Psychiatric conditions and general practitioner attendance prior to HPV vaccination and the risk of referral to a specialized hospital setting because of suspected adverse events following HPV vaccination: a register-based, matched case-control study.
No association between human papilloma virus (HPV) vaccination and numerous diseases has been found. Still, a large number of Danish women are reporting suspected adverse events. Other factors may play a role, and the aim of this study is to examine the association between psychiatric conditions, general practitioner (GP) attendance and indicators of psychological symptoms prior to HPV vaccination and the risk of referral to an HPV center following vaccination. Register-based, matched case-control study. Cases were identified from five Danish, regional HPV centers, and health data for cases and controls were obtained from national registries. Cases were defined as women referred to an HPV center between January 1, 2015 and December 31, 2015 (n=1,496). Each case was matched with five controls on age, region and time of first vaccine registration. The total study population consisted of 8,976 women. Overall, women above 18 years who had been referred to an HPV center were more likely to have used psychiatric medication (odds ratio [OR]: 1.88 [95% CI 1.48-2.40]) or to have been hospitalized because of a psychiatric disorder within 5 years prior to the first vaccine registration (OR: 2.13 [95% CI 1.59-2.86]). Specifically, referred women were more likely to have used antipsychotics, antidepressants, attention deficit hyperactivity disorder (ADHD) medication or anxiolytics, and to have been hospitalized for affective disorders or anxiety, but not to have been hospitalized for schizoid, ADHD or eating disorders. In addition, they were more likely to have had talk therapy or psychometric test performed prior to vaccination (OR: 1.72 [95% CI 0.1.35-2.18] and OR: 1.67 [95% CI 1.30-2.13], respectively). Referred women of all ages had higher use of GP before vaccination. Population attributable fraction analyses indicated that psychiatric medication, hospitalization due to a psychiatric disorder and use of talk therapy, or psychometric test "explained" 13%, 10%, 12% and 11% of the referrals, respectively. Results did not change substantially when adjusted for potential confounders. Women referred to HPV centers because of suspected adverse events after vaccination more often had preexisting psychiatric conditions, psychological symptoms or frequent GP attendance prior to HPV vaccination.


Association between electrocardiographic and echocardiographic atrial abnormalities and prognosis in cryptogenic stroke.
The role of atrial fibrillation in cryptogenic stroke (CS) is well known. However, the usefulness of left atrial (LA) electrical and morphological abnormalities to identify more disabling strokes in sinus rhythm patients is less studied. We evaluated the association between electrocardiographic P-wave abnormalities and echocardiographic LA measures with neurological disability in patients with cryptogenic stroke. In a retrospective cohort, we included all consecutive hospitalized patients with cryptogenic stroke. Patients were classified according to modified Rankin scale at hospital discharge and at 3 months. LA abnormalities were identified by electrocardiographic (ECG) P-wave, axis and LA enlargement criteria, and by bidimensional echocardiograph through left atrial diameter and volume index. Among the 143 patients with CS (63.4 ± 14.2 years, 53% women), 70 patients were classified as non-disabling stroke (Rankin score < 2) and 73 patients as disabling stroke (Rankin score ≥ 2) at hospital discharge. On echocardiogram, more patients with disabling stroke presented with enlarged LA volume index (48% vs. 25%; p = 0.01). This difference remained significant after adjustment for age, gender, CHA2DS2-VASc and NIHSS scores (p = 0.02) and even when the LA volume index was analyzed as a continuous variable (p = 0.055). Also, enlarged LA volume index was more prevalent (52% vs. 25%; p = 0.03) among those with disabling stroke at 3 months after hospital discharge. Among ECG criteria, only the LA enlargement assessed by downward deflection was more prevalent in disabling stroke. Our study demonstrated an association between left atrial enlargement, assessed by downward deflection from ECG and volume index from echocardiogram, and more disabling cryptogenic strokes. This information could help to identify patients with poorer prognosis, or a subgroup where atrial cardiopathy may play a role in cardioembolic pathway.


Determination of urinary triclosan by stir bar sorptive extraction and thermal desorption-gas chromatography-mass spectrometry.
We have developed an analytical method for the determination of urinary 5-chloro-2-(2,4-dichlorophenoxy)phenol (triclosan), which utilizes stir bar sorptive extraction (SBSE) and thermal desorption (TD)-gas chromatography-mass spectrometry (GC-MS). Human urine sample is de-conjugated by treatment with beta-glucuronidase and sulfatase. A stir bar coated with polydimethylsiloxane (PDMS) is added to the urine sample in a vial and the sample is stirred for 60 min at room temperature (25 degrees C). Then, the PDMS stir bar is subjected to TD-GC-MS. The detection limit of triclosan is 0.05 ng mL(-1). The method shows linearity over the calibration range (0.1-10 ng mL(-1)) and the correlation coefficient (r) is higher than 0.993 for triclosan standard solution. The average recoveries of triclosan in human urine sample are 102.8-113.1% (RSD: 2.4-6.7%). This simple, sensitive, and selective analytical method may be used in the determination of trace amounts of triclosan in human urine samples.


Allyship for Diversity, Equity, and Inclusion in Hand Surgery.
This article endeavors to be a resource to those individuals interested in becoming an ally or educating potential allies in the field of Hand Surgery. The definitions of allyship, its history, and its expected benefits are considered. The qualities of a good ally are enumerated, and approaches to becoming a better ally are described. The authors provide personal experience with impactful allies and describe strategies and resources on a local and national level. The authors conclude with "Bigger Questions": those issues that seem essential to have allyship succeed in expanding diversity, equity, and inclusion in the specialty.


Oroxylin A reversed Fibronectin-induced glioma insensitivity to Temozolomide by suppressing IP3R1/AKT/β-catenin pathway.
Cell adhesion mediated-drug resistance (CAM-DR) is one of main reasons for. the limitation to chemotherapy, but the underlying mechanism remains unclear in glioma. In this study, we investigated the mechanism of CAM-DR induced by Fibronectin (Fn). Besides, we studied the reversal effect of Oroxylin A, a natural flavonoid extracted from Scutellaria radix, on Temozolomide (TMZ) insensitivity of glioma cells. Human Fn protein was used to mimic cell adhesion model and investigate its effect on the insensitivity of glioma cells to TMZ. Moreover, Oroxylin A was studied regarding its reversal effect on TMZ insensitivity of glioma via multiple molecular biological methods such as MTT, cell apoptosis assay, siRNA transfection, western blot, immunofluorescence assay. Fn could decrease the apoptosis-inducing effect of TMZ and led to the CAM-DR in glioma cells. Further studies showed that up-regulations of IP3R1 and intracellular Ca2+ level induced the activation of AKT kinase which increased the phosphorylation of GSK-3β and subsequently caused the entry of β-catenin into the nucleus. Knocking down IP3R1 significantly improved the sensitivity of glioma cells to TMZ. Meanwhile, after treatment with low-toxic concentration of Oroxylin A, the apoptosis induced by TMZ under Fn condition increased dramatically. Furthermore, our results revealed that Oroxylin A markedly inhibited the expression of IP3R1 and the activation of AKT/β-catenin pathway. Oroxylin A could reverse the insensitivity of TMZ via suppressing IP3R1/AKT/β-catenin pathway and it might be helpful for enhancing the anti-cancer effect of TMZ in glioma.


Effects of body position on intracranial pressure and cerebral perfusion in patients with large hemispheric stroke.
The purpose of this study was to prospectively evaluate the effects of body position in patients with large supratentorial stroke. We performed 43 monitoring sessions in 18 patients with acute complete or subtotal middle cerebral artery (MCA) territory stroke. Intracranial pressure (ICP) was monitored with a parenchymal probe. Mean arterial blood pressure, ICP, and MCA peak mean flow velocity (VmMCA) were continuously recorded. Patients with acute ICP crises were excluded. After baseline values at a 0 degree supine position were attained, the backrest was elevated in 2 steps of 5 minutes each to 15 degrees and 30 degrees and then returned to 0 degree. Baseline mean arterial pressure was 90.0+/-1.6 mm Hg and fell to 82.7+/-1.7 mm Hg at 15 degrees and 76.1+/-1.6 mm Hg at 30 degrees backrest elevation (P<0.0001). ICP decreased from 13.0+/-0.9 to 12.0+/-0.9 mm Hg at 15 degrees and 11.4+/-0.9 mm Hg at 30 degrees backrest elevation (P<0.0001). As a result, cerebral perfusion pressure decreased from a baseline value of 77.0+/-1.8 to 70.0+/-1.8 mm Hg at 15 degrees and 64.7+/-1.7 mm Hg at 30 degrees backrest elevation (P<0.0001). VmMCA was already higher on the affected side during baseline measurements. VmMCA decreased from 72.8+/-11.3 cm/s at 0 degree to 67.2+/-9.7 cm/s at 15 degrees and 61.2+/-8.9 cm/s at 30 degrees on the affected and from 49.9+/-3.7 cm/s at 0 degree to 47.7+/-3.6 cm/s at 15 degrees and 46.2+/-2.2 cm/s at 30 degrees on the contralateral side (P<0.0001). In patients with large hemispheric stroke without an acute ICP crisis, cerebral perfusion pressure was maximal in the horizontal position although ICP was usually at its highest point. If adequate cerebral perfusion pressure is considered more desirable than the absolute level of ICP, the horizontal position is optimal for these patients.


Associated and Mediating Variables Related to Job Satisfaction among Professionals from Mental Health Teams.
Using a structural analysis, this study examines the relationship between job satisfaction among 315 mental health professionals from the province of Quebec (Canada) and a wide range of variables related to provider characteristics, team characteristics, processes, and emergent states, and organizational culture. We used the Job Satisfaction Survey to assess job satisfaction. Our conceptual framework integrated numerous independent variables adapted from the input-mediator-output-input (IMOI) model and the Integrated Team Effectiveness Model (ITEM). The structural equation model predicted 47% of the variance of job satisfaction. Job satisfaction was associated with eight variables: strong team support, participation in the decision-making process, closer collaboration, fewer conflicts among team members, modest knowledge production (team processes), firm affective commitment, multifocal identification (emergent states) and belonging to the nursing profession (provider characteristics). Team climate had an impact on six job satisfaction variables (team support, knowledge production, conflicts, affective commitment, collaboration, and multifocal identification). Results show that team processes and emergent states were mediators between job satisfaction and team climate. To increase job satisfaction among professionals, health managers need to pursue strategies that foster a positive climate within mental health teams.


Metabolism of dihydrotestosterone to 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide is greater in the peripheral compartment than in the splanchnic compartment.
To compare the peripheral versus the splanchnic contribution to the formation of 3 alpha-diol G. Prospective study in various groups of women and men. Reproductive Endocrine service of our University Medical Center. Six normal ovulatory women, five hirsute women with polycystic ovary syndrome, and six normal men. All subjects received IV dihydrotestosterone (DHT) infusions as well as percutaneous administration of DHT. Serum was obtained at multiple time points before and after each administration of DHT. Comparison of serum levels of DHT, 3 alpha-androstanediol (3 alpha-diol), 3 alpha-diol G, and androsterone glucuronide in the three groups. Steady-state levels of DHT were similar in the three groups and were also similar after the two different routes of administration. However, ratios of 3 alpha-diol G to DHT were significantly greater after percutaneous gel than after IV administration in all three groups. This also was the case for the ratio of unconjugated serum 3 alpha-diol to DHT. Levels of androsterone glucuronide were similar with the different routes of administration. Using normal routes of administration and, in attempting to assess in vivo metabolism of DHT, our data confirm that the skin is the major site of unconjugated 3 alpha-diol and 3 alpha-diol G formation. Serum 3 alpha-diol G, therefore, appears largely to reflect skin DHT metabolism.


The relationships between physical function, nutrition, cognitive function, depression, and sleep quality for facility-dwelling older adults with dynapenia.
The growing population of older adults worldwide is associated with an extended life expectancy and an increasing proportion of older adults with dynapenia. Most research on dynapenia has involved only populations of older adults living in the community; little research has examined the effects of risk factors on sleep quality among older adults with dynapenia residing in assisted living facilities. This study examined the relationships among physical function, nutrition, cognitive function, depression, and sleep quality among older adults with dynapenia residing in assisted living facilities. In this cross-sectional study, data on physical function, nutrition, cognitive function, depression, and sleep quality was collected from 178 older adults with dynapenia residing in assisted living facilities, who were selected using purposive sampling. Descriptive statistical analysis, independent-sample t tests, chi-squared tests, and logistic regression analysis were performed using SPSS 25.0. The statistical analyses revealed correlations between sleep quality and age (t = 2.37, p < 0.05), level of education (χ2 = 3.85, p < 0.05), grip strength (t = 3.40, p < 0.01), activities of daily living (t = 4.29, p < 0.001), instrumental activities of daily living (t = 2.23, p < 0.001), calf circumference (t = 2.89, p < 0.01), Mini Nutritional Assessment scores (t = 2.29, p < 0.05), Mini Mental State Exam (MMSE) scores (t = 4.50, p < 0.001), and Geriatric Depression Scale (GDS) scores (t = - 4.20, p < 0.001). Calf circumference (OR = 0.8, 95% CI = 0.650.97, p < 0.05), GDS score (OR = 1.42, 95% CI = 1.05-1.92, p < 0.05), and MMSE score (OR = 0.85, 95% CI = 0.73-0.97, p < 0.05) were related to sleep quality among the sample population. Physical function, nutrition, cognitive function, and depression affect the sleep quality of older adults with dynapenia residing in assisted living facilities. Facility nurses must regularly assess these aspects of their patients to ensure that facility-dwelling older adults can maintain their physical function and improve their health to improve the quality of their sleep.


Prospective Analysis of Premilitary Mental Health, Somatic Symptoms, and Postdeployment Postconcussive Symptoms.
Many recent studies of service members returning from deployment have focused on the health impacts of mild traumatic brain injury (mTBI), including persistent postconcussive symptoms (PCS). However, cross-sectional study designs have made it difficult to understand the role of mental health in the etiology of persistent PCS. Participants were 3319 military personnel (primarily men [90%] of 25-34 years [54%]) who had completed health surveys at basic training and after deployment, on average, 4.6 years later. Negative binomial regression was used to assess the association of PCS with demographic covariates, premilitary mental health and somatic symptoms, combat experiences and mTBI during deployment, in addition to postdeployment mental health and non-PCS somatic symptoms. Premilitary mental health and somatic symptoms predicted PCS even when adjusting for other variables, yielding an elevated incidence rate ratio (IRR) for posttraumatic stress disorder (PTSD; IRR = 1.23, 95% confidence interval [CI] = 1.06-1.41) and somatic symptoms (mild versus minimal somatic symptoms: IRR = 1.43, 95% CI = 1.31-1.55; moderate/severe versus minimal somatic symptoms: IRR = 1.69, 95% CI = 1.43-2.06), but not for depressive symptoms. When postdeployment mental health and somatic symptom measures were added to the model, the effect of premilitary somatic symptoms remained significant. Findings point to potential etiological contributions of premilitary characteristics, particularly a tendency to experience somatic symptoms and PTSD, as well as mTBI and combat experiences, to the development of PCS. PCS were also strongly related to concurrent postdeployment mental health.


Neurotrophic control of channel properties at neuromuscular synapses of rat muscle.
1. Ectopic neuromuscular synapses formed when the fibular nerve was implanted into the proximal part of rat soleus muscle and the soleus nerve was cut. The gating properties of acetylcholine (ACh) receptor channels in the newly formed ectopic and in the denervated original end-plates were examined at various stages of ectopic synapse formation.2. At ectopic end-plates the apparent mean open time of ACh receptor channels changes during synaptic development. Channels in immature ectopic end-plates, examined 1 week after cutting the soleus nerve, have apparent mean open times of approximately 4 ms (at -70 mV, 22 degrees C), similar to those of the extrasynaptic ACh receptor channels of completely denervated fibres. The channel gating of mature ectopic end-plates, examined 3-7 weeks after nerve section, is characterized by a mean open time of approximately 1 ms and resembles that found in normal end-plates of adult fibres.3. The conversion of end-plate channel gating occurs during the second and third week of synapse formation. During this period two discrete classes of channels with different gating behaviour are present in the ectopic end-plate.4. Examination of ectopic end-plates in the electron microscope reveals that junctional folds begin to appear in the subsynaptic membrane during the period of channel conversion.5. At the denervated original end-plates of ectopically innervated fibres the apparent mean open time of ACh receptor channels remains similar to that of normally innervated end-plates. Original end-plates retain the normal synaptic class of channel for at least 42 days after denervation. At this time, most of the ACh receptors present originally in the membrane have been replaced by newly inserted receptors.6. At former end-plates of completely denervated fibres ACh activates two classes of channels, even when most of the ACh receptors originally present in the end-plate have been replaced by new receptors.7. The results show that during synapse formation a neurally controlled conversion of ACh receptor channels occurs about 2-3 weeks after establishment of the nerve muscle contact. Thereafter end-plate channel properties are independent of neural influences. These observations are consistent with a mechanism of channel conversion whereby the nerve modifies not the ACh receptor channel itself, but another constituent of the end-plate membrane which determines the gating properties of end-plate channels.


Persistent low level Epstein-Barr virus DNAemia in childhood cancer survivors.
Clinical observation of Epstein-Barr virus (EBV) status has not documented in childhood cancer survivors (CCSs) sustaining long-term remission of malignant diseases. Thus, the aim of this study was to evaluate the EBV status in children with various malignant diseases after they completed their treatments. Thirty consecutive children with various malignant diseases previously received treatment at the University of Tsukuba Hospital. Nine cases had acute lymphoblastic leukemia (ALL), 10 had solid tumors, 4 had lymphoma, 4 had CNS tumors, and 3 had acute myeloid leukemia (AML). EBV DNA in 328 whole blood samples were monitored by real-time QPCR for all cases after treatment. Clinical records and laboratory data were also reviewed. There were 6/30 (20%) cases with continuous detection of EBV DNA while there were 24/30 (80%) cases without continuous EBV DNA. EBV DNAemia was persistently observed in 4/9 (44.4%) cases with ALL and in 2/4 (50%) cases with lymphoma. Persistent EBV DNAemia can be observed for >5 years without any EBV associated symptoms or diseases. Childhood cancer survivors have persistent EBV DNAemia more frequently, which is thought to be observed in cases with ALL and lymphoma with higher tendency for >5 years after treatment. Persistent EBV DNAemia is frequent in CCSs aged 5-10 years. Any immunological alteration is speculative in a pathophysiology of persistent EBV DNAemia.


fMRI analysis of active, passive and electrically stimulated ankle dorsiflexion.
Ankle dorsiflexion (ADF) is an integral component in gait. The objective of this study was to define, using functional magnetic resonance imaging (fMRI) in healthy volunteers (n=12), the brain regions that are activated during Electrical Stimulation (ES)-induced ADF movements, and compare this to the pattern of activation occurring during active and passive ADF. Concurrent electromyography (EMG) was used to monitor the tibialis anterior muscle activity so as to allow EMG-guided fMRI analysis to be performed. Patterns of cortical and sub-cortical activation in response to active, passive and ES-induced ADF movement were identified. EMG-guided fMRI analysis was shown to improve detection and reduce inter-session variance for active and ES tasks. A significantly greater number of voxels were activated during active and ES-induced ADF compared to passive ADF in contralateral primary motor (M1), primary sensory (SI), and secondary somatosensory (SII) areas, as well as in supplementary motor area (SMA) and cingulate motor areas (CMA); bilateral dorsal and ventral premotor areas and cerebellum VI. The contrast of active greater than ES-induced ADF showed increased activation in SMA, contralateral PMdr; bilateral PMvr, dorsolateral prefrontal cortex and CMA; and ipsilateral cerebellum IV. Active ADF generated greater activation in brain areas responsible for motor planning, execution and visuomotor co-ordination. ES-induced activation was greater in bilateral SII and insula than for active ADF, hypothesised to result from increased sensory integration, but also possibly due to a nociceptive component to ES.


Transition from Pediatric to Adult Health Care in Patients with Chronic Illnesses: An Integrative Review.
A systematic review of the literature was performed to identify barriers, themes, or additional insight specific to the transitional care processes from a pediatric to an adult health care setting for patients with spina bifida.


Transferrin receptors in developing murine erythroid cells.
Techniques of cell separation were used to isolate murine erythroid cells at different stages of maturation. The number of transferrin receptors in these cell populations was assayed by measuring binding of 125I-labelled transferrin. Nearly 23 times as many receptors were found in the least mature cells, chiefly pronormoblasts, as in reticulocytes. Iron transport, determined by measurement of the rate of 59Fe uptake from 59Fe-labelled transferrin, was proportional to the number of receptors at all stages of differentiation. Electron microscope radioautographic studies of the interaction of 125I-labelled transferrin with erythroid precursor cells demonstrated that 15-33% of cell associated transferrin was intracellular in erythroid precursors.


Vascular injury triggers Krüppel-like factor 6 mobilization and cooperation with specificity protein 1 to promote endothelial activation through upregulation of the activin receptor-like kinase 1 gene.
Activin receptor-like kinase-1 (ALK1) is an endothelial transforming growth factor β receptor involved in angiogenesis. ALK1 expression is high in the embryo vasculature, becoming less detectable in the quiescent endothelium of adult stages. However, ALK1 expression becomes rapidly increased after angiogenic stimuli such as vascular injury. To characterize the molecular mechanisms underlying the regulation of ALK1 on vascular injury. Alk1 becomes strongly upregulated in endothelial (EC) and vascular smooth muscle cells of mouse femoral arteries after wire-induced endothelial denudation. In vitro denudation of monolayers of human umbilical vein ECs also leads to an increase in ALK1. Interestingly, a key factor in tissue remodeling, Krüppel-like factor 6 (KLF6) translocates to the cell nucleus during wound healing, concomitantly with an increase in the ALK1 gene transcriptional rate. KLF6 knock down in human umbilical vein ECs promotes ALK1 mRNA downregulation. Moreover, Klf6(+/-) mice have lower levels of Alk1 in their vasculature compared with their wild-type siblings. Chromatin immunoprecipitation assays show that KLF6 interacts with ALK1 promoter in ECs, and this interaction is enhanced during wound healing. We demonstrate that KLF6 is transactivating ALK1 gene, and this transactivation occurs by a synergistic cooperative mechanism with specificity protein 1. Finally, Alk1 levels in vascular smooth muscle cells are not directly upregulated in response to damage, but in response to soluble factors, such as interleukin 6, released from ECs after injury. ALK1 is upregulated in ECs during vascular injury by a synergistic cooperative mechanism between KLF6 and specificity protein 1, and in vascular smooth muscle cells by an EC-vascular smooth muscle cell paracrine communication during vascular remodeling.


Unicompartmental Oxford Meniscal knee arthroplasty.
Unicompartmental knee arthroplasty is an attractive concept, but some reports on its use are unfavorable. A meniscal bearing prosthesis has many advantages in this mode of arthroplasty. The authors present preliminary results of 25 unicompartmental knee replacements done with the Oxford Meniscal knee, with a follow-up period of 12-54 months (mean, 21 months). They discuss the scientific basis of unicompartmental knee arthroplasty, which they conclude may be the most appropriate treatment for selected cases of degenerative arthritis of the knee.


A survey on federated learning: challenges and applications.
Federated learning (FL) is a secure distributed machine learning paradigm that addresses the issue of data silos in building a joint model. Its unique distributed training mode and the advantages of security aggregation mechanism are very suitable for various practical applications with strict privacy requirements. However, with the deployment of FL mode into practical application, some bottlenecks appear in the FL training process, which affects the performance and efficiency of the FL model in practical applications. Therefore, more researchers have paid attention to the challenges of FL and sought for various effective research methods to solve these current bottlenecks. And various research achievements of FL have been made to promote the intelligent development of all application areas with privacy restriction. This paper systematically introduces the current researches in FL from five aspects: the basics knowledge of FL, privacy and security protection mechanisms in FL, communication overhead challenges and heterogeneity problems of FL. Furthermore, we make a comprehensive summary of the research in practical applications and prospect the future research directions of FL.


Chronic treatment with IL-25 increases renal M2 macrophages and reduces renal injury in obese Dahl salt-sensitive rats during the prepubescent stage.
Recently, we have reported that the early progression of proteinuria in the obese Dahl salt-sensitive (SS) leptin receptor mutant (SSLepRmutant) strain was associated with increased renal macrophage infiltration before puberty. Macrophages can be divided into two distinct phenotypes: M1 (proinflammatory) and M2 (anti-inflammatory). Moreover, previous studies have demonstrated that interleukin (IL)-25 converts resting macrophages and M1 into M2. Therefore, the present study examined whether treatment with IL-25 would reduce the early progression of renal injury in SSLepRmutant rats by increasing renal M2. We also investigated the impact of IL-25 on M2 subtypes: M2a (wound healing/anti-inflammatory), M2b (immune mediated/proinflammatory), M2c (regulatory/anti-inflammatory), and M2d (tumor associated/proangiogenic). Four-wk-old SS and SSLepRmutant rats were treated with either control (IgG) or IL-25 (1 µg/day ip every other day) for 4 wk. The kidneys from SSLepRmutant rats displayed progressive proteinuria and renal histopathology versus SS rats. IL-25 treatment had no effect on these parameters in SS rats. However, in the SSLepRmutant strain, proteinuria was markedly reduced after IL-25 treatment. Chronic treatment with IL-25 significantly decreased glomerular and tubular injury and renal fibrosis in the SSLepRmutant strain. Although the administration of IL-25 did not change total renal macrophage infiltration in both SS and SSLepRmutant rats, IL-25 increased M2a by >50% and reduced M1 by 60% in the kidneys of SSLepRmutant rats. Overall, these data indicate that IL-25 reduces the early progression of renal injury in SSLepRmutant rats by inducing M2a and suppressing M1 and suggest that IL-25 may be a therapeutic target for renal disease associated with obesity. NEW & NOTEWORTHY For the past few decades, immune cells and inflammatory cytokines have been demonstrated to play an important role in the development of renal disease. The present study provides strong evidence that interleukin-25 slows the early progression of renal injury in obese Dahl salt-sensitive rats before puberty by increasing systemic anti-inflammatory cytokines and renal M2a macrophages.


Remote monitoring of head and neck free flaps using near infrared spectroscopic tissue oximetry.
Near infrared spectroscopy (NIRS) measures tissue oximetry and perfusion of free tissue transfer with the advantage of remote wireless monitoring for free tissue transfer. It has been widely used in breast and extremity reconstruction but has had limited adoption in the head and neck. A retrospective review of head and neck microvascular reconstruction by three different surgical services over 15 months at one tertiary care hospital was performed. Demographics, flap type, monitoring technique, complications, and flap outcomes were recorded. Monitoring techniques were (1) implantable/handheld Doppler or (2) NIRS. Flap monitoring outcomes were evaluated using multivariate analysis. 119 flaps were performed by four surgeons with a success rate of 92% (109/119). Flaps were monitored with Doppler (40%) or NIRS (60%). There was no difference in flap success based on monitoring technique. An ROC analysis identified that the optimal cutoff in immediate StO2 for classifying flap success at discharge was 68%. NIRS was successfully implemented in a high-volume head and neck reconstructive practice. NIRS remote monitoring allowed for flap surveillance without requiring in-hospital presence and was able to identify both arterial and venous compromise.


Should we retransplant a patient who is non-adherent? A literature review and critical reflection.
The majority of transplant centers around the world face an ethical debate whether to retransplant a young non-adherent patient. Non-adherence to lifelong immunosuppressants presents a significant risk for graft loss, yet rates remain consistently high. Despite a number of these patients presenting for retransplantation, there is little evidence to guide professionals in their decision-making. This paper aims to provide such guidance, by systematically reviewing the existing outcome data for retransplantation in patients who are known to be non-adherent to their immunosuppressants. This review searched for original papers that addressed retransplantation of a solid organ and included quantitative data on adherence or graft function. Only one original research paper was found to meet the inclusion criteria. This paper is reviewed, and details of the protocol to determine eligibility for retransplantation are summarized. The findings are discussed within the ethical context that transplant professionals work within, and the arguments for and against retransplantation are considered. The need for effective integration of adherence management into routine practice is highlighted, with an emphasis on reliable measurement of adherence throughout the patient's life. Examples of good practice are discussed, favoring prevention over cure.


The anatomy of cavus foot deformity.
The term "cavus foot" is used to describe a spectrum of foot shapes that have in common a high arch. The components of cavus are increased pitch and varus of the hindfoot, plantar flexion of the midfoot, and varus and adduction of the forefoot. The cavus shape is associated with changes in the mechanics of the foot. It is less flexible and balanced than a neutral foot. Although one fifth to one quarter of the population has a cavus foot, there is little anatomic description in the literature. This manuscript describes the anatomy and function of cavus foot.


Tentative identification of 20(S)-protopanaxadiol metabolites in human plasma and urine using ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry.
20(S)-Protopanaxadiol (PPD), the aglycone part of 20(S)-protopanaxadiol ginsenosides, possesses antidepressant activity among many other pharmacological activities. It is currently undergoing clinical trial in China as an antidepressant. In this study, an ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass tandem mass spectrometry method was established to identify the metabolites of PPD in human plasma and urine following oral administration in phase IIa clinical trial. A total of 40 metabolites in human plasma and urine were identified using this method. Four metabolites identified were isolated from rat feces, and two of them were analyzed by NMR to elucidate the exact structures. The structures of isolated compounds were confirmed as (20S,24S)-epoxydammarane-12,23,25-triol-3-one and (20S,24S)-epoxydammarane-3,12,23,25-tetrol. Both compounds were found as metabolites in human for the first time. Upon comparing our findings with the findings of the in vitro study of PPD metabolism in human liver microsomes and human hepatocytes, metabolites with m/z 475.3783 and phase II metabolites were not found in our study whereas metabolites with m/z 505.3530, 523.3641, and 525.3788 were exclusively detected in our experiments. The metabolites identified using ultra-performance liquid chromatography coupled with triple quadrupole time-of-flight mass spectrometry in our study were mostly hydroxylated metabolites. This indicated that PPD was metabolized in human body mainly through phase I hepatic metabolism. The main metabolites are in 20,24-oxide form with multiple hydroxylation sites. Finally, the metabolic pathways of PPD in vivo (human) were proposed based on structural analysis.


Neurofilament Light Chain in Cerebrospinal Fluid and Blood as a Biomarker for Neurodegenerative Diseases: A Systematic Review and Meta-Analysis.
Neurofilament light chain (NFL) as a potential biomarker of neurodegenerative diseases has been studied in a number of studies. Thus, a comprehensive meta-analysis is warranted to assess NFL performance in neurodegenerative diseases. To assess the performance of NFL in blood and cerebrospinal fluid (CSF) as a biomarker for neurodegenerative diseases. A total of 36 studies with comparison of NFL level between individuals with neurodegenerative diseases and controls were retrieved from PubMed, Web of Science and Science Direct, and the ratio of means method and delta method based on the random-effect model were used to analyze the differentiation of NFL between patients and controls. Differentiation of CSF NFL between patients with neurodegenerative diseases and controls showed significant results. Although a few studies on blood NFL available were included in the meta-analysis, the results still showed a distinct possibility that NFL could be a potential biomarker for neurodegenerative diseases. NFL levels were increased significantly in dementias, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, and Huntington's disease. By contrast, NFL levels were not increased in Parkinson's disease (PD), although they were increased significantly in PD-related disorders (multiple system atrophy and progressive supranuclear palsy). In our study, in addition to PD, NFL was suggested to be a global diagnostic biomarker for neurodegenerative diseases. Moreover, it could be used in differential diagnosis of PD and PD-related disorders. However, it was worth noting that NFL was not appropriate for diagnosis or differential diagnosis without clinical symptoms and other auxiliary examinations.


Anti-biofilm activity of a novel nanoemulsion containing Curcuma xanthorrhiza oil.
We aimed to solubilize Curcuma xanthorrhiza oil (CXO) using nanoemulsification and evaluate its inhibitory effects against biofilm formation. The components of CXO were evaluated through high-performance liquid chromatography (HPLC) analysis. Healthy human saliva was inoculated onto hydroxyapatite discs to form microcosm biofilms for four days and treated six times with each antimicrobial agent: distilled water (DW), CXO emulsion (EM), CXO nanoemulsion (NE), and positive controls (Listerine and chlorhexidine). Biofilm fluorescence imaging was performed using quantitative light-induced fluorescence, and cell viability and dry-weight measurements were obtained. We compared the bacterial cell and extracellular polysaccharide (EPS) biovolume and thickness using confocal laser scanning microscopy (CLSM). HPLC analysis revealed that CXO was composed of approximately 47% xanthorrhizol. Compared with DW, NE exhibited significantly lower red fluorescence intensity and area (42% and 37%, p < 0.001 and p < 0.001, respectively), and reduced total and aciduric bacterial cell viability (7.3% and 3.9%, p < 0.001, p = 0.01, respectively). Furthermore, the bacterial cell and EPS biovolume and thickness in NE decreased by 40-80% compared to DW, similar to chlorhexidine. Conversely, EM showed a significant difference only in cell viability against total bacteria when compared with DW (p = 0.003), with EPS biovolume and thickness exhibiting higher values than DW. Nanoemulsification successfully solubilized CXO and demonstrated superior anti-biofilm effects compared to the emulsion form. These findings suggest the potential use of NE as a novel antimicrobial agent for preventing oral diseases.


The dermis graft: another autologous option for acute burn wound coverage.
Split-thickness skin autografts are the gold-standard in providing permanent acute wound closure in major burns. Split-thickness dermal grafts harvested from the same donor site may provide an additional autologous option for permanent acute coverage and increase the number of potential autologous donor sites. We performed 16 dermis grafts (DG) harvested from the skin of the back in 9 consecutive burn patients. A control donor site consisted of an area of adjacent back skin from which a standard split-thickness skin graft was harvested. The mean age was 63 years (range 23-79 years). The mean initial burn size was 24% TBSA (range 2-40% TBSA). The size of the 16 DG recipient wound beds ranged from 20 to 180 cm2, with mean and median sizes of 62 and 45 cm2, respectively. Dermis graft take was complete in 15/16 cases. All grafts recorded >90% epithelialisation by 4 weeks. There was no significant difference in dermis graft and control donor site healing times (p value 0.05). Dermis grafts can provide an additional autologous option for permanent coverage in acute major burn wounds without increasing donor site size or morbidity.


Intraperitoneal insemination (IPI) in couples with infertility unrelated to female organic pelvic disease.
6 couples, (4 with male subfertility, 1 with cervical mucus insufficiency, 1 with unexplained infertility), underwent direct intraperitoneal insemination of capacitated sperm in combination with induced and timed ovulation. 2 pregnancies were obtained, both of them in couples with male subfertility.


The effect of sex, season and gametogenic cycle on gonad yield, biochemical composition and quality traits of Paracentrotus lividus along the North Atlantic coast of Portugal.
Sea urchin population harvest in the North Atlantic coast of Portugal was characterized in terms of gonad yield, nutritional composition and important market-related traits, over one reproductive cycle (March 2016 to March 2017). Most of the quality attributes showed a seasonal variation strongly dependent on sea urchin sex. Maximum gonad yield (18%) was observed in March 2017. A single spawning event occurred between May and July. Gonads are rich sources of protein (12-18% WW) with low fat content (≤6% WW), that increase during the gametogenic stages of recovery and growing (November-December). Polyunsaturated fatty acids were the dominant class in both sexes (4.2-14.7 mg.g-1 WW), being preferentially accumulated in females. Total gonads carotenoid varied seasonally, with the highest level being observed in males during spawning season. Echinenone was the main pigment present in gonads, showing highest concentrations in males during spawning and gonad recovering. During the growing and early maturation period gonads were more reddish, yellowish and brighter, as well as more firm, irrespectively of the sex. Based on all seasonal changes affecting gonad yield and quality, the period between November and February seems the most suitable to harvest high quality gonads in the Atlantic coast of Portugal.


Riboflavin and ultraviolet A as adjuvant treatment against Acanthamoeba cysts.
Experimental studies have shown that the standard dose of riboflavin (R) or R + ultraviolet-A (UVA) as solo treatment are not able to exterminate Acanthamoeba cysts or even trophozoites. The purpose of this study is to determine whether the application of R + UVA can enhance the cysticidal effects of cationic antiseptic agents in vitro. The log of either polyhexamethylene biguanide or chlorhexidine minimal cysticidal concentration in solutions containing riboflavin (concentrations 0.1, 0.05 and 0.025%) plus either Acanthamoeba castellanii cysts or Acanthamoeba polyphaga cysts was determined and compared in groups treated with UVA 30 mW/cm(2) for 30 min and in control groups (with no exposure to UVA). A permutation test was used to determine the P value associated with treatment. Regardless of the riboflavin concentration and UVA treatment condition, no trophozoites were seen in plates where the cysts were previously exposed to cationic antiseptic agent concentrations ≥200 µg/mL for Acanthamoeba castellanii samples and ≥100 µg/mL for A. polyphaga samples. There was no statistical evidence that R + UVA treatment was associated with minimal cysticidal concentration (P = 0.82). R + UVA in doses up to 10 times higher than recommended for corneal crosslinking does not enhance the cysticidal effect of either polyhexamethylene biguanide or chlorhexidine in vitro.


Complications from pharmacotherapy.
The pharmacotherapy management of cancers of the nervous system has significant overlap with systemic solid cancers that may utilize similar drugs or agents. There is however a unique aspect related to central nervous system (CNS) cancers where therapies directed against a malignant process may have enhanced toxicities or toxicities unique to the CNS. In addition, many agents used to treat CNS malignancies have unique CNS toxicities that may require a specific intervention. This chapter attempts to review conventional and biologic therapies utilized for CNS malignancies and characterize expected and, if known, unique toxicities.


Inhibitory and excitatory mechanisms in the human cingulate-cortex support reinforcement learning: A functional Proton Magnetic Resonance Spectroscopy study.
The dorsal anterior cingulate cortex (dACC) is crucial for motivation, reward- and error-guided decision-making, yet its excitatory and inhibitory mechanisms remain poorly explored in humans. In particular, the balance between excitation and inhibition (E/I), demonstrated to play a role in animal studies, is difficult to measure in behaving humans. Here, we used functional magnetic-resonance-spectroscopy (1H-fMRS) to measure the brain's major inhibitory (GABA) and excitatory (Glutamate) neurotransmitters during reinforcement learning with three different conditions: high cognitive load (uncertainty); probabilistic discrimination learning; and a control null-condition. Participants learned to prefer the gain option in the discrimination phase and had no preference in the other conditions. We found increased GABA levels during the uncertainty condition, potentially reflecting recruitment of inhibitory systems during high cognitive load when trying to learn. Further, higher GABA levels during the null (baseline) condition correlated with improved discrimination learning. Finally, glutamate and GABA levels were correlated during high cognitive load. These results suggest that availability of dACC inhibitory resources enables successful learning. Our approach helps elucidate the potential contribution of the balance between excitation and inhibition to learning and motivation in behaving humans.


Serum and seminal plasma prolactin concentrations in men with normospermia, oligospermia, or azoospermia.
Semen analyses were performed and serum and seminal plasma prolactin (PRL) concentrations were determined in 165 samples from 120 men seen with their wives because of infertility. The mean (+/- standard deviation) serum and seminal plasma PRL concentrations were 6.5 +/- 3.3 and 7.5 +/- 3.1 ng/ml, respectively. The mean concentrations of PRL in serum and seminal plasma were similar in groups of men divided by sperm concentration. Seven men had an increased serum PRL concentration. Three of these 7 men had sperm concentrations less than 20 million/ml and none of these 7 men had an increased seminal plasma PRL concentration. Four men had an increased seminal plasma PRL concentration; the serum PRL concentration, sperm concentrations, and motilities were normal in all 4. No man had a decreased serum or seminal plasma PRL concentration. Increased serum PRL concentrations were found infrequently and the increase was slight (23.2 ng/ml or less). Seminal plasma PRL concentrations were related directly to sperm concentrations and motilities, relationships that were statistically significant.


Respiratory syncytial virus, pneumonia virus of mice, and influenza A virus differently affect respiratory allergy in mice.
Respiratory viral infections in early childhood may interact with the immune system and modify allergen sensitization and/or allergic manifestations. In mice, respiratory syncytial virus (RSV) infection during allergic provocation aggravates the allergic T helper (Th) 2 immune response, characterized by the production of IL-4, IL-5, and IL-13, and inflammatory infiltrates. However, it is unclear whether the RSV-enhanced respiratory allergic response is a result of non-specific virus-induced damage of the lung, or virus-specific immune responses. In the present study we investigated whether RSV, pneumonia virus of mice (PVM) and influenza A virus similarly affect the allergic response. BALB/c mice were sensitized and challenged with ovalbumin (OVA), and inoculated with virus during the challenge period. Pulmonary inflammation, lung cytokine mRNA responses, and IgE production in serum were assessed after the last OVA-challenge. Like RSV, PVM enhanced the OVA-induced pulmonary IL-4, IL-5, and IL-13 mRNA expression, which was associated with enhanced perivascular inflammation. In addition, PVM increased the influx of eosinophils in lung tissue. In contrast, influenza virus decreased the Th2 cytokine mRNA expression in the lungs. However, like PVM, influenza virus enhanced the pulmonary eosinophilic infiltration in OVA-allergic mice. The Paramyxoviruses RSV and PVM both are able to enhance the allergic Th2 cytokine response and perivascular inflammation in BALB/c mice, while the Orthomyxovirus influenza A is not.


The distribution of zinc, cadmium, lead and copper within the woodlouse Oniscus asellus (Crustacea, Isopoda).
The concentrations of zinc, cadmium, lead and copper have been determined in the hepatopancreas, hindgut and rest of the body tissues of Oniscus asellus collected from eight sites in the U.K. The hepatopancreas is by far the most important storage organ of heavy metals, particularly cadmium, and at each site, contains a mean of at least 89% of the total body load of this element. Specimens of Oniscus asellus from contaminated sites may contain concentrations of zinc, cadmium, lead and copper in the hepatopancreas of about 1%, 0.5%, 2.5% and 3% of the dry weight respectively, which are among the highest so far recorded in the soft tissues of any animal.There is a significant positive correlation between the mean relative dry weight of the hepatopancreas of Oniscus asellus and the concentrations of zinc or cadmium in leaf litter from all eight sites. It is suggested that animals from sites which are contaminated heavily with zinc or cadmium have a large hepatopancreas because this enables them to 'de-toxify' a greater amount of the metal.


Involvement of neural cell adhesion molecule signaling in glial cell line-derived neurotrophic factor-induced analgesia in a rat model of neuropathic pain.
Since neuropathic pain is resistant to conventional analgesics such as opiates and non-steroidal anti-inflammatory drugs, the development of new types of drugs for its treatment has been awaited. Several key molecules associated with nociception have been suggested as potential targets for new analgesics. Glial cell line-derived neurotrophic factor (GDNF) has a variety of functions affecting the survival and development of specified neural cell populations, mediated via transmission of intracellular signals through binding to its high-affinity receptor, GFR*1, and subsequent activation of a tyrosine receptor kinase, RET, neural cell adhesion molecule (NCAM), or other signaling molecules. GDNF also exhibits analgesic effects in rodent models of neuropathic pain, although the underlying mechanisms are still largely unknown, including the intracellular signal transduction involved. We report here that NCAM signaling plays a role in mediating the analgesic effect of GDNF in rats with chronic constrictive injury (CCI). We found that NCAM was expressed in intrinsic neurons in the spinal dorsal horn and in dorsal root ganglion neurons with small cell bodies. Reduction of NCAM expression by NCAM antisense oligodeoxynucleotide administration to CCI rats abolished the analgesic effect of GDNF without affecting RET signaling activation. An NCAM mimetic peptide, C3d, partially reduced the chronic pain induced by CCI. These findings suggest that NCAM signaling plays a critical role in the analgesic effect of GDNF and that development of new drugs activating GDNF-NCAM signaling may represent a new strategy for the relief of intractable pain.


Olivocerebellar connections in sheep studied with the retrograde transport of horseradish peroxidase.
We describe here the morphology of the inferior olive and the localization of labeled cells after HRP injections into various lobules of vermis and hemisphere of the cerebellum of the sheep. The medial part of the caudal half of the medial accessory olive projects to a medial zone in the anterior lobe, the simple lobule, and the lobules VII and VIII. The lateral part of the medial accessory olive projects to more lateral parts of these lobules with the exception of lobule VII. The group beta projects in a differential manner to the lateral parts of the lobules VII and VIII and the medial parts of the lobules IX and X. The dorsomedial cell column projects to lobules VIII, IX, and X; the connections of the dorsal cap are restricted to lobule X. Fibers from the caudal limb of the dorsal accessory olive terminate in the B zone, the simple lobule, and in lobule VIII. The rostral half of the medial accessory olive projects to lobule IX and to the hemisphere. The other projections of the accessory olives and the principal olive to the hemisphere are similar to those reported for the cat. An accessory cell group in the sheep, located between the principal and the dorsal accessory olive, has connections with the caudal vermis and the hemisphere.


Habituation of electro-dermal responses in tension-headache sufferers and non-tension-headache controls.
Ten tension headache sufferers (TH) were compared with ten anxious neurotics (AN) and ten normal subjects in terms of electrodermal responses habituation (RH). TH sufferers showed less impaired RH than AN group, the normals showed least impairment. Moreover, it was evident that phasic elevation of electrodermal responses, rather than tonic measure, was a better indicator of individual differences between TH and AN groups.


Infantile onset spinocerebellar ataxia with sensory neuropathy (IOSCA): neuropathological features.
Infantile onset spinocerebellar ataxia (IOSCA, MIM 271245) is a recessively inherited, progressive neurological disease, which we have described in 19 Finnish patients. The clinical symptoms of IOSCA include ataxia, athetosis, hypotonia, hearing deficit, ophthalmoplegia, sensory neuropathy, female hypogonadism, and epilepsy as a late manifestation. We have mapped the IOSCA locus to 10q24. In our two autopsy cases of IOSCA, the neuropathological findings were almost uniform. The cerebral hemispheres were quite well preserved, but the brain stem and the cerebellum were moderately atrophic. The most severe atrophic changes were seen in the spinal cord: in the dorsal roots, the posterior columns and the posterior spinocerebellar tracts. There was a severe neuronal loss in the dorsal nucleus (Clarke's column) of both cases and slight atrophy of the intermediolateral column in one case. The cerebellar peduncles, the inferior olives, the accessory cuneate nuclei and especially the dentate nuclei were atrophic and gliotic. The eighth cranial nerve and nucleus were atrophic. The ventral pontine nuclei and transverse fibers were slightly affected. Tegmental nuclei and tracts, especially sensory structures, were more severely affected. In mesencephalon, there was atrophy of the oculomotor nuclear complex and periaqueductal gray matter. The cerebellar cortex showed patchy atrophy. Degenerative changes were seen in dorsal root ganglia, and there was a severe axonal loss in the sural nerve. The neuropathological picture of IOSCA thus seems close to that reported in Friedreich's ataxia, another recessively inherited usually childhood-onset ataxia.


Glutathione depletion in human erythrocytes as an indicator for microsomal activation of cyclophosphamide and 3-hydroxyacetanilide.
A model system for the detection of reactive metabolites, using glutathione depletion after microsomal activation, has been described previously. We developed a battery of complementary test systems using rat liver microsomes for metabolism and aqueous glutathione solutions, human erythrocytes or hemolysate derived therefrom, as target. Reactive metabolite formation and the ability of metabolites to pass the erythrocyte membrane were tested using 3-hydroxyacetanilide (3-HAA) and cyclophosphamide (CP) as substrates. Neither unchanged 3-HAA nor CP depleted glutathione in erythrocytes or in aqueous reduced glutathione solutions (GSH solutions). Addition of fortified normal or liver microsomes from rats pretreated with phenobarbital (PB microsomes) induced a 3-HAA/CP concentration-dependent glutathione depletion in both systems. With PB microsomes, higher depletions were found. While unchanged 3-HAA did not deplete aqueous GSH solutions or glutathione in erythrocytes, a significant depletion in hemolysate was found. The results indicate that both CP and 3-HAA metabolites are able to pass through the erythrocyte membrane. While both substances can metabolically be activated by rat liver microsomes, only 3-HAA can be activated by soluble factors in erythrocytes. However, unchanged 3-HAA has no effect on GSH in erythrocytes. This might be caused by an inability of unchanged 3-HAA to enter the erythrocyte. More generally, an adequate combination of the test systems described can be used to detect (a) the reactivity of unchanged substances and their metabolites, and (b) the ability of unchanged substances and their reactive metabolites to pass through the erythrocyte membrane.


Infrared thermography fails to visualize stimulation-induced meridian-like structures: comment by Rixin Chen and Zhimai Lv and reply from Gerhard Litscher.
A comment on G. Litscher: Infrared thermography fails to visualize stimulation-induced meridian-like structures. Biomed. Eng. OnLine 2005, 4:38 (15 June 2005), with a response by the author.


Operative technique in myocardial revascularization.
This article necessarily deals exclusively with vein and artery bypass grafts. The venous autograft remains the most versatile operation and data thus far compiled verify its reliability. We advocate normotensive, normothermic perfusion and recommend the interrupted suture technique for most anastomoses. Our guidelines for IMA grafting indicate its applicability for most anterolateral wall vessels, except for unstable emergency patients and those with a large left ventricular mass. We emphasize that the technical details are far more important than the steps involved in coronary artery operations. The operative techniques described and discussed herein are deceptively simple, and direct coronary artery surgery often appears uncomplicated to the inexperienced observerer. However, one should not attempt myocardial revascularization without the benefit of high quality cinecoronary arteriograms. An organized and experienced operative team is mandatory and, above all, the procedure itself must not be an endurance contest between surgeon and patient. Expeditious revascularization produces less morbidity and better overall results.


Technical Aspects and Validation of a New Biofeedback System for Measuring Lower Limb Loading in the Dynamic Situation.
A variety of techniques for measuring lower limb loading exists, each with their own limitations. A new ambulatory biofeedback system was developed to overcome these limitations. In this study, we described the technical aspects and validated the accuracy of this system. A bench press was used to validate the system in the static situation. Ten healthy volunteers were measured by the new biofeedback system and a dual-belt instrumented treadmill to validate the system in the dynamic situation. Bench press results showed that the sensor accurately measured peak loads up to 1000 N in the static situation. In the healthy volunteers, the load curves measured by the biofeedback system were similar to the treadmill. However, the peak loads and loading rates were lower in the biofeedback system in all participants at all speeds. Advanced sensor technologies used in the new biofeedback system resulted in highly accurate measurements in the static situation. The position of the sensor and the design of the biofeedback system should be optimized to improve results in the dynamic situation.


Pathogenesis and pharmacorrection of early postresuscitation cardiac arrhythmia.
Effect of acute lethal blood loss on character and frequency of cardiac arrhythmias in postresuscitation period has been studied. Experiments were carried out on mongrel male rats resuscitated after 4- and 6-min clinical death caused by acute blood loss. Electric cardiac instability was found in early postresuscitation period. Pacemaker migration, paroxysmal ventricular tachycardia, blockades and extrasystole that lead to ventricular fibrillation were observed in 20 percent of cases. Supported by correlative analysis it has been established that the main arrhythmogenic factors are abundance of catecholamines, free fatty acids, dienic conjugates, lactate and inhibition of Ca dependent ATPase. Antiarrhythmogenic effects of antihypoxant gutimin, the beta-adrenoreceptor blocker inderal, antioxidant oxypiridin-6 were noticed after their separate administration before clinical death. The same effect of carnosine and phosphocreatine administered during resuscitation also was noticed.


Phase I and pharmacokinetic study of intraperitoneal topotecan.
To determine the maximum tolerated dose and pharmacokinetics of topotecan when administered by the intraperitoneal route. A dose-escalating Phase I trial was conducted in which fifteen % of the total dose was given as an intraperitoneal bolus in two litres of D5W and the remainder was given as a continuous intraperitoneal infusion over 24 hours. Treatments were given every 21 days. Pharmacokinetic analyses were performed at the recommended phase II dose. Seventeen patients received a total of 43 cycles at 21-day intervals. The maximum tolerated dose was 4 mg/m2 and acute dose-limiting toxicity was neutropenia. Other toxicities included leukopenia, anemia, emesis, fever, and abdominal pain. Although no objective responses were achieved, five of ten patients with ascites had a decrease in fluid accumulation with administration of intraperitoneal topotecan. The recommended phase II dose is 3 mg/m2. Pharmacokinetic analysis performed at a dose of 3 mg/m2 demonstrated that elimination from the peritoneal cavity followed second-order kinetics with k1 = 1.6 hr(-1), k2 = 0.3 hr(-1) and first and second-phase half-lives of 0.49 and 2.7 hours, respectively. Plasma pharmacokinetic behavior was best described by first-order kinetics with k = 0.5 hr(-1) and a half-life of 3.9 hours. The pharmacologic advantage, expressed as the peritoneal to plasma AUC ratio was 31.2. Intraperitoneal administration of topotecan at 3 mg/m2 results in a substantial increase in drug exposure for the peritoneal cavity without compromising systemic exposure; this may be beneficial for the treatment of patients with ovarian cancer or intraperitoneal carcinomatosis.


II. On the construction of a phylogenetic tree.
For the construction of a phylogenetic tree in algorithm is described. This, allows the correction of the original data and the proper selection, in each step of the process, of the nearest neighbours of a common ancestor.


MOXAIC: A classification of major maxillofacial wounds, concerning 310 cases.
Although classification for facial fractures have been extensively described in the literature, corresponding systems for major maxillofacial wounds (MMW) are few. We would like to present MOXAIC: a new classification system for MMW. A retrospective study of 310 patients with MMW who underwent emergency operation between January 2005 and December 2016. MMW was defined as a facial wound longer than 10 cm, which includes damage to the craniofacial bone or other important facial structures such as the carotid arteries, facial nerves, parotid gland, Stensen's duct, or the eye. All the patients were followed at least 36 months. Based on the shape of the wound, the severity, and the mechanism of injury we were able to classify the MMW into five types: O, X, A, I, C. For each wound type we then looked at the treatment required and the outcome, objectively classified as good, satisfactory, or poor, concerning anatomical correction, aesthetics, and function. + Type OCircumferential wound: 81.6% result good. + Type X-Oblique wound: only 48.1% good, despite initial multidisciplinary approach. + Type A-Transverse facial wound: 78.1% good. + Type I-Direct wound: Immediate airway management and hemorrhage control are important. 48.8% good. + Type CCut wound: 88.1% good. The above classification was named MOXAIC which is a mnemonic of 'Maxillofacial' and the five wound types: O, X, A, I, C. This classification is highly reproducible, easy to use, and allows quick treatment work up and prognosis. However, this classification requires further specialist review and study.


Biodegradable triblock copolymer of PLGA-PEG-PLGA enhances gene transfection efficiency.
A tri-block copolymer of PLGA-PEG-PLGA was used as an excipient to enhance the gene transfection efficiency of various cationic polymeric carriers. Luciferase plasmid DNA was complexed with polyethylenimine for gene transfection. Various concentrations of PLGA-PEG-PLGA copolymer up to 0.5% were added in the transfection medium to explore whether the copolymer increased the level of gene expression. Pluronic F68 was used as a control. Various polyplexes and different cell lines were used to verify the effect of the triblock copolymer on gene transfection. The cellular uptake extent of radiolabeled plasmid was quantitatively determined as a function of PLGA-PEG-PLGA concentration. PLGA-PEG-PLGA copolymer significantly enhanced gene transfection efficiency at a concentration as low as 0.25% (w/v), which was more effective than Pluronic F68 at the same concentration range. The additive effect of the triblock copolymer in the transfection medium was clearly observed for various cationic polyplexes and cell lines, although the gene expression extents largely depended on polymers and cell lines used. Five- to 10-fold increment of gene transfection levels were attained in the presence of the PLGA-PEG-PLGA tri-block copolymer. The enhanced gene transfection efficiency was attributed to the increased cellular uptake of PEI/DNA complexes in the presence of the PLGA-PEG-PLGA tri-block copolymer. Biodegradable PLGA-PEG-PLGA tri-block copolymer that facilitates the endocytic process can be used as a novel additive in non-viral gene transfection.


Intrathoracic lobe of the liver. Case report and review of the literature.
A case of a heterotopic intrathoracic lobe of the liver connected through a normal diaphragm to the main organ by a vascular and biliary pedicle is described. Eight similar cases reported in the literature are reviewed and a comparative evaluation is undertaken to elucidate the correct clinical diagnosis and the indications for operative exploration. Because the occurrence of ectopic supradiaphragmatic hepatic tissue should be considered, it is believed that the preoperative evaluation of a solid, smooth lump in the diaphragmatic region should include gallium liver scans prior to invasive procedures.


Evidence-based care in high- and low-risk groups following whiplash injury: a multi-centre inception cohort study.
Studies aimed at improving the provision of evidence-based care (EBC) for the management of acute whiplash injuries have been largely successful. However, whether EBC is broadly provided and whether delivery of EBC varies based on risk of non-recovery, is uncertain. Receiving EBC should improve recovery, though this relationship has yet to be established. Further, mitigating the effect of EBC is the relationship with the practitioner, a phenomenon poorly understood in WAD. This study aimed to determine the proportion of individuals with whiplash, at differing baseline risk levels, receiving EBC. This study also aimed to determine whether receiving EBC and the therapeutic relationship were associated with recovery at 3 months post injury. Participants with acute whiplash were recruited from public hospital emergency departments, private physiotherapy practices, and State Insurance Regulatory Authority (SIRA) databases. Participants completed questionnaires at baseline (demographics, risk of non-recovery) and 3-months (treatment received, risk identification, therapeutic relationship) post injury. Primary health care providers (HCPs) treating these participants also completed questionnaires at 3-months. Recovery was defined as neck disability index ≤4/50 and global perceived effect of ≥4/5. Two-hundred and twenty-eight people with acute whiplash, and 53 primary care practitioners were recruited. The majority of the cohort reported receiving EBC, with correct application of the Canadian C-spine rule (74%), and provision of active treatments (e.g. 89% receiving advice) high. Non-recommended (passive) treatments were also received by a large proportion of the cohort (e.g. 50% receiving massage). The therapeutic relationship was associated with higher odds of recovery, which was potentially clinically significant (OR 1.34, 95% CI 1.18-1.62). EBC was not significantly associated with recovery. Guideline-based knowledge and practice has largely been retained from previous implementation strategies. However, recommendations for routine risk identification and tailored management, and reduction in the provision of passive treatment have not. The therapeutic relationship was identified as one of several important predictors of recovery, suggesting that clinicians must develop rapport and understanding with their patients to improve the likelihood of recovery.


Phenyl-Bridged Graphitic Carbon Nitride with a Porous and Hollow Sphere Structure to Enhance Dissociation of Photogenerated Charge Carriers and Visible-Light-Driven H2 Generation.
Graphitic carbon nitride (CN) suffers from rapid recombination of photoexcited charges due to the existing highly symmetrical tri-s-triazine ring and long charge diffusion path, resulting in moderate photocatalytic activity. The bridged phenyl embedded in the CN structure was used to reduce the symmetry of the tri-s-triazine ring. In addition, the CN material was constructed with a porous and hollow sphere structure to shorten the diffusion path of charge carriers. Herein, simple thermal polymerization of a trimesic acid-doped melamine-cyanuric acid (MCA) supramolecular was employed to construct phenyl-bridged graphitic carbon nitride (Ph-CN-MCA) with a hollow sphere structure composed of porous nanosheets for visible-light catalytic H2 evolution. The porous and hollow sphere-structured Ph-CN-MCA possessed increased degree of polymerization, more negative conduction band potential, enlarged Brunauer-Emmett-Teller (BET) surface area, and shortened charge diffusion path. In addition, bridged phenyl embedded in the Ph-CN-MCA structure not only accelerated the dissociation of photogenerated carriers but also narrowed the band gap and extended the visible-light absorption. Further, the separated highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of Ph-CN-MCA facilitated the spatial dissociation of photogenerated charges, which was also confirmed by theoretical calculations. As a consequence, compared with the reference CN-MA catalyst prepared from melamine, Ph-CN-MCA showed approximately 48.42 times the photocatalytic H2 evolution under visible-light irradiation. The developed synthetic method herein highlights that phenyl-bridged graphitic carbon nitride with a porous and hollow sphere structure could provide an efficient platform to boost the dissociation of photoexcited charge carriers and photocatalytic H2 evolution.


Characterization of beta-D-xyloside-initiated glycosaminoglycan synthesized by human skin fibroblasts in the presence of tunicamycin.
Human skin fibroblasts were incubated with a fluorogenic xyloside, 4-methylumbelliferyl-beta-D-xyloside (Xyl-MU), in the presence or absence of tunicamycin. The xyloside-initiated glycosaminoglycans (GAG-MUs) were isolated from the culture medium, and their structures characterized. When the cells were incubated with Xyl-MU in the presence of 0.2 microg ml(-1) tunicamycin, the synthesis of GAG-MU was increased about three fold, compared with the control value in the absence of tunicamycin (cells exposed to Xyl-MU alone). The structures of GAG-MUs synthesized in the presence or absence of tunicamycin were compared by HPLC analysis using gel-filtration and ion-exchange columns, enzymatic digestion, and unsaturated disaccharide composition analysis. The data indicated that cells incubated with tunicamycin produced more undersulfated and shorter GAG-MUs than cells without tynicamycin. These results suggest that tunicamycin inhibits the elongation and sulfation of glycosaminoglycan (GAG) chains and that, as a result, GAG-MUs with shorter chains and undersulfated residues, but possessing a large number of GAG chains, are synthesized in the presence of tunicamycin.


Nonaccidental head injury.
Nonaccidental head injury in children (NAHI), most often due to abusive head trauma (AHT), is not uncommon and carries a high risk of mortality and morbidity. Intracranial lesions encountered are mainly subdural hematomas. Despite heterogeneous clinical presentation, symptoms are related to brain edema with intracranial hypertension and/or seizures that should prompt early diagnosis and treatment. Two main differential diagnoses are glutaric aciduria type 1 and Menkes disease, two inborn errors of metabolism that require specific diagnostic procedures and treatment. The aim of emergency treatment is to control seizures, prevent seizure recurrence, and decrease intracranial pressure. Because NAHI/AHT carries a worse prognosis than accidental head traumatism - with specific risk factors such as initial clinical status, age, aspect of initial CT scan, associated retinal hemorrhage, seizure recurrence - these children need close clinical, neurological, and radiological monitoring in neurointensive care units. It is therefore important to identify the nonaccidental origin of the injury at the earliest opportunity so that the appropriate intervention, including social evaluation and reporting suspected cases to judicial authorities, can be made to protect the child from further harm.


Household food waste conversion to biohydrogen via steam gasification over copper and nickel-loaded SBA-15 catalysts.
Household food waste (FW) was converted into biohydrogen-rich gas via steam gasification over Ni and bimetallic Ni (Cu-Ni and Co-Ni) catalysts supported on mesoporous SBA-15. The effect of catalyst method on steam gasification efficiency of each catalyst was investigated using incipient wetness impregnation, deposition precipitation, and ethylenediaminetetraacetic acid metal complex impregnation methods. H2-TPR confirmed the synergistic interaction of the dopants (Co and Cu) and Ni. Furthermore, XRD and HR-TEM revealed that the size of the Ni particle varied depending on the method of catalyst synthesis, confirming the formation of solid solutions in Co- or Cu-doped Ni/SBA-15 catalysts due to dopant insertion into the Ni. Notably, the exceptional activity of the Cu-Ni/SBA-15-EMC catalyst in FW steam gasification was attributed to the fine distribution of the concise Ni nanoparticles (9 nm), which resulted in the highest hydrogen selectivity (62 vol%), gas yield (73.6 wt%). Likewise, Cu-Ni solid solution decreased coke to 0.08 wt%.


Vitamin E succinate induces ceramide-mediated apoptosis in head and neck squamous cell carcinoma in vitro and in vivo.
Vitamin E succinate (alpha-TOS) inhibits the growth of cancer cells without unacceptable side effects. Therefore, the mechanisms associated with the anticancer action of alpha-TOS, including ceramide-mediated apoptosis, were investigated using head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. Five different human HNSCC cell lines (JHU-011, JHU-013, JHU-019, JHU-022, and JHU-029) were treated with alpha-TOS, and its effects on cell proliferation, cell cycle progression, ceramide-mediated apoptosis, and ceramide metabolism were evaluated. The anticancer effect of alpha-TOS was also examined on JHU-022 solid tumor xenograft growth in immunodeficient mice. Alpha-TOS inhibited the growth of all the HNSCC cell lines in vitro in a dose- and time-dependent manner. Thus, JHU-013 and JHU-022 cell lines were more sensitive to alpha-TOS than the other cell lines. Cellular levels of ceramide, sphingomyelinase activity, caspase-3, and p53 were elevated with increasing time of exposure to alpha-TOS. The degradation of poly(ADP-ribose) polymerase protein in JHU-022 cells treated with alpha-TOS provided evidence for apoptosis. The amounts of nuclear factor kappaB, Bcl-2, and Bcl-X(L) proteins were reduced in the cells treated with alpha-TOS for 6 hours. The levels of caspase-9, murine double minute-2, and IkappaB-alpha proteins were unchanged after alpha-TOS treatment. I.p. administration of alpha-TOS slowed tumor growth in immunodeficient mice. Alpha-TOS showed promising anticancer effects to inhibit HNSCC growth and viability in vivo and in vitro. The induction of enzymes involved in ceramide metabolism by alpha-TOS suggests that ceramide-mediated apoptosis may expand therapeutic strategies in the treatment of carcinoma.


Tricuspid and mitral regurgitation detected by color flow Doppler in the acute phase of Kawasaki disease.
Valvular lesions in the acute phase of Kawasaki disease were studied in 19 children. The patients were intensively observed by color flow Doppler every day from the day of hospitalization up to 12 days after the onset of the disease and 2 or more times a week thereafter, for up to 28 days. Mitral regurgitation (MR) was found in 9 patients (47%) and tricuspid regurgitation (TR) in 10 (53%). MRs were of transient type and confirmed from 7.5 +/- 1.6 (mean +/- standard deviation) to 13.1 +/- 6.5 days after the onset of the disease. Both types of valvular regurgitation were mild. The direction of regurgitation was from the center of valvular coaptation toward the posterior wall of the atrium. Neither valvular prolapse nor valvular deformity was noted. In patients with MR, left ventricular ejection fraction on M-mode echocardiography was significantly lower in the acute phase than in the convalescent phase of the disease (p less than 0.05). Using gallium-67 scintigram, the positive uptake of the isotope was noted in 7 (88%) of 8 patients with MR, but not found at all in 8 patients free of MR. These results suggest that MR and TR are often transient in the acute phase of Kawasaki disease and could be attributed to myocarditis.


Auditory brain stem responses in chronic alcoholic patients.
Auditory brain stem responses (ABRs) were obtained from 66 chronic alcoholic patients. Forty-one percent of the patients had abnormal ABR indicated by prolonged interwave intervals. The incidence of brain stem abnormalities was related to age, the type and number of alcoholic neurological complications, and cerebral atrophy in computerized tomographic (CT) scan. There was a progressive increase in the incidence of abnormal ABRs with age and the number of alcoholic neurological diseases. Among the neurological complications of alcoholism, patients with cerebellar degeneration had the highest incidence of abnormal ABRs (83%). There was a high correlation between cerebral atrophy in CT scan and abnormal ABRs. The data suggest that laboratory methods such as the ABR and CT scan are useful in evaluating the extent of CNS abnormalities in alcoholic patients.


Evaluation of a robotic arm-assisted endoscope to facilitate endoscopic submucosal dissection (with video).
Endoscopic submucosal dissection (ESD) is considered technically difficult and challenging using a conventional flexible endoscope, mainly due to the lack of proper countertraction to expose the submucosal dissection plane. This study aimed to evaluate the feasibility of a traction method using a dexterous robotic arm in ex vivo gastric ESD. ESD was performed in a total of 45 procedures using a portable endoscopic tool handler (PETH) (n = 30) and using the conventional method (n = 15) at various locations in the stomach. For each procedure, the performance data were recorded, including the total procedure time (minutes), incision time (minutes), dissection speed (mm2/minute), and blind dissection rate (%), to enable a comparison of the 2 ESD methods. The total procedure time was significantly shorter with PETH-ESD than in conventional ESD (23 vs 36 minutes, P = .011). This result is mainly attributed to the dissection speed, which was significantly faster, by more than 2.5 times, using the PETH (122.3 ± 76.5 vs 47.5 ± 26.9 mm2/minute, P < .001). The blind dissection rate was greatly decreased in PETH-ESD (0 vs 20%, P < .001). There was no significant difference in the incision time (6.1 ± 5.0 vs 5.5 ± 2.9 min, P = .612). The countertraction method using the PETH significantly improved the dissection speed and reduced blind dissection by enhancing direct visualization of the submucosal plane. With the advantages of multidirectional traction, fine tension control, and regrasping, this new device is expected to improve the performance of ESD and further facilitate advanced endoscopic procedures.


Serum sterols in patients with primary biliary cirrhosis and acute liver failure before and after liver transplantation.
Liver diseases modify sterol metabolism. Liver transplantation (LTX) provides a model to evaluate the impact of disease-affected liver on sterol metabolism. We studied serum sterol profiles and their relationships to other biochemical markers in consecutive cholestatic patients with acute liver failure (ALF, n=39) and end-stage primary biliary cirrhosis (PBC, n=67) before and 27d after LTX. Accordingly, we determined serum levels of sterols, bilirubin and prealbumin. Due to weak cholesterol synthesis of ALF-patients before LTX, their serum levels of cholesterol, lathosterol/cholesterol, cholestanol/cholesterol and lathosterol/campesterol were 18%-41% lower (P<0.05 for each) than in PBC, but ratios of phytosterols to cholesterol were equal. In general, non-cholesterol sterol ratios reflected bilirubin and prealbumin concentrations. Interrelation of surrogate sterols showed that homeostasis of cholesterol metabolism prevailed in lowest cholestanol tertile of ALF-patients consistently, but not in PBC. After LTX, cholesterol levels and lathosterol ratios increased in both groups and phytosterol ratios decreased (P<0.01). Cholestanol decreased profoundly in PBC, but remained 26% higher than in ALF (P<0.05). Homeostasis of cholesterol metabolism was maintained only in ALF. Metabolism of phytosterols was equal in study groups. PBC- and ALF-patients have differential patterns in their serum sterols and cholesterol metabolism.


[Fistulous atresia of the distal part of the rectum in adults].
Based on an analysis of the surgical treatment of 19 adult patients with atresia of the anal canal with a fistula into the vagina or perineum, not operated for this disease in their childhood the author has established specific indications for their treatment. The adequate choice of the method of operation with special reference to anatomical features of the developmental defect and complications resulting from its long existence is responsible for success of the treatment.


[CD4+ and CD8+ T cells in gastric mucosa in children infected with Helicobacter pylori].
To study the changes of gastric mucosal CD4(+) and CD8(+) T cells in Helicobacter pylori (Hp) infected children. Seventy nine patients with digestive tract symptoms were assessed by endoscopy, rapid urease test and histology. Forty four patients had Hp positive chronic superficial gastritis (Hp(+)CSG) and 35 patients had Hp negative chronic superficial gastritis (Hp(-)CSG). Gastric biopsy specimens were obtained from each patient. Peripheral blood samples were obtained from 33 patients (12 with Hp(+)CSG, 21 with Hp(-)CSG). Hp infection was identified by rapid urease test and histology. Hp infection was confirmed when a patient was positive for both of these tests. Four pieces of gastric antrum mucosal specimens were placed in Hank's balanced salt solution containing 1 mmol/L dithiothreitol (DTT) and 1 mmol/L ethylenediamine tetraacetic acid (EDTA). The specimens were treated with collagenase type I (120 U/ml) for three hours at 37 degrees C with agitation. The mononuclear cells were collected by removing undigested material and washed three times with RPMI 1640. Isolated gastic mononuclear cells were stained with CD3-FITC (fluorescein isothiocyanate), CD4-PE (R-phycoerthrin), CD8-PerCP (Peridinin-chlorophyll-alpha-protein) and measured by flow cytometry. Mucosal T lymphocytes were gated for the expression of CD3. Peripheral blood lymphocyte subsets were analysed by direct immunofluorescence. The percentage of isolated gastric mononuclear cells within the CD3 gate were 3.26 +/- 1.98 in Hp(-)CSG, 4.37 +/- 1.97 in Hp(+)CSG. Relative CD4(+)(%), CD8(+)(%) and CD4(+)/CD8(+) of the CD3(+) cells respectively were 23.74 +/- 10.37, 47.04 +/- 12.00, 0.52 +/- 0.23 in Hp(-)CSG group, 40.28 +/- 11.35, 27.91 +/- 8.84, 1.55 +/- 0.52 in Hp(+)CSG group. CD4(+)(%), CD4(+)/CD8(+) in Hp(+)CSG group were significantly higher than those of Hp(-)CSG group and CD8(+)(%) was lower than those of Hp(-)CSG group (P < 0.01). There were no significant differences in peripheral blood T lymphocyte subsets between the two groups. The difference of gastric T lymphocyte response between Hp(+)CSG and Hp(-)CSG in children indicated that the local cellular immune reaction may play a critical role in the pathogenesis of Hp infection.


Genetic abnormalities in biopsy-proven, adult-onset hemolytic uremic syndrome and C3 glomerulopathy.
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) have been linked to mutations in many of the proteins that are involved in alternative complement pathway activation. Age and etiology confounded, the prevalence of such mutations has been reported to be over 30 to 50% in these diseases. However, the cohorts studied included many children or individuals with a familial history of complement-related disorders and genetic tests were usually limited to exome sequencing of known causative or risk-associated genes. In this study, a retrospective adult cohort of 35 patients with biopsy-proven thrombotic microangiopathy (the largest in Canada) and 10 patients with C3 glomerulopathy was tested through an extended exome panel to identify causative defects in associated or candidate genes including those of the alternative and terminal complement pathways. A variant of unknown significance was also analyzed for pathogenicity through in vitro studies. To our surprise, the prevalence of known causative or risk-associated variants in either of these cohorts was found to be less than ~ 15% overall. However, the panel used and analyses carried out allowed to identify novel variants of potential clinical significance and a number of candidate genes. The prevalence of known genetic defects in adult-onset aHUS and C3G is thus probably much lower than 30 to 50%. Our results also point towards the importance of investigating diseases of the alternative complement pathway through extended exome panels and in vitro analyses. KEY MESSAGES: The alternative complement pathway plays a major role in the pathogenesis of hemolytic uremic syndrome and C3 glomerulopathy. Based on previous studies, both disorders have been commonly linked to variants in the various intermediates that sustain or regulate this pathway. The prevalence of such mutations in the adult-onset and sporadic forms of these diseases is probably much lower than expected based on larger series. The sporadic forms of complementopathies are likely to involve additional genes that are yet to be uncovered.


Assessing empirical research in bioethics.
Empirical research can aid ethical reflection in bioethics by identifying issues, by seeing how they are currently resolved, and by assessing the consequences of these current resolutions. This potential can be misused when the ethical issues in question are fundamentally non-consequentialist or when they are consequentialist but the empirical research fails to address the important consequences. An example of the former problem is some recent studies about bad consequences resulting from commercialized living kidney donor programs. These consequences could be avoided, but the crucial non-consequentialist ethical issues about exploitation and commercialization would still remain. Examples of the latter problem are provided by recent studies of the allocation of ICU beds and of physician deception, where important consequences were not adequately studied.


The effect of micronutrient supplementation on bioavailability, antioxidants activity, and weight gain in response to Infectious Bursal Disease vaccination in commercial broilers.
The effect of supplementing organic selenium and zinc on bioavailability, oxidative stress, weight gain in commercial broilers was studied. A total of 180-day-old chicks were divided into six groups: NSUV (Not supplemented, unvaccinated), NSV (Not supplemented, vaccinated), VS (vaccinated, supplemented selenium), VZ (vaccinated supplemented zinc), VSZ (vaccinated supplemented selenium and zinc), UVSZ (unvaccinated supplemented selenium and zinc). 1 mg/kg selenium and 60 mg/kg zinc were added to the feed of supplemented groups. The concentration of selenium (0.05 ± 0.00 mg/L) in VS and zinc (0.66 ± 0.13 mg/L) in VZ were lower on day 27 post-vaccination compared to day 10 (VS= 0.07 ± 0.01 mg/L; VZ= 1.46 ± 0.30 mg/L). Glutathione peroxidase and catalase concentrations were highest in the supplemented groups compared to unsupplemented groups on day 27 post vaccination, expressing a similar trend with the micronutrients. There was no difference (P ≥ 0.05) in the glutathione concentration between all groups except on day 27 post vaccination where SZV group was significantly higher (P=0.02) compared to the NSV group. Catalase concentration was significantly decreased in the NSV group compared to SZV (P=0.04) on day 27 post vaccination. The NSV group (1.64 ± 0.13 kg) weighed significantly lower (P=0.02) than the VSZ (2.00 ± 0.12 kg) in the fifth week, while on the sixth week, the SZV group gained the highest weight (2.04 ± 0.18 kg). The supplementation of organic selenium and zinc in broilers increased the serum micronutrients bioavailability, decreased oxidative stress, increased weight gain, thus, enhancing immunity in the broilers.


Successful treatment of mediastinal seminoma with vinblastine, bleomycin, and cis-platinum.
We report on 2 patients with extensive primary mediastinal seminoma treated with vinblastine, bleomycin, and cis-dichlorodiammine platinum who achieved complete remission. These patients are alive forty-six months and sixty-six months without evidence of recurrence of disease. These long-term survivors extend the experience reported previously in the literature. Mediastinal seminoma with extent beyond a rational field of radiation therapy can be treated successfully with chemotherapy.


Intraparenchymal Stereotaxic Delivery of rAAV and Special Considerations in Vector Handling.
Stereotaxic surgery enables precise and consistent microinjections to discrete neural nuclei. Using stereotaxic surgery to deliver viral vectors is a powerful tool that provides the ability to manipulate gene expression in specific regions, or even specific cell types in the brain. Here, we describe the proper handling and stereotaxic delivery of recombinant adeno-associated virus to various neuroanatomical structures of the rodent brain.


Brainstem neurons with descending projections to the spinal cord of two elasmobranch fishes: thornback guitarfish, Platyrhinoidis triseriata, and horn shark, Heterodontus francisci.
We studied two cartilaginous fishes and described their brainstem supraspinal projections because most nuclei in the reticular formation can be identified that way. A retrogradely transported tracer, horseradish peroxidase or Fluoro-Gold, was injected into the spinal cord of Platyrhinoidis triseriata (thornback guitarfish) or Heterodontus fransisci (horn shark). We described labeled reticular cells by their position, morpohology, somatic orientation, dendritic processes, and laterality of spinal projections. Nineteen reticular nuclei have spinal projections: reticularis (r.) dorsalis, r. ventralis pars alpha and beta, r. gigantocellularis, r. magnocellularis, r. parvocellularis, r. paragigantocellularis lateralis and dorsalis, r. pontis caudalis pars alpha and beta, r. pontis oralis pars medialis and lateralis, r. subcuneiformis, r. peduncularis pars compacta, r. subcoeruleus pars alpha, raphe obscurus, raphe pallidus, raphe magnus, and locus coeruleus. Twenty nonreticular nuclei have spinal projections: descending trigeminal, retroambiguus, solitarius, posterior octaval, descending octaval, magnocellular octaval, ruber, Edinger-Westphal, nucleus of the medial longitudinal fasciculus, interstitial nucleus of Cajal, latral mesencephalic complex, periventricularis pretectalis pars dorsalis, central pretectal, ventromedial thalamic, posterior central thalamic, posterior dorsal thalamic, the posterior tuberculum, and nuclei B, F, and J. The large number of distinct reticular nuclei with spinal projections corroborates the hypothesis that the reticular formation of elasmobranches is complexly organized into many of the same nuclei that are found in frogs, reptiles, birds, and mammals.


Quantitative NMR analysis of L-Dopa in seeds from two varieties of Mucuna pruriens.
L-Dopa, a key neurotransmitter used to treat neural disorders such as Parkinson's disease, is found in the seeds of the genus Mucuna at a sufficient concentration for possible commercial use. To develop a simple and reliable method to extract L-Dopa from M. pruriens seeds in an aqueous medium and then quantitate this compound using a 1 H qNMR method (internal standard); and also to evaluate the accuracy and reproducibility of this method with an NMR calibration curve. The extraction method of L-Dopa from M. pruriens was optimized. The quantitation with single point quantitative NMR (qNMR) and NMR calibration curve was based on the resonance properties of the main functional groups of the L-Dopa molecule, in particular the signals of the three aromatic protons, which were compared with the signal of an internal standard such as syringic acid. The accuracy (precision and trueness) and reproducibility of both NMR techniques were evaluated. The methods of single point qNMR and NMR calibration curve, applied to the seeds of two M. pruriens varieties, gave very similar L-Dopa contents: 3.0-3.2% and 3.0-3.1%, respectively. The statistical analysis confirmed the accuracy and reproducibility of this single point qNMR method (internal standard) for determining L-Dopa, as well as other commercial preparations of this species, without performing an NMR calibration curve.


Whole genomic analysis reveals atypical non-homologous off-target large structural variants induced by CRISPR-Cas9-mediated genome editing.
CRISPR-Cas9 genome editing has promising therapeutic potential for genetic diseases and cancers, but safety could be a concern. Here we use whole genomic analysis by 10x linked-read sequencing and optical genome mapping to interrogate the genome integrity after editing and in comparison to four parental cell lines. In addition to the previously reported large structural variants at on-target sites, we identify heretofore unexpected large chromosomal deletions (91.2 and 136 Kb) at atypical non-homologous off-target sites without sequence similarity to the sgRNA in two edited lines. The observed large structural variants induced by CRISPR-Cas9 editing in dividing cells may result in pathogenic consequences and thus limit the usefulness of the CRISPR-Cas9 editing system for disease modeling and gene therapy. In this work, our whole genomic analysis may provide a valuable strategy to ensure genome integrity after genomic editing to minimize the risk of unintended effects in research and clinical applications.


Investigation of Selected Medicinal Plants for Their Anti-Obesity Properties.
Obesity, which is a risk factor for diabetes, hypertension, cardiovascular diseases, and cancer, is caused serious health problems and economic costs on a global scale. Nowadays, pancreatic lipase inhibitors that cause inhibition of lipid digestion and lipid absorption are one of the limited treatment approaches for obesity. Plant-derived secondary metabolites can be used for treating obesity. The aim of this study was to research the antiobesity potential of Amaranthus albus L. (Amaranthaceae), Helichrysum compactum Boiss. (Asteraceae), Chenopodium album L. (Chenopodiaceae), and Agrimonia eupatoria L. (Rosaceae). To detect the antiobesity potentials of the plants, in vitro lipase inhibitory activity studies by spectroscopic method and quantitative analysis studies of some anti-obesity effective secondary metabolites by reversed-phase high performance liquid chromatography (RP-HPLC) technique were carried out. In vitro lipase inhibitory studies showed that all plant extracts possess lipase inhibitory effect, and the highest lipase inhibitory potential was observed for H. compactum (IC50: 45.70 μg/mL ± 2.3618). According to HPLC analyses, p-coumaric acid (0.27 mg/g) in A. albus; benzoic acid (0.33 mg/g) in C. album; vanillic acid (7.32 mg/g), syringaldehyde (14.97 mg/g), quercetin (4.66 mg/g), p-coumaric acid (0.71 mg/g), and benzoic acid (3.43 mg/g) in H. compactum; p-coumaric acid (0.71 mg/g) and benzoic acid (3.43 mg/g) in A. eupatoria were detected. In conclusion, H. compactum is the most remarkable natural source for the study. The fact remains that all plants may be promising candidates for treating obesity.