasonic instruments or diamond burs, with or without acid etching. A total of 140 extracted bovine incisor teeth were divided into two groups, enamel and dentin. A split tooth model was employed: each tooth having a randomly allocated combination of diamond burs, ultrasonic instrument, etching, and no etching treatments on their labial surface. Lithium disilicate glass ceramic specimens were bonded to the prepared surfaces and tensile testing was carried out. Force was applied to failure, and linear mixed models were used to analyze the data. Etching increased the bond strength of the dentin samples by 7.63 MPa (P < 0.001). When bonding to dentin, ultrasonic instrument preparation produced a 2.88 MPa greater bond strength compared to burs (P < 0.001). Ultrasonic preparation produced greater bond strengths compared to rotary instruments. Etching improved the bond strength of all preparations, with enamel having consistently greater bonding values than dentin.


Supramaximal Resection for Glioblastoma: Redefining the Extent of Resection Criteria and Its Impact on Survival.
Glioblastomas (GBMs) are the most common and aggressive primary brain tumors, and despite advances in treatment, prognosis remains poor. The extent of resection has been widely recognized as a key factor affecting survival outcomes in GBM patients. The surgical principle of "maximal safe resection" has been widely applied to balance tumor removal and neurological function preservation. Historically, T1-contrast enhanced (T1CE) extent of resection has been the focus of research; however, the "supramaximal resection" concept has emerged, advocating for even greater tumor resection while maintaining neurological function. Recent studies have demonstrated potential survival benefits associated with resection beyond T1CE extent in GBMs. This review explores the developing consensus and newly established criteria for "supramaximal resection" in GBMs, with a focus on T2-extent of resection. Systematic reviews and meta-analyses on supramaximal resection are summarized, and the Response Assessment in Neuro-Oncology (RANO) resect group classification for extent of resection is introduced. The evolving understanding of the role of supramaximal resection in GBMs may lead to improved patient outcomes and more objective criteria for evaluating the extent of tumor resection.


Type 1 and type 2 cervical carcinomas: some cervical cancers are more difficult to prevent with screening.
Although the Papanicolaou (Pap) smear is medical history's most successful cancer screening test, some cervical cancers are more difficult to prevent with screening than others. Cervical cancers that are difficult to prevent are seen disproportionately among interval cancers arising in previously screened women and in Pap test litigation. These include (i) rapidly progressing cervical cancers; (ii) cervical cancers in younger women; (iii) glandular cervical cancers; and (iv) cervical cancers in elderly women. Screening protocols have generally been designed to optimize prevention of slower-growing cervical squamous carcinomas in middle-aged women. To focus further attention on the heterogeneous screening challenges posed by different cervical cancers, we designate the more screening preventable majority as type 1 cervical cancers and the more difficult to prevent minority as type 2 cervical cancers. We review available data on why some cervical cancers are more difficult to prevent with screening and newer methods that may improve prevention.


Addition of lidocaine to bupivacaine for spinal anaesthesia compared with bupivacaine spinal anaesthesia and local infiltration anaesthesia.
Two spinal anaesthesia techniques were compared with local infiltration anaesthesia (LIA) to test the hypothesis that the addition of lidocaine to bupivacaine would decrease the spinal block's duration and provide shorter recovery to discharge. Ninety-three patients undergoing outpatient herniorrhaphy were randomised into three groups. Spinal anaesthesia: the BL Group (bupivacaine-lidocaine) received 2 ml hyperbaric bupivacaine (10 mg) + 0.6 ml 1% lidocaine (6 mg), the BS Group (bupivacaine-saline) received 2 ml hyperbaric bupivacaine (10 mg) + 0.6 ml saline. LIA: the LIA group received plain bupivacaine + lidocaine. Resolution of the nerve blocks were compared between spinal anaesthesia groups, and post-operative pain scores, analgesic requirements, post-anaesthesia care unit (PACU) time, and discharge time were compared among all groups. Spinal block resolved faster in the BL group vs. the BS group: 194.8 [standard deviation (SD) 29.2] min vs. 236.8 (SD 36.5) min (P = 0.000). PACU and discharge time were shortest in the LIA group [PACU time: 108.7 (SD 27.6) min vs. 113.0 (SD 39.4) min and 151.9 (SD 43.7) min in the BL and BS groups (P = 0.000), and discharge time 108.5 (SD 29.5) min vs. 145.8 (SD 37.3) min and 177.1 (SD 32.0) min in the BL and BS groups, respectively (P = 0.000)]. Pain scores and analgesic consumption were lower, with the time to first analgesic intake being longer in the LIA group. Addition of lidocaine to bupivacaine reduced the duration of the spinal block and was associated with shorter recovery times. However, LIA provided the fastest recovery to discharge after outpatient inguinal herniorrhaphy.


The Practical Use of White Cell Inflammatory Biomarkers in Prediction of Postoperative Delirium after Cardiac Surgery.
: Introduction: Postoperative delirium (POD) is associated with unfavorable outcomes. It may result from neuroinflammation and oxidative stress. The aim of this study was to evaluate the role of routinely available inflammatory markers derived from white blood cell count (WBC), for prognostic value in diagnosing delirium after cardiac surgery. We performed an analysis of data collected from patients undergoing planned coronary artery bypass grafting (CABG). Differential WBC and CRP concentration were evaluated preoperatively (T0) and postoperatively at day 1 (T1), 3 (T3), 5 (T5) after CABG. Differences in neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and platelet-to-WBC ratio (PWR) between patients with (Del+) and without delirium (Del-) were evaluated. Patients were screened using CAM-ICU. We included 968 patients in the study. Incidence of delirium was 13.3%. In the group with POD, the majority of patients were men (87/129, 67.44%), and the mean age was 72 years. Preoperative WBC (8.21 ± 3.04 G/l vs. 7.55 ± 1.86 G/l, p = 0.029) were higher and mean platelet count was lower (217.7 ± 69.07 G/l vs. 227.44 ± 59.31 G/l, p = 0.031) in patients with POD. Lower pre-operative PLR values (109.87 ± 46.38 vs. 120.36 ± 52.98, p = 0.026) and PWR values (27.69 7.50 vs. 31.32 9.88 p < 0.001) were found in patients with POD. Association was strongest for PWR and remained significant at T1 (p < 0.001), T3 (p < 0.001) and T5 (p < 0.001). Basing on coefficients of logistic regression a model for optimal prediction of POD was calculated: CARDEL Index = 0.108 × Age + 0.341 × HBA1C - 0.049 × PWR with AUC of 0.742 (p < 0.001). The results of this study show that lower pre-operative levels of PLR and PWR were associated with POD after cardiac surgery. Pre-operative PWR showed strongest correlation with POD and may be a potential new biomarker associated with postoperative delirium. CARDEL prognosis index composed of age, HbA1c and PWR is good at predicting development of delirium after CABG.


[The abdominal brain: neuroanatomic perspectives for the abdominal surgeon].
The "abdominal brain" does not only consist of a separate enteric nervous system but also of bidirectional connections to the autonomous nerve system with parasympathicus und sympathicus as well as brain and spinal cord. Novel studies have shown that these connections can quickly transfer information on the ingested nutrients to the brain to conduct the feeling of hunger and more complex behaviour, such as "reward-related learning". However, even emotional experience, in particular, stress, has a strong impact onto the gastrointestinal system. The immune system, motility and barrier function of the gastrointestinal tract are modulated by the intestinal microbiota. Local bacteria may directly influence neuronal communication by released metabolic products and neuropeptides as well as may control inflammatory factors. Intensive research over the last 10 years was able to provide evidence that intestinal microbiota may affect emotional and cognitive aspects of our behaviour and, thus, it might be in the focus of numerous neuropsychiatric diseases, such as depressions and anxiety disorders.The presented review is to provide a short summary of the I): anatomic basics of the so-called gut-brain axis and II): modi of the bidirectional regulation. Through indirect connections to the limbic system, gut-brain axis can substantially influence stress and anxiety but also the pain processing. In addition, the role of microbiota is outlined and future paths are shown, e.g., how the (microbiota-)gut-brain axis may alter emotional experience, pain processing and intestinal function. Such associations are relevant for further development of visceral medicine, and, thus, also for the abdominal surgeon to derive future treatment concepts with interdisciplinary orientation.


Weil's disease in a patient with chronic viral hepatitis and history of alcohol abuse.
Clinical and laboratory diagnosis of severe leptospirosis (Weil's disease) may be difficult when other pathological processes that may cause similar clinical syndromes or affect immune response to infections coexist. In addition, the optimal management of the disease remains to be defined. We report on a case of Weil's disease, in which concurrent chronic hepatitis B virus infection and alcohol abuse caused diagnostic and therapeutic difficulties.


Novel functions of B cells.
T cells clearly help B cells to produce antibodies and acquire memory. Recently, B cells were found to support some T-cell responses through antigen presentation, and perhaps more importantly, through the generation of diverse T cells and lymphoid organogenesis. These new findings show that the development and function of T cells depend on B cells independently of specific antibody production.