Abdominal electric stimulation facilitates penile vibratory stimulation for ejaculation after spinal cord injury: a single-subject trial.
To compare the success rate of penile vibratory stimulation (PVS) alone with PVS and abdominal electric stimulation (AES). Single-subject trials. Outpatient. Man with chronic T3 complete (American Spinal Injury Association Impairment Scale grade A) spinal cord injury. Spasticity, Babinski response, anal wink, and bulbocavernosus reflexes were all present. Stimulation was presented to the frenulum using a Ferti Care Personal vibrator set at maximal settings (frequency, 110 Hz; amplitude, 3.55 mm). AES was applied to the abdomen using a commercially available muscle stimulator at maximal stimulus intensity and duration settings. Trials were randomized to PVS only or PVS plus AES. Presence or absence of ejaculation, and time to ejaculation. Only 4 of 30 trials were positive with PVS alone, while 31 of 34 trials were positive with PVS plus AES. Additionally, 17 of 26 PVS trials, which were initially negative with PVS alone, were then positive with the addition of AES. This represents a clinically relevant improvement with use of AES. Time to ejaculation for positive trials with either technique was not statistically significant. AES significantly lowered the threshold for ejaculation elicited with vibratory stimulation and increased the success rate over that when PVS alone was used.


Treatment of severe gluteal muscle contracture in children.
To investigate the efficacy of a combination therapy on gluteal muscle contracture, 286 definitely diagnosed patients were subjected to surgical treatment, and then functional exercises and physical therapy. The patients with severe symptoms were asked to have a set of specially-designed functional exercises. All the patients were followed up for 3 to 24 months by hospital visit, correspondence or telephone interview. The effective rate was 100%, and the curative rate was up to 94.6%. Few patients developed complications and relapse was rare. It is concluded that the combination therapy, including surgical removal of diseased tissues, functional exercises and physical therapy, is an effective approach for the treatment of severe juvenile gluteal muscle contracture.


Video-assisted versus open ileocolic resection in primary Crohn's disease: a comparative case-matched study.
Despite the technical difficulties, laparoscopic ileocolic resection for Crohn's disease (CD) has become widely accepted in recent years, due to its potential benefits. There are numerous reports concerning the use of laparoscopy in successfully treating CD, including two randomized trials and few comparative studies. For the most part, these reports outline use of laparoscopic approach in primary distal ileal or ileocolic disease, with a careful selection of the patients. The purpose of this comparative case-control study was to point out potential advantages and disadvantages in short- and long-term outcomes of the laparoscopic approach compared with the open one. From January 1999 to January 2004, 200 patients were admitted in our Surgical Unit for complicated primary CD. 100 patients (group 1) underwent a laparoscopic ileocolic resection, 100 patients (group 2), with alike demographic and clinical characteristics, underwent the same procedure using a traditional approach. The incidence of perforative disease was 32 and 40% in groups 1 and 2, respectively. Average operative time was 140 min (range 90-245 min) in the video-assisted group and 98 min (range 65-255 min) in group 2 (P < 0.05). Postoperative morbidity was 6 and 8% in groups 1 and 2, respectively (P = NS). Recovery of peristalsis occurred within 2-3 days in group 1 and 3-4 days in group 2 (P = NS). Median postoperative hospitalization was 7 days (range 5-18 days) in group 1 and 9 days (range 7-22 days) in control group (P < 0.05). The overall rate of surgical relapse of CD was 8 and 13% in groups 1 and 2, respectively (P = NS), at a mean follow-up of 52 and 60 months, respectively. The 1-year surgical recurrence rate was similar (3%) for the two groups. In conclusions, in spite of the technical difficulties, video-assisted surgery for CD offers advantages over laparotomy, including less postoperative pain, reduced postoperative hospital stay, less disability of the patient, and better cosmetic results. Potential advantages are: easier approach for re-resection, lower rate of postoperative adhesions and bowel obstruction, and lower rate of wound complications.


Simultaneous nitrification and denitrification of municipal wastewater in aerobic membrane bioreactors.
Simultaneous nitrification-denitrification (SND) of municipal wastewater was investigated in a laboratory-scale membrane bioreactor (MBR) operated at two different hydraulic retention times (HRTs), 0.5 and 1 day, dissolved oxygen 3.0 to 0.5 mg/L, and solids retention time (SRT) between 28 and 120 days. The organic loading rate (OLR) (0.11 to 0.64 kg chemical oxygen demand [COD]/m3/d) and influent soluble COD (SCOD)/ total Kjeldahl nitrogen (TKN) ratio (5 to 19) were varied by the addition of glucose. The ammonia-nitrogen and TKN removals were over 97%, and total nitrogen removal was approximately 89% in the MBR. The maximum specific nitrification rates (98 mg N/d/g VSS) and specific denitrification rates (81 mg N/d/g VSS) occurred at an SCOD/TKN ratio of 9.1. The optimum conditions for maximum total nitrogen removal by SND in a single reactor MBR have been found to be low dissolved oxygen (< 0.6 mg/L) and high OLR (approximately 0.64 kg COD/m3/d) at an HRT of 0.5 day and SRT of approximately 85 days.


Silicon substituted hydroxyapatite/VEGF scaffolds stimulate bone regeneration in osteoporotic sheep.
Silicon-substituted hydroxyapatite (SiHA) macroporous scaffolds have been prepared by robocasting. In order to optimize their bone regeneration properties, we have manufactured these scaffolds presenting different microstructures: nanocrystalline and crystalline. Moreover, their surfaces have been decorated with vascular endothelial growth factor (VEGF) to evaluate the potential coupling between vascularization and bone regeneration. In vitro cell culture tests evidence that nanocrystalline SiHA hinders pre-osteblast proliferation, whereas the presence of VEGF enhances the biological functions of both endothelial cells and pre-osteoblasts. The bone regeneration capability has been evaluated using an osteoporotic sheep model. In vivo observations strongly correlate with in vitro cell culture tests. Those scaffolds made of nanocrystalline SiHA were colonized by fibrous tissue, promoted inflammatory response and fostered osteoclast recruitment. These observations discard nanocystalline SiHA as a suitable material for bone regeneration purposes. On the contrary, those scaffolds made of crystalline SiHA and decorated with VEGF exhibited bone regeneration properties, with high ossification degree, thicker trabeculae and higher presence of osteoblasts and blood vessels. Considering these results, macroporous scaffolds made of SiHA and decorated with VEGF are suitable bone grafts for regeneration purposes, even in adverse pathological scenarios such as osteoporosis. STATEMENT OF SIGNIFICANCE: For the first time, the in vivo behavior of scaffolds made of silicon substituted hydroxyapatites (SiHA) has been evaluated under osteoporosis conditions. In order to optimize the bone regeneration properties of these bioceramics, 3D macroporous scaffolds have been manufactured by robocasting and implanted in osteoporotic sheep. Our experimental design shed light on the important issue of the biological response of nano-sized bioceramics vs highly crystalline bioceramics, as well as on the importance of coupling vascularization and bone growth processes by decorating SiHA scaffolds with vascular endothelial growth factor.


Moral distress experienced by non-Western nurses: An integrative review.
Moral distress has been identified as a significant issue in nursing practice for many decades. However, most studies have involved American nurses or Western medicine settings. Cultural differences between Western and non-Western countries might influence the experience of moral distress. Therefore, the literature regarding moral distress experiences among non-Western nurses is in need of review. The aim of this integrative review was to identify, describe, and synthesize previous primary studies on moral distress experienced by non-Western nurses. Whittemore and Knafl's integrative review methodology was used to structure and conduct the review of the literature. Key relevant health databases included the Ovid MEDLINE, CINAHL, Web of Science, and Google Scholar databases. Two relevant journals, Nursing Ethics and Bioethics, were manually searched. We have considered and respected ethical conduct when performing a literature review, respecting authorship and referencing sources. A total of 17 primary studies published between 1999 and 2019 were appraised. There was an inconsistency with regard to moral distress levels and its relationship with demographic variables. The most commonly cited clinical causes of moral distress were providing futile care for end-of-life patients. Unit/team constraints (poor collaboration and communication, working with incompetent colleagues, witnessing practice errors, and professional hierarchy) and organizational constraints (limited resources, excessive administrative work, conflict within hospital policy, and perceived lack of support by administrators) were identified as moral distress's stimulators. Negative impacts on nurses' physical, psychological, and spiritual well-being were also reported. Further research is needed to investigate moral distress among other healthcare professions which may further build understanding. More importantly, interventions to address moral distress need to be developed and tested.


Women's preferences for vaginal antimicrobial contraceptives. I. Methodology.
Sexually transmitted diseases, including AIDS, and unplanned pregnancies continue to be a serious worldwide problem. A number of organizations are developing woman-controlled vaginal formulations to prevent these problems. However, little information is available regarding the types of products women prefer even though such knowledge is essential to obtain widespread use. This is the first of several articles that describe the results of a consumer preference study for such vaginal formulations performed in Campinas, São Paulo State, Brazil. Because no published methodology was available, the instruments and interview techniques were developed first and procedures established for the identification and participation of research subjects. After preparation of a questionnaire, a pilot study was performed to evaluate it, to establish the interview technique, and to determine the optimal method for subject recruitment. Based on the results, the approach was selected and applied to 635 subjects from different age and socioeconomic groups. The developed methodology and questionnaire, the advantages and the problems encountered, are presented.


One step towards the understanding of hope: a concept analysis.
Hope is an essential concept in nursing which has not been satisfactorily explored. The purpose of this article is to elucidate the concept of hope, using a technique of concept analysis described by Walker and Avant (1995). The critical attributes revealed were; future-orientation, positive expectation, intentionality, activity, realism, goal-setting, and inter-connectedness. Various illustrative cases are presented as well as antecedents and outcomes. The discussion highlights some critical aspects of the method used and the results of this analysis may serve as a guide for further empirical research. In order to grasp the true nature of hope, complementary research studies employing a variety of methodological approaches are needed.


[Direct selection of Aspergillus terricola variants having different toxicity on a culture of fibroblasts].
A direct method is proposed to select less toxic mutants of Aspergillus terricola on a culture of fibroblasts. The conidia are first irradiated with UV, and then are used to grow colonies on the glass surface of tubes or flasks containing medium 199. The cells of fibroblasts are added thereupon and the two cultures are being grown together for 24--48 hours. The colonies which inhibit the growth of fibroblasts to a less extent are selected using microscopy. The method can be used for primarily selection of experimentally produced mutants of Aspergillus which form fibrinolytic enzymes possessing low toxicity.


Ectopic perineal testicle: Case report and review of literature.
A small subset of males presenting with cryptorchidism are found to have ectopic testes. The most common location for an ectopic testicle is the superficial inguinal pouch, but there are several other possibilities, necessitating a thorough physical exam. A 4-month-old term male presented for evaluation of a nonpalpable right testicle. Examination revealed an ectopic right testicle located in the perineum. The patient underwent successful right orchiopexy. Ectopic testes are rare but remain in the differential diagnoses for patients with cryptorchidism. Patients should undergo prompt orchiopexy to avoid potential complications and allow maximal preservation of testicular function.


Macrophage elastase (MMP12) critically contributes to the development of subretinal fibrosis.
Macular subretinal fibrosis is the end-stage complication of neovascular age-related macular degeneration (nAMD). We previously developed a mouse model of two-stage laser-induced subretinal fibrosis that mimics closely the dynamic course of macular fibrosis in nAMD patients. This study was aimed to understand the molecular mechanism of subretinal fibrosis. Subretinal fibrosis was induced in C57BL/6J mice using the two-stage laser-induced protocol. Twenty days later, eyes were collected and processed for RNA sequencing (RNA-seq) analysis. DESeq2 was used to determine the differentially expressed genes (DEGs). Gene Ontology (GO) and KEGG were used to analyze the enriched pathways. The expression of the selected DEGs including Mmp12 was verified by qPCR. The expression of MMP12 in subretinal fibrosis of mouse and nAMD donor eyes was examined by immunofluorescence and confocal microscopy. The expression of collagen 1, αSMA and fibronectin and cytokines in bone marrow-derived macrophages from control and subretinal fibrosis mice were examined by qPCR, immunocytochemistry and Luminex multiplex cytokine assay. The MMP12 specific inhibitor MMP408 was used to evaluate the effect of MMP12 on TGFβ-induced macrophage-to-myofibroblast transition (MMT) in vitro and its role in subretinal fibrosis in vivo. RNA-seq analysis of RPE-choroid from subretinal fibrosis eyes uncovered 139 DEGs (fold change log2(fc) ≥ 0.5, FDR < 0.05), including 104 up-regulated and 35 were down-regulated genes. The top 25 enrichment GO terms were related to inflammation, blood vessels/cardiovascular development and angiogenesis. One of the most significantly upregulated genes, Mmp12, contributed to 12 of the top 25 GO terms. Higher levels of MMP12 were detected in subretinal fibrotic lesions in nAMD patients and the mouse model, including in F4/80+ or Iba1+ macrophages. BMDMs from subretinal fibrosis mice expressed higher levels of MMP12, collagen-1, αSMA and fibronectin. MMP408 dose-dependently suppressed TGFβ-induced MMT in BMDMs. In vivo treatment with MMP408 (5 mg/kg) significantly reduced subretinal fibrosis accompanied by reduced F4/80+ macrophage infiltration. MMP12 critically contributes to the development of subretinal fibrosis, partially through promoting MMT.


Ascending somatosensory projections to the dorsal accessory olive: an anatomical study in cats.
The cells in the gracile nucleus that project to the dorsal accessory olive were identified in cats with retrograde tracing techniques. In the same animals, the retrograde labeling patterns in the lateral cervical nucleus and the lumbosacral spinal cord were also examined. Small injections of wheat germ agglutinin complexed to horseradish peroxidase were made in the ventrolateral portion of the dorsal accessory olive without involving the medial accessory olive and without damaging the medial lemniscus. The tissue was processed with tetramethyl benzidine. In each of the three relay nuclei, the neurons that project to the ventrolateral portion of the contralateral dorsal accessory olive are highly concentrated in small regions. In the gracile nucleus these cells are found almost exclusively in the transitional zone, just caudal to the obex and rostral to the clusters. In the lateral cervical nucleus they are concentrated in the dorsolateral tip. In the lumbosacral spinal cord in segments L5 and L6 the cells are found primarily in lamina V, while in segments L7 and S1 they are found along the ventromedial edge of the ventral horn. In the gracile and lateral cervical nuclei there is no segregation of neurons that project to the rostral and caudal portions of the dorsal accessory olive. Comparison of these results with physiological data suggests that each of the three sources of ascending somatic input conveys some distinct aspect of sensory information from the hindlimb to the dorsal accessory olive.


Domperidone (R 33812) in the prophylactic treatment of chemotherapy-induced emesis. A multicentre evaluation.
Domperidone (R 33812) was injected i.v. for the prevention of nausea and vomiting in a total of 395 cytostatic treatment courses in 172 patients. The total dose ranged from 1 to 40 mg and was given in one or several doses. Even after the administration of severely emetic substances, vomiting and nausea were largely prevented in hospitalized patients, but the results were rather poor in ambulatory patients. In all of the cytostatic treatment schedules very favourable results were obtained.


The value of ultrafast computed tomography in the investigation of pediatric chest disease.
Ultrafast computed tomography (CT) can be performed in almost all children with little or no sedation. The benefit has to be balanced against financial cost and radiation dose. Since observing a steady increase in numbers of scans performed, we analyzed the contribution to management of 106 pediatric chest CT scans performed over a 12-month period. Forty-eight of 106 yielded a positive diagnosis and a further 43/106 provided clearly useful information. CT was most useful in children with chronic productive cough (21/48 scans showed bronchiectasis) and suspected interstitial lung disease. It was least useful in the preoperative assessment of empyema complicating community-acquired pneumonia (0/11 scans giving information that changed management). We conclude that the increased ease of performance of chest CT in children has not led to a large number of inappropriate requests. In the large majority of cases, diagnostically useful information was provided.


Ulnar impingement syndrome after Darrach procedure: treatment by advancement lengthening osteotomy of the ulna.
The Darrach procedure was the standard treatment for painful disorders of the radioulnar joint for several decades. However, recent articles have described unsatisfactory results after this procedure including dorso-palmar instability of the ulna, clicking upon rotation of the forearm, ulnar translocation of the carpus, and a painful ulnar impingement syndrome. Management of these problems following an ulnar shortening procedure requires restoration of ulnar length to provide stability to the triangular fibrocartilage complex and ulnar sling mechanism. Also, recurrent impingement must be prevented. A technique of ulnar lengthening by advancement step osteotomy in conjunction with a "matched" resection of the advanced ulna is presented. Three case reports illustrate its use.


Perspectives of nursing students on end-of-life nurse education: A qualitative study of the guided death experience.
Although various studies reported on educational methods for end-of-life care, there is lack of evidence on how nursing students experience simulated death. This study explored the experiences of undergraduate nursing students who participated in a guided death experience. The research utilized a qualitative descriptive design. The research was conducted at a Japanese university nursing school. A total of 82 nursing students were recruited to complete an end-of-life course in which they participated in a guided death experience as part of their third-year curriculum. Descriptions of the guided death experience were analyzed using content analysis. Nursing students' experiences in the guided death experience fell into two main categories: "subjective experience of immersing oneself in the world of the patient who is dying" and "formation of nursing perspectives of end-of-life care." The former focused on subjective experiences of nursing students vividly expressing their own emotions such as grief, anger, fear, and depression during the guided death experience process. The latter expressed recognition of the essence of end-of-life-care through the guided death experience, such as thinking about needs of the person who is dying, being present, and listening to the individual. In end-of-life nurse education, the guided death experience allows students to face first-person death. This fosters a core view of nursing in palliative and end-of-life care. Overall, the guided death experience is an important means of preparatory education for relevant clinical practice.


Concurrent bariatric surgery and surgical resection of massive localized lymphedema of the thigh. A case report.
Massive localised lymphedema (MLL) is considered a rare large, pendulous localised benign overgrowth of lymphoproliferative tissue commonly seen in patients with morbid obesity. Histologically, it may be mistaken for well-differentiated liposarcoma; hence, it is also known as pseudosarcoma. We describe the successful management of MLL of the left medial thigh in a 35-year-old man weighing 220 kgs (BMI 80.8 kgs/m2). He underwent a concurrent laparoscopic sleeve gastrectomy with surgical resection of the MLL. He recovered well and during our last follow up six months after the operation, he is ambulating well and weighs 148 kgs (BMI 54.4 kgs/m2). MLL is a form of secondary lymphedema resulting in disruption or compression of normal lymphatic drainage due to fat accumulation in obese patients. Patients usually delay treatment for even up to a decade, when it becomes sufficiently large enough to restrict mobility and daily activities, or when it becomes infected. MLL is primarily a clinical diagnosis. A detailed history regarding its slow growth spanning over the years makes malignancy less likely. However, if left untreated, MLL may progress to angiosarcoma. Imaging studies such as computed tomography (CT) and a Magnetic Resonance Imaging (MRI) are usually performed to rule out malignancy or vascular malformations. A tissue biopsy is not recommended unless there are suspicious pigmented lesions. MLL remains to be underdiagnosed. Due to the obesity epidemic, clinicians must be aware of this once rare disease. The role of concurrent bariatric surgery with surgical resection of MLL warrants further studies.


Transventricular mitral valve operations.
We report transventricular mitral valve operations in 2 patients with severe mitral regurgitation and postinfarction left ventricular rupture and pseudoaneurysm. The first patient had direct papillary muscle involvement necessitating replacement of the mitral valve. The second patient had indirect mitral involvement allowing for placement of an atrial mitral annuloplasty ring via the left ventricle. Both patients showed no mitral valve regurgitation after replacement or repair and had uneventful postoperative recoveries. These cases demonstrate a feasible, alternative, transventricular approach to mitral valve replacement and repair.


Wonder and the clinical encounter.
In terms of intervening in embodied experience, medical treatment is wonder-full in its ambition and its metaphysical presumption; yet, wonder's role in clinical medicine has received little philosophical attention. In this paper, I propose, to doctors and others in routine clinical life, the value of an openness to wonder and to the sense of wonder. Key to this is the identity of the central ethical challenges facing most clinicians, which is not the high-tech drama of the popular conceptions of medical ethics but, rather, the routine of patients' undramatic but unremitting demands for the clinician's time and respectful attention. Wonder (conceived as an intense and transfiguring attentiveness) is a ubiquitous ethical source, an alternative to the more familiar respect for rational autonomy, a source of renewal galvanizing diagnostic imagination, and a timely recalling of the embodied agency of both patient and clinician.


Functional characterization of ent-copalyl diphosphate synthase from Andrographis paniculata with putative involvement in andrographolides biosynthesis.
To characterize the ent-copalyl diphosphate (ent-CPP) synthase involved in the biosynthetic pathway of andrographolides in a medicinal plant, Andrographis paniculata. The ent-CPP synthase (ent-CPS) gene was cloned from A. paniculata and its encoded ApCPS was demonstrated to react with (E,E,E)-geranylgeranyl diphosphate to form ent-CPP through recombinant expression in Escherichia coli. Site-directed mutagenesis of the Asp to Ala in the conserved DXDD motif of ApCPS resulted in loss of function. One Arg is located in the conserved position close to DXDD motif indicating the involvement of ApCPS in specialized metabolism. In addition, RT-PCR analysis revealed that ApCPS was expressed in all tissues of A. paniculata at all growth stages, which is consistent with andrographolides accumulating in these organs. Methyl jasmonate induced ApCPS gene expression, matching inducible accumulation of andrographolides in vivo. ApCPS is the first ent-CPS characterized in A. paniculata and is suggested to be involved in biosynthesis of andrographolides that have high pharmaceutical values.


Use of the reference source method to determine the half-lives of radionuclides of importance in nuclear medicine.
The reference source method associated with HPGe gamma-ray spectrometric techniques has been applied to half-life determinations of radionuclides used in nuclear medicine. Simultaneous measurements were undertaken for radiopharmaceutical nuclides such as 67Ga, 99Tcm, 123I, 131I and another radionuclide as reference. Besides optimizing the analysis time, this procedure was shown to be independent of the instrumental technique, environmental and radiochemical impurity interferences for most radionuclides. However, some restrictions were observed in samples that contained impurities with the same emission energy or an energy that was very close to the energy of the radionuclide to be measured. The measurement conditions improved the quoted accuracy of the half-life by reducing the type B component uncertainty.


Balancing risk and benefit of extended pelvic lymph node dissection in patients undergoing radical cystectomy.
The optimal extent of pelvic lymph node dissection (PLND) during radical cystectomy (RC) in patients with urothelial carcinoma of the bladder (UCB) is the subject of ongoing debate. In this study, we compared local recurrence-free and overall survival, in addition to complication rates, after extended PLND (ePLND) compared to standard PLND (sPLND). We reviewed the charts of 314 patients who underwent RC for UCB between 2008 and 2013. ePLND was performed in 105 patients, and 105 matched patients who underwent standard PLND (sPLND) were selected based on clinical parameters. Local recurrence-free and overall survival rates were assessed using Kaplan-Meier survival analysis, and Cox proportional hazards models were used to assess potential determinants of these outcomes. Complications were assessed at 30 and 90 days using the Clavien-Dindo reporting system. More lymph nodes were removed by ePLND (median 21) compared to sPLND (median 9; P < 0.001), but the rate of nodal involvement was not different. In multivariable analysis, ePLND was associated with a better local recurrence-free survival (HR = 0.63, P = 0.005), but was not an independent predictor of overall survival (HR = 1.06, P = 0.84). Estimated blood loss was greater with ePLND (1047.3 vs. 584.5 ml P < 0.001), but there was no significant difference in complications. Extended PLND appears to reduce the risk of local recurrence, but was not an independent predictor of overall survival in this cohort. ePLND was associated with greater blood loss compared to sPLND, but not with other perioperative complications.


[Effectiveness evaluation of prosthetic revision for aseptic loosening in oncology prosthesis].
To evaluate the effectiveness of prosthetic revision using custom-made long stem prosthesis and allograft-prosthesis composite (APC) for aseptic loosening after bone tumor resection. Between January 2002 and June 2008, 14 patients with aseptic loosening after bone tumor resection were treated. There were 8 males and 6 females, aged 21-70 years (mean, 43.9 years). The locations were distal femur (8 cases), proximal femur (2 cases), and proximal tibia (4 cases). Pain of the affected limb occurred after 6-31 years of prosthesis replacement and worsened when bearing and walking; 6 patients had shortened limb. The functional results were assessed quantitatively according to the functional rating system of the Musculoskeletal Tumor Society (MSTS). The MSTS score was 16.36 +/- 1.50 before revision. The X-ray films showed obvious prosthetic loosening and subsidence. The average time of symptom was 4.5 years (range, 3-9 years). In 7 patients having severe bone loss (the decrease of the thickness of cortical bone was more than 50%) and the prosthetic subsidence was more than 2 cm, the revision operation with the APC was performed; in 7 patients having less bone loss (the decrease of the thickness of cortical bone was less than 50%), the custom-made long stem prosthesis was performed. All wound healed by first intention. Two patients had temporary peroneal nerve paralysis and recovered after 3 months. All the patients were followed up 3.6 years on average (range, 2 years and 2 months- 7 years) after revision. After revision, pain was relieved and the range of joint was improved. The MSTS score was 23.43 +/- 2.56 at 12 months after revision showing significant difference when compared with the preoperative score (t = 8.910, P = 0.024). The X-ray films showed that lucency space line around stem cement in 2 patients at 12 months, and no prosthesis loosening and infection occurred. The prosthetic revision after limb salvage surgery with prosthesis for bone tumors was acceptable. The good functional results can be achieved by the revision with the APC or the custom-made long stem prosthesis according to the bone loss.


Critical illness neuromuscular disease: clinical, electrophysiological, and prognostic aspects.
Critical illness neuromuscular disease, which has been recognised as a distinct clinical entity in adults, remains poorly described in children. To assess retrospectively the clinical, electrophysiological, and prognostic features of the disease. Retrospective study in a children's university hospital. Five critically ill patients presented with generalised paralysis, associated with long lasting failure to breathe in three. The cause of the generalised paralysis was critical illness neuropathy in two, acute myopathy in two, and mixed neuromyopathy in one. Neuromuscular disease should be suspected in critically ill children with muscle weakness. Because corticosteroids and muscle relaxants appear to trigger some types of intensive care unit neuromuscular disease in children, their use should be restricted or administered at the lowest doses possible.


Quantitation of N-ethyl-3,4-methylenedioxyamphetamine and its major metabolites in human plasma by high-performance liquid chromatography and fluorescence detection.
A HPLC method has been developed for the analogue of Ecstasy MDE and its major metabolites N-ethyl-4-hydroxy-3-methoxyamphetamine (HME) and 3,4-methylenedioxyamphetamine (MDA) in human plasma. In the course of our investigations we found that the methylenedioxyamphetamines and HME exhibit fluorescence at 322 nm. Therefore the detection could be carried out with a fluorescence (FL) detector. Solid-phase extraction was used for sample preparation and yielded high recovery rates greater than 95%. The limit of quantitation for MDE and its metabolites in the extracts was between 1.5 and 8.9 ng/ml and the method standard deviations were less than 5%. This sensitive, rapid and reliable analytical method has been used successfully in the quantitation of the substances in plasma samples obtained from 14 volunteers in two clinical studies after p.o. administration of 100 to 140 mg MDE*HCI. The maximum plasma concentrations were 235-465 ng/ml (MDE), 67-673 ng/ml (HME) and 7-33 ng/ml (MDA), respectively. Pharmacokinetic parameters have been investigated using the plasma concentration curves.


Emerging health challenges for children with physical disabilities and their parents during the COVID-19 pandemic: The ECHO French survey.
The daily lives of children with physical disabilities and their families have been significantly affected by the COVID-19 pandemic. The children face health risks, especially mental, behavioral, social and physical risks. This study aimed to identify potential healthcare issues relating to the wellbeing of disabled children, continuity of rehabilitation and medical care, and parental concerns during the COVID-19 lockdown. The Enfant Confinement Handicap besOins (ECHO [child lockdown disability needs]) national survey was developed by a multidisciplinary group and disseminated in France from April 6, 2020 via email and social networks. This online survey was addressed to the parents of children with physical disabilities aged 0 to 18 years. It explored the experiences of children and their families during the lockdown. Information regarding children's wellbeing, rehabilitation and family organization was collected. The first 1000 eligible surveys were analyzed. The children (mean [SD] age 9.5 [4.8] years) mostly had cerebral palsy (42%) or neuromuscular diseases (11%). The lockdown had negative effects on morale (44% of children), behaviour (55% of children) and social interactions (55% no contact with other children). Overall, 44% of children stopped physical activities; 76% were educated at home; 22% maintained medical follow-up, and 48% and 27% continued physiotherapy and occupational therapy respectively. For more than 60% of children, parents performed the therapy. The main parental concern was rehabilitation (72%) and their main difficulty was the mental load (50%); parents complained of lack of help and support (60%). This study highlighted substantial effects on the health of children with physical disabilities and loss of opportunity, with a massive interruption of medical follow-up and rehabilitation, during the lockdown. Regular assessment of the health benefit/risk is essential to support families and ensure continuity of care during a pandemic.


Annual rates of change in pre- vs. post-bronchodilator FEV1 and FVC over 4 years in moderate to very severe COPD.
While the slope of decline in FEV1 has traditionally been calculated from the post- rather than the pre-bronchodilator measurement in COPD interventional trials, it is not clear whether and to what extent these two slopes differ in symptomatic patients with COPD. Therefore, we used data from the 4-year UPLIFT trial of tiotropium 18 mcg QD vs. placebo to compare annual rates of change in pre- vs. post-bronchodilator FEV1 in 5041 patients with moderate to very severe COPD (mean FEV1 48% pred) in whom the post-bronchodilator FEV1 was measured after 4 inhalations of two different classes of short-acting inhaled bronchodilators at baseline and 1 month and every 6 months post-randomization over 4 years. Linear mixed effects models were used to estimate annual rates of decline in FEV1 and FVC pre- and post-bronchodilator in each treatment group separately, after adjusting for height, gender, smoking status, baseline % predicted FEV1 or FVC, and baseline acute % improvement in lung function. The slopes of the post-bronchodilator FEV1 and FVC were significantly steeper than the pre-bronchodilator slopes regardless of treatment arm (p < 0.001), while the estimated variances of the slopes were similar. Post-bronchodilator increases in FEV1 and FVC diminished progressively and significantly (p < 0.0001) over the 4-year trial, suggesting a possible explanation for the significant differences between the pre- and post-bronchodilator slopes. While the reasons for these differences are not completely clear, they are important to consider when assessing treatment effects on rates of decline in FEV1 and FVC.


The usefulness of a free thinned deep inferior epigastric artery perforator flap and measurement of the vascular pedicle length: A thin flap with a long pedicle.
The thinned deep inferior epigastric perforator (DIEP) flap branching from the main trunk to the superolateral direction may be useful because of its long vascular pedicle. DIEP flap is used as an axial-pattern adipose flap. The vascular pedicle length of the thinned DIEP flap was investigated using originally developed software. The clinical application of the thinned DIEP flap was verified in a case series. In 40 patients with enhanced computed tomography (CT) data, the vascular pedicle length of the longest thinned DIEP flap was simulated using the software. A free thinned DIEP flap was used in 10 clinical cases of facial or breast reconstruction. In all simulated cases, the vascular pedicle of the DIEP branching to the superolateral direction was the longest, and the vascular pedicle could be lengthened up to 34.8% by dissecting the vessels on the fascia as a vascular pedicle. In all the clinical cases, the reconstruction of a complex form defect or reconstruction requiring a long vascular pedicle could be achieved in one stage without any perioperative complications. The intraclass correlation coefficient between simulated pedicle length and dissected pedicle length was 0.99. Thinned DIEP flaps with long vascular pedicles could be elevated safely. Multiple adipose or muscle flaps could be combined without complications. The length of the winding vascular pedicle could be measured using imaging data using the software first developed in the present study. This software would be useful in the planning of a thinned DIEP flap and other free flaps.


Inhibitory effect of methylated derivatives of guanylic acid for protein synthesis with reference to the functional structure of the 5'-'cap' in viral messenger RNA.
Guanylic acid modified variously with methyl groups on base or sugar moieties were synthesized chemically and their inhibitory effects on protein synthesis were tesetd in a wheat germ cell-free system using mRNAs from cytoplasmic polyhedrosis virus and tobacco mosaic virus. The confronting dinucleotide m7G5' pppA that corresponds to the most simple 'cap' structure of an eukaryotic mRNA is a strong inhibitor of protein synthesis, but non-methylated G5' pppA or G5' ppA is not inhibitory. The strong inhibitory effect is observed only by 7-methylguanylic acid (pm7G). Among 11 derivatives of pG, the most effective inhibitors are methylated at the 7-position. Further methylation at the other position sometimes cancels the inhibitory effect. Although pm7G carries a positively charged base, other nucleotides which carry a plus charged base (1-methyladenylic acid and 2-methylthio-7-methylinosinic acid) were not inhibitory. Thus, methylation at the 7-position on guanylic acid is specifically required for the inhibitory effect. Addition of pm7G was inhibitory for the formation of the initiation complex for eukaryotic protein synthesis. These results suggest that the 'cap' component containing 7-methylguanylic acid in viral mRNA participates during protein synthesis, especially in its initial steps. Protein synthesis in a bacterial cell-free system was not inhibited by addition of m7GpppA or pm7G when either TMV RNA or phage MS2 RNA was used as an mRNA.


Growth and cardiovascular measures in hyperactive individuals as young adults and in matched normal controls.
Height, weight, pulse rate and blood pressure were measured in 65 hyperactive individuals 17 to 24 years of age who had not taken stimulant medication during childhood and in 39 control subjects matched for age, sex, intelligence quotient and socioeconomic class. There were no significant differences in the physiologic measures between the two groups. Both the hyperactive and the control subjects seemed to have reached their growth plateau by the age of 17 to 24 years, though the exact time the plateau was reached was not determined. Hyperactive individuals who had taken phenothiazines during childhood were significantly taller (P less than 0.046) than those who had never taken medication. This finding may reflect stimulation of growth by phenothiazines at a critical period of growth, but more detailed reserach on this finding is necessary. The physiologic measures obtained in the hyperactive individuals who had never taken stimulant medication provide an important baseline against which to assess values in hyperactive individuals who have taken such medication.


Effects of biological DNA precursor pool asymmetry upon accuracy of DNA replication in vitro.
Deoxyguanosine triphosphate is underrepresented among the four common deoxyribonucleoside triphosphates (dNTPs), typically accounting for just 5-10% of the total dNTP pool. We have asked whether this pool asymmetry affects the fidelity of DNA replication, by use of an in vitro assay in which an M13 phagemid containing the Escherichia coli lacZalpha gene and an SV40 replication origin is replicated by extracts of human cells. By monitoring reversion of either a TGA or TAA codon within the lacZalpha gene, we found that replication in "biologically biased" dNTPs, representing our estimate of the concentrations in HeLa cell nuclei, is not significantly more accurate than when measured in reaction mixtures containing the four dNTPs at equimolar concentrations. However, sequence analysis of revertants revealed significantly different patterns of mispairing events leading to mutation. During replication at biased dNTP levels, mutations at the site 5' to C in the template strand for the TGA triplet were less frequent than seen in equimolar reaction mixtures, suggesting that extension from mismatches at this site is relatively slow, and proofreading efficiency high, when dGTP is the next nucleotide to be incorporated. Mismatches opposite template C, which might have been favored by the low physiological concentrations of dGTP, were not favored in our in vitro system, although one particular substitution at this site, TGA-->TTA, was strongly favored at low [dGTP]. An excess of one dNTP was found in our system to be more mutagenic than a corresponding deficiency. We also estimated dNTP concentrations in non-transformed human fibroblasts and found that in vitro replication at these levels caused significantly fewer mutations than we observed under equimolar conditions (100 microM each dNTP). This increased replication fidelity may result from increased proofreading efficiency at the lower dNTP levels; however, replication rates were decreased only slightly at these non-transformed fibroblast concentrations.


Noradrenaline increases pain facilitation from the brain during inflammatory pain.
Antidepressants that inhibit the recapture of noradrenaline have variable effects in chronic pain which may be related to the complex role of noradrenaline in pain modulation. Whereas at the spinal cord noradrenaline blocks nociceptive transmission, both antinociception and pronociception were reported after noradrenaline release in the brain. To study the role of noradrenaline in pain modulatory areas of the brain, we elected the dorsal reticular nucleus (DRt), a key pain facilitatory area located at the medulla oblongata. Three studies were performed. First, we show that the infusion in the DRt of nomifensine, which increases local extracellular levels of noradrenaline as shown by in vivo microdialysis, also enhances pain behavioral responses during both phases of the formalin test, a classic inflammatory pain model. Then, we demonstrate that the formalin test triggers the release of noradrenaline in the DRt in a biphasic pattern that matches the two phases of the test. Finally, we show that reducing noradrenaline release into the DRt, using an HSV-1 vector which decreases the expression of tyrosine hydroxylase in noradrenergic DRt-projecting neurons, attenuates pain behavioral responses in both phases of the formalin test. The increased noradrenaline levels induced by the infusion of nomifensine at the DRt, along with the hyperalgesic effects of noradrenaline released at the DRt upon noxious stimulation, indicates that noradrenaline may enhance pain facilitation from the brain. It is important to evaluate if antidepressants that inhibit noradrenaline recapture enhance pain facilitation from the brain herein attenuating their analgesic effects.


Task-specific oscillatory synchronization of prefrontal cortex, nucleus reuniens, and hippocampus during working memory.
Working memory requires maintenance of and executive control over task-relevant information on a timescale of seconds. Spatial working memory depends on interactions between hippocampus, for the representation of space, and prefrontal cortex, for executive control. A monosynaptic hippocampal projection to the prefrontal cortex has been proposed to serve this interaction. However, connectivity and inactivation experiments indicate a critical role of the nucleus reuniens in hippocampal-prefrontal communication. We have investigated the dynamics of oscillatory coherence throughout the prefrontal-hippocampal-reuniens network in a touchscreen-based working memory task. We found that coherence at distinct frequencies evolved depending on phase and difficulty of the task. During choice, the reuniens did not participate in enhanced prefrontal-hippocampal theta but in gamma coherence. Strikingly, the reuniens was strongly embedded in performance-related increases in beta coherence, suggesting the execution of top-down control. In addition, we show that during working memory maintenance the prefrontal-hippocampal-reuniens network displays performance-related delay activity.


Parental perceptions surrounding risks and benefits of immunization.
In recent years, parental concerns about vaccine safety have increased as the threat of disease has decreased. A national survey showed that, in general, parents agree that vaccines benefit their children and that their children may be at risk for contracting a disease if unvaccinated. When asked about understanding the benefits and risks of vaccines, most parents (57%) found numbers and statistics most helpful. A substantial minority (17%) of parents were somewhat or not confident in vaccine safety. Parents less confident in vaccine safety agreed less with the statement that they usually followed the advice of their child's doctor. Incomes and education levels affected responses. This positive relationship between confidence in vaccine safety and reliance on doctors for advice may indicate the need for healthcare providers to identify opportunities to (1) solicit questions about vaccine safety, (2) address vaccine safety-related questions in a way meaningful to parents, and (3) strengthen doctor-patient relationships. A parent communication tool is proposed.


Role of the paleostriatum in species-typical display behavior of the lizard (Anolis carolinensis).
In a comparative study of forebrain mechanisms of species-typical behavior, unilateral lesions were placed in the subpallial telencephalon of male green anolis lizards (Anolis carolinsis), in which there is an almost complete decussation of the optic nerve. Responses to a conspecific male antagonist in a territorial confrontation were then tested when the subject's vision was limited to an eye leading to either the normal or lesioned hemisphere. In lizards with lesions involving the paleostriatum and lateral forebrain bundle, there was an elimination of or marked deficit in the performance of the challenge display while signature displays and measures of general activity were not significantly affected. Lesions predominantly in anterior or posterior dorsal ventricular ridge resulted in no significant deficit in any behavioral measure.


Does off-pump coronary artery bypass grafting beneficially affect renal function?
Off-pump coronary artery bypass grafting (CABG) has been reported to beneficially affect renal function, but this remains to be confirmed. The purpose of the present paper was to study the effects of off-pump CABG on renal function and analyse predictors of postoperative renal impairment in patients who received off-pump CABG. A total of 451 patients who underwent isolated CABG between January 1999 and August 2003 were retrospectively studied. No patient was receiving dialysis. A total of 300 patients (228 men) underwent off-pump CABG (off-pump group) and 151 patients (104 men) underwent on-pump CABG (on-pump group). Perioperative serum creatinine levels and creatinine ratios (peak postoperative creatinine level/preoperative creatinine level) were compared between the groups. Renal impairment (serum creatinine >1.5 mg/dL) developed postoperatively in 12.7% of the off-pump group and 18.5% of the on-pump group (P = 0.1). The creatinine ratio was significantly lower in the off-pump group (1.2 +/- 0.4) than in the on-pump group (1.4 +/- 0.7, P = 0.003). Logistic regression analysis demonstrated that the strongest predictors of postoperative renal impairment in off-pump CABG were left ventricular dysfunction (odds ratio 10.8) and multivessel grafting (odds ratio 4.3). Off-pump CABG provides better renal protection than on-pump CABG. However, perioperative renal function should be closely monitored in patients who have left ventricular dysfunction or who undergo multivessel grafting, even when off-pump CABG is performed.


Non invasive urodynamic assessment in children--are they reliable? Validation of non-invasive urodynamics in children with functional voiding disorders.
To validate the non-invasive tests that can predict the type of bladder dysfunction normally diagnosed by invasive urodynamics. Children below 12 yrs of age were evaluated prospectively. Non-invasive urodynamic evaluation included history, clinical examination, frequency volume charting, ultrasonographic scan, urine analysis and renal function tests. Micturating cystourethrogram was carried out in children with recurrent urinary tract infections. All children underwent invasive urodynamic studies and the significance of association of the parameters of noninvasive assessment with invasive urodynamics was determined. Chi square test using Epi 6 software was used for statistical analysis of data. 41 children underwent invasive urodynamic studies. The commonest disorder was detrusor instability in 28 (68.2%). Dysynergic voiding was noted in 8 (19.5%). The study was normal in 5 (12.1%). Nocturnal enuresis with day time symptoms, holding maneuvers, small frequent voiding pattern (p<0.05) and a small capacity bladder with insignificant residue (p=0.0003) predicts detrusor instability. Straining (p=0.0006), large capacity bladder with significant post void residue in the absence of vesicouretric reflux (p<0.05) predicts dysyneric voiding. On combining the various non-invasive tests and validating them against invasive urodynamics in diagnosing detrusor instability and dysnergic voiding, they have a sensitivity of 88.4% and 87.5%, specificity of 72.7% and 69.2%, positive predictive value of 0.88 and 0.63 and positive likelihood ratio of 3.1 & 2.2 respectively. Functional voiding disorders can be diagnosed with reasonable accuracy by minimally invasive methods.


Assessment of the relationship between endocan and obstructive sleep apnea severity.
Obstructive sleep apnea (OSA) and endothelial dysfunction are associated with cardiovascular risk factors and the development of atherosclerosis. Endocan is a marker of endothelial dysfunction, while obstructive sleep apnea is one of the causes of endothelial dysfunction. In this study, we investigated the relationship between endocan and obstructive sleep apnea severity. A total of 179 patients with snoring complaints were included. All patients underwent polysomnography, and based on the results, the participations were allocated to the control group (n = 39) or to the obstructive sleep apnea group (n = 140). The OSA group was classified as having mild (apnea-hypopnea index (AHI) = 5-15; n = 43), moderate (AHI = 15-30; n = 42), or severe OSA (AHI > 30; n = 55). All participations had their endocan levels measured. Endocan levels in OSA patients were significantly higher than in the control group (11.8 (3.13-200) vs 3.13 (3.13-23) ng/ml, p < 0.001). Also, endocan levels were significantly higher in the severe OSA group than moderate and mild obstructive OSA (13.2 (3.13-200), 12.6 (3.13-200) and 8.44 (3.13-50.5) ng/ml, p = 0.015, respectively). Multiple logistic regression analysis showed that smoking, age and endocan levels were independent predictors of OSA severity (p = 0.024, p = 0.037, p = 0.004, respectively). Endocan seems to be a potential risk stratification marker in this patient population.


Central nervous system pathology in MFP2 deficiency: insights from general and conditional knockout mouse models.
Multifunctional protein-2 (MFP2), also known as D-bifunctional protein, is a central enzyme of the peroxisomal β-oxidation pathway. Defects in this enzyme are associated with a spectrum of neurological disorders encompassing developmental and degenerative pathologies. In order to investigate the cellular and molecular mechanisms of these neuropathologies, mouse models with general and cell type selective loss of MFP2 were generated. In this review the distinct anomalies in the CNS of adult Mfp2 knockout mice are discussed, in particular the cerebellar degeneration and neuroinflammation. The potential underlying mechanisms are considered with regard to the cellular origin and biochemical causes. Finally, the similarities and differences between the CNS phenotypes of mice lacking MFP2 and mice with peroxisome biogenesis disorders are assessed.


Periaortic Abdominal Fat Area as a Predictor of Surgical Difficulties during Extraperitoneal Laparoscopic Para-aortic Lymphadenectomy.
To evaluate whether obesity is a marker of surgical difficulty during extraperitoneal para-aortic lymphadenectomy. Retrospective observational cohort study. Tertiary medical center in the Kanazawa area of Japan. Eighty-four patients with primary endometrial cancer who underwent extraperitoneal laparoscopic para-aortic lymphadenectomy (LPAND) between January 2005 and December 2017 were included. We investigated the correlation between operative times and body mass indexes, visceral fat areas, and periabdominal artery fat areas (PAFAs). The number of lymph nodes harvested was used as an indicator of the degree of surgical completion. There was no correlation between the operative time and body mass index. Significant correlations were observed between operative time and visceral fat area (p = .026; r = 0.243) and between operative time and PAFA (p = .007; r = 0.293). A multivariate analysis showed that PAFA was a significant independent marker that could be used to predict prolonged operative times for extraperitoneal LPAND (p = .045; odds ratio, 3.05). The number of para-aortic lymph nodes harvested was not significant in the high- and low-PAFA groups (22 and 25, respectively; p = .525). PAFA is an adequate marker of prolonged operative time for extraperitoneal LPAND among patients with endometrial cancer.


Evaluation of Hugo RAS System in Major Urologic Surgery: Our Initial Experience.
Background: The Hugo RAS is a newly launched robotic system for clinical use. This article provides the initial experience of the authors using Hugo RAS in urologic procedures. Methodology: Patients undergoing major urologic procedures, including nephrectomy and prostatectomy, were included in this prospective clinical trial. Institutional ethical approval was obtained, and patients were counseled preoperatively with informed consent. Both intraoperative and postoperative data were carefully recorded. Results: A total of seven patients were included in this initial study. This includes radical prostatectomy (n = 3), simple prostatectomy (n = 1), radical nephrectomy (n = 1), and simple nephrectomy (n = 2). The total operative time, port placement time, time to dock the ports, blood loss and length of hospital stay, and 30-day morbidity and mortality were recorded. There were no intraoperative or postoperative complications up to 1 month follow-up. Conclusion: From the early experience with the Hugo RAS™ platform, it appears to be a safe robotic platform for major urologic procedures and is a good addition to the existing arsenal of surgical robots.


[Prognostic value of first fasting glucose measurement compared with admission glucose level in patients with acute coronary syndrome].
The admission plasma glucose (APG) level is a recognized prognostic factor in patients with acute coronary syndrome (ACS). However, little is known about the prognostic value of the first fasting plasma glucose (FPG) measurement. The aim of this study was to determine the prognostic value of the first FPG measurement relative to that of the APG level in patients with ACS. The study involved 547 consecutive patients who were admitted to our center with a diagnosis of ACS in 2006. Patients were divided into three groups according to their first FPG or APG level (i.e., <126 mg/dL, 126-200 mg/dL, or >200 mg/dL). The primary endpoint was the combined outcome of death or reinfarction during hospitalization. The primary endpoint was observed in 46 patients, 25 of whom died. Patients in this group were older, were more often diabetics or smokers, more often had had a prior myocardial infarction, were in a higher admission Killip class, showed more than one vessel disease on catheterization, had a lower left ventricular ejection fraction, and had higher admission creatinine, APG, and first FPG levels. Multivariate analysis, adjusted for previously identified factors, revealed that the first FPG level was an independent risk factor for death or reinfarction (126-200 mg/dL, odds ratio [OR]=5.26; 95% confidence interval [CI], 1.09-25.45; >200 mg/dL, OR=6.66; 95% CI, 2.05-21.63), but that the APG level was not (126-200 mg/dL, OR=0.84; 95% CI, 0.63-1.05; >200 mg/dL, OR=1.14; 95% CI, 0.29-4.51). The first FPG level was found to be a better predictor of an adverse outcome (i.e., death or reinfarction) during hospitalization in ACS patients than the APG level.


Effects of chronic administration of huperzine A on memory in guinea pigs.
Effects of subchronic administration of huperzine A, a cholinesterase inhibitor, on spatial memory were studied in guinea pig. Spatial memory was appreciated by the Morris water maze test. At a dose of 0.25 microgram/h, inhibiting 36% of blood AChE and 14-20% of central AChE, no effect on spatial learning was found. At a dose of 1 microgram/h, inhibiting 20% of blood AChE and 14-20% of central AChE, no memory impairment was found, on the other hand, a memory enhancing effect, limited to the first day was shown. It thus appears that subchronic administration of huperzine A did not induce deleterious effects on spatial memory.


A controlled trial of nebulized aminoglycoside and oral flucloxacillin versus placebo in the outpatient management of children with cystic fibrosis.
Six children with cystic fibrosis who had persistently had Pseudomonas aeruginosa isolated from their respiratory tract, completed a double-blind cross-over comparison of oral flucloxacillin and nebulized aminoglycoside versus double placebo. The patients had higher FEV1 results at the end of the month of active treatment than after the month of placebo.


Octogenarian Survival After Neurosurgical Procedures To Treat Severe Head Trauma.
Falls are common for persons of advanced age and can result in severe traumatic brain injury (TBI). The purpose of the present study was to determine the survival benefit from aggressive operative intervention. The trauma quality improvement program database from 2013 to 2016 was accessed for the present study. All patients aged 80-89 years who had sustained a severe TBI with a Glasgow coma scale (GCS) score of ≤8 and brain abbreviated injury scale score of ≥3 and had undergone operative intervention (craniotomy or craniectomy) were included in the present study. The patients were divided into 2 groups, those who had survived and those who had died, and the characteristics, injury severity score (ISS), types of intracranial hemorrhage, and comorbidities were compared. Multivariable logistic regression analysis was performed to determine the factors associated with survival. A receiving operating characteristic curve was created to test the model, and the area under the curve was calculated. Of the 1266 patients who had met the inclusion criteria for the present study, only 477 (37.68%) had survived. A lower ISS, higher GCS score, and no history of coagulopathy were factors indicating a greater chance of survival. Operative intervention for epidural hematoma, brain contusion, and subdural hematoma was associated with 3.5, 2.25, and 1.86 odds of survival, respectively. Procedure type (craniectomy vs. craniotomy) did not affect the outcome. The area under the curve was 0.723 (95% confidence interval, 0.694-0.752). The octogenarians who had undergone craniotomy or craniectomy for severe TBI after a fall had very high mortality. A lower ISS, higher GCS score, no history of coagulopathy and evacuation of subdural hematoma, epidural hematoma, or brain contusion indicated a greater probability of survival.


Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome.
Proximal symphalangism is an autosomal-dominant disorder with ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive deafness. These symptoms are shared by another disorder of joint morphogenesis, multiple synostoses syndrome. Recently, it was reported that both disorders were caused by heterozygous mutations of the human noggin gene (NOG). To date, seven mutations of NOG have been identified from unrelated families affected with joint morphogenesis. To characterize the molecular lesions of proximal symphalangism, we performed analyses of NOG in three Japanese individuals with proximal symphalangism. We found three novel mutations: g.551G>A (C184Y) in a sporadic case of symphalangism, g.386T>A (L129X) in a familial case of symphalangism, and a g.58delC (frameshift) in a family with multiple synostosis syndrome. Characteristic genotype-phenotype correlations have not been recognized from the mutations in the NOG gene.


The Role of Manual Detorsion in Pediatric Testicular Torsion During the Global COVID-19 Pandemic: Experience From 2 Centres.
To evaluate the role of emergency manual detorsion as first line management for testicular torsion in the context of the COVID-19 pandemic. This retrospective observational study includes 90 pediatric patients ≤14 years old with diagnosis of testicular torsion made at 2 tertiary centers between October 2020 and June 2022. Variables examined included age, presentation delay, surgical wait time, number of attempts at manual testicular detorsion, and manual testicular detorsion success. All patients finally underwent surgery, including contralateral testicular fixation. Outcomes included predictors of successful manual detorsion, testicular findings at surgery, and operation time. Mean (SD) age at diagnosis was 11.51 (2.64) years. Mean presentation delay was 11.76 (13.79) hours. Detorsion was attempted in 72 (80%) patients, resulting successful in 58 (80.5%). Surgical wait time after successful manual detorsion was 22.85 (16.94) hours. On multivariable analysis, successful manual detorsion was associated with a presentation delay<6 hours (odds ratios [OR] 0.154, 95% confidence intervals (CI) 0.036-0.655, P = 0.01) and absence of scrotal edema (OR 0.171, 95% CI 0.038-0.769, P = 0.02). Vice versa, a heterogeneous echo-texture (OR 0.57, 95% CI 0.007-0.461, P = 0.007) and absent blood flow on Doppler ultrasound scan (OR 0.256, 95% CI 0.067-0.971, P = 0.045) were significantly associated with the likelihood of manual detorsion failure. In our experience, manual detorsion provided safe and effective emergency treatment for pediatric testicular torsion, especially in absence of edema and when presentation delay is <6 hours. This maneuver should be more widely attempted immediately after diagnosis as temporizing rescue.


Pneumatic reduction of ileocolic intussusception in children.
Pneumatic reduction of ileocolic intussusception in children has been used in Argentina and in China for more than 25 years but has only recently been attempted in North America. It is reported to be safer and more effective than reduction by the hydrostatic pressure of a barium suspension. Our preliminary experience with four patients has been rewarding and we believe it may become the method of choice.


Sox15 is up regulated in the embryonic mouse testis.
The mammalian sex determining region on the Y chromosome, SRY, is the founding member of the SOX gene family. SOX genes share a common DNA-binding motif termed the HMG box and have diverse roles in vertebrate embryonic development and tissue differentiation. Sox15 expression was analysed during mouse embryogenesis by whole-mount in situ hybridisation and Real Time RT-PCR. Sox15 was found to be expressed in developing mouse gonads from 11.5 dpc to 13.5 dpc with a peak of expression at 12.5 dpc. Expression was approximately twice as high in the male gonad as in the female gonad.


The cyclical nature of patient safety.
John Tingle, Lecturer in Law, Birmingham Law School, University of Birmingham, discusses some recent patient safety reports.


Cloning and expression of the nucleocapsid gene of virulent Kabete O strain of rinderpest virus in baculovirus: use in differential diagnosis between vaccinated and infected animals.
Rinderpest (RP) is a viral disease of ruminants with > 95% morbidity and mortality. We have cloned the cDNA of the nucleocapsid (N) gene of the virulent Kabete O strain of rinderpest virus (RPVK) and compared its nucleotide and deduced amino acid sequences with those of the N genes of the lapinized strain of rinderpest virus (RPVL), measles virus (MV), and canine distemper virus (CDV). The gene has an open reading frame of 1575 nucleotides and encodes a protein of 525 amino acids with a molecular weight of 59 kDa. The nucleotide sequence of the coding region of the N gene of RPVK is 88.6, 68.9, and 63.2% homologous with N genes of RPVL, MV, and CDV, respectively. We have developed a recombinant baculovirus that expresses the N protein (rRVN) of RPVK in insect cells (Sf9) and larvae (Spodoptera frugiperda). rRVN was used as a coating antigen in an ELISA to distinguish vaccinated animals from those infected with RPV and was also used successfully in the diagnosis of two other morbilliviruses, MV and peste des petits ruminants (PPRV). Crude lysate of a single infected larva (0.2-0.3 g) was sufficient to coat 150 ELISA plates for serological diagnosis of 7200 serum samples in duplicate.


Gender-based violence and mental disorders in female college students.
To assess the association between gender-based violence and DSM-IV Axis I disorders in female college students. A stratified random sample of 1,043 college women (average age 22.2 years) participated in the study. We collected sociodemographic, socioeconomic and academic information as well as information on the participants' experience of gender-based violence victimization. The presence of mental disorders during the 12 months preceding the study was assessed by clinically trained interviewers applying the Structured Clinical Interview for DSM-IV Axis I disorders-Clinician Version (SCID-CV). 15.2% of the participants reported lifetime gender-based violence victimization. Almost two-thirds of the victims had suffered some Axis I disorder during the past year, a significantly larger proportion than among non-victims (OR = 3.72; 95% CI 2.61-5.30). Mood disorders and anxiety disorders were both significantly more common among victims than non-victims (OR = 4.26; 95% CI 2.81-6.46 and OR = 1.97; 95% CI 1.20-3.24, respectively). The most prevalent individual disorder among victims was major depressive disorder (26.41%). Among victims of purely psychological violence, the overall rate of Axis I disorder was similar to the rate among other victims (67 and 61%, respectively). Among female university students, the experience of physical or psychological gender-based violence is associated with mental disorder. These findings suggest the need for treatment and prevention interventions designed specifically for this population.


Unlocked Nucleic Acids for miRNA detection using two dimensional nano-graphene oxide.
In this study we have used Unlocked Nucleic Acids (UNAs) to discriminate a breast cancer oncomiR from two other miRNAs in the same RNA family using two-dimensional graphene oxide nanoassemblies. Fluorescently labeled single stranded probe strands and graphene oxide nanoassemblies have been used to detect miR-10b and discriminate it from miR-10a, which differs by only a single nucleotide (12th base from the 5' end), and miR-10c, which differs by only two nucleotides (12th and 16th bases from the 5' end). We have determined the discrimination efficacy and detection capacity of a DNA probe with two inserted UNA monomers (UNA2), and compared it to the DNA probe with two purposefully inserted mutations (DNAM2) and full complementary sequence (DNAfull). We have observed that UNA2 is 50 times more powerful than DNAfull in discriminating miR-10b from miR-10c while generating an equally high fluorescence signal. This fluorescence signal was then further enhanced with the use of the highly specific endonuclease dsDNase for an enzymatic amplification step. The results demonstrate that the underutilized UNAs have enormous potential for miRNA detection and offer remarkable discrimination efficacy over single and double mismatches.


Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study.
JTE-052 is a novel Janus kinase inhibitor presently under clinical development for the topical treatment of atopic dermatitis (AD). To evaluate the efficacy and safety of JTE-052 ointment in Japanese adult patients with AD. Patients with moderate-to-severe AD were randomized (2: 2: 2: 2: 1: 1) to receive JTE-052 ointment at 0·25%, 0·5%, 1% or 3%, the vehicle ointment or tacrolimus 0·1% ointment (reference) twice daily for 4 weeks. The primary efficacy end point was the percentage change in modified Eczema Area Severity Index (mEASI) score from baseline at the end of treatment (EOT). Secondary efficacy end points included change from baseline in the pruritus numerical rating scale (NRS) score. In total, 327 patients were enrolled. At EOT, the least-squares mean percentage changes from baseline in mEASI score for JTE-052 at 0·25%, 0·5%, 1% and 3% and the vehicle ointment were -41·7%, -57·1%, -54·9%, -72·9% and -12·2%, respectively. All JTE-052 groups showed significant reductions of mEASI score vs. the vehicle group (P < 0·001 for all). In the tacrolimus group, the mean percentage change in mEASI score was -62·0%. The JTE-052 groups also showed significant improvement in other parameters; notably, the pruritus NRS score was reduced as early as day 1 night-time. JTE-052 ointment at doses up to 3% was safe and well tolerated. Topical JTE-052 markedly and rapidly improved clinical signs and symptoms in Japanese adult patients with moderate-to-severe AD, with a favourable safety profile. The study results indicate that topical JTE-052 is a promising therapeutic option for AD. The trial registration number is JapicCTI-152887.


Combined evolutionary and metabolic engineering improve 2-keto-L-gulonic acid production in Gluconobacter oxydans WSH-004.
The direct fermentation of the precursor of vitamin C, 2-keto-L-gulonic acid (2-KLG), has been a long-pursued goal. Previously, a strain of Gluconobacter oxydans WSH-004 was isolated that produced 2.5 g/L 2-KLG, and through adaptive evolution engineering, the strain G. oxydans MMC3 could tolerate 300 g/L D-sorbitol. This study verified that the sndh-sdh gene cluster encoded two key dehydrogenases for the 2-KLG biosynthesis pathway in this strain. Then G. oxydans MMC3 further evolved through adaptive evolution to G. oxydans 2-KLG5, which can tolerate high concentrations of D-sorbitol and 2-KLG. Finally, by increasing the gene expression levels of the sndh-sdh and terminal oxidase cyoBACD in G. oxydans 2-KLG5, the 2-KLG accumulation in the 5-L fermenter increased to 45.14 g/L by batch fermentation. The results showed that combined evolutionary and metabolic engineering efficiently improved the direct production of 2-KLG from D-sorbitol in G. oxydans.


Novel eco-friendly methodology to determine polycyclic aromatic hydrocarbons in polyurethane foam for air monitoring: Application to spatial and temporal distribution survey.
This study aimed at developing a new method for the extraction of polycyclic aromatic hydrocarbons (PAHs) in polyurethane foam (PUF). In the field of PAH monitoring, passive samplers using PUF disks are widely used. However, current extraction methods are time and solvent consuming. This new method employs 3 times a sixteenth of the PUF disk, with method detection limits (MDL) values below 5 and 13 ng/sampler for 3- and 4-rings PAHs, respectively. The use of only parts of the disk allows extraction by ultrasounds using exclusively 120 mL of ethanol, making it environmentally friendly. Ethanolic extracts are then purified and concentrated using microextraction by packed sorbent (MEPS) before GC-MS analyses. This method was applied for an environmental survey in a French urban area with an oceanic climate. Variations in PAH concentrations were observed depending on the site studied (urban, traffic, periurban and rural), as well as temporal variations.


The role of serum non-cholesterol sterols as surrogate markers of absolute cholesterol synthesis and absorption.
To study the whole-body cholesterol metabolism in man, cholesterol synthesis and absorption need to be measured. Because of the complicated methods of the measurements, new approaches were developed including the analysis of serum non-cholesterol sterols. In current lipidologic papers and even in intervention studies, serum non-cholesterol sterols are frequently used as surrogate markers of cholesterol metabolism without any validation to the absolute metabolic variables. The present review compares serum non-cholesterol sterols with absolute measurements of cholesterol synthesis and absorption in published papers to find out whether the serum markers are valid indicators of cholesterol metabolism in various conditions. During statin treatment, during interventions of dietary fat, and in type 2 diabetes the relative and absolute variables of cholesterol synthesis and absorption were frequently but not constantly correlated with each other. In some occasions, especially in subjects with apolipoprotein E3/4 and E4/4 phenotypes, the relative metabolic markers were even more sensitive than the absolute ones to reflect changes in cholesterol metabolism during dietary interventions. Even in general population at very high absorption the homeostasis of cholesterol metabolism is disturbed damaging the validity of the serum markers. It is worth using several instead of only one precursor and absorption sterol marker for making conclusions of altered synthesis or absorption of cholesterol, and even then the presence of at least some absolute measurement is valuable. During consumption of plant sterol-enriched diets and in situations of interfered cholesterol homeostasis the relative markers do not adequately reflect cholesterol metabolism. Accordingly, the validity of the relative markers of cholesterol metabolism should not be considered as self-evident.


Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4+ T cell fate.
Follicular helper T (Tfh) cells are essential for germinal center (GC) B cell responses. However, it is not clear which PD-1+CXCR5+Bcl6+CD4+ T cells will differentiate into PD-1hiCXCR5hiBcl6hi GC-Tfh cells and how GC-Tfh cell differentiation is regulated. Here, we report that the sustained Tigit expression in PD-1+CXCR5+CD4+ T cells marks the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas Tigit-PD-1+CXCR5+CD4+ T cells upregulate IL-7Rα to become CXCR5+CD4+ T memory cells with or without CCR7. We demonstrate that pre-Tfh cells undergo substantial further differentiation at the transcriptome and chromatin accessibility levels to become GC-Tfh cells. The transcription factor c-Maf appears critical in governing the pre-Tfh to GC-Tfh transition, and we identify Plekho1 as a stage-specific downstream factor regulating the GC-Tfh competitive fitness. In summary, our work identifies an important marker and regulatory mechanism of PD-1+CXCR5+CD4+ T cells during their developmental choice between memory T cell fate and GC-Tfh cell differentiation.


Fetal Therapy for Renal Anhydramnios.
The most severe forms of congenital anomalies of the kidney and urinary tract present in fetal life with early pregnancy renal anhydramnios and are considered lethal due to pulmonary hypoplasia without fetal therapy. Due to the high rate of additional structural anomalies, genetic abnormalities, and associated syndromes, detailed anatomic survey and genetic testing are imperative when stratifying which pregnancies are appropriate for fetal intervention. Restoring amniotic fluid around the fetus is the principal goal of prenatal treatment. The ongoing multi-center Renal Anhydramnios Fetal Therapy (RAFT) trial is assessing the safety and efficacy of serial amnioinfusions to prevent pulmonary hypoplasia so that the underlying renal disease can be addressed.


Langerhans cell histiocytosis mimicking a residual cyst.
Langerhans cell histiocytosis (LCH) is an uncommon myeloid neoplasm characterized by clonal neoplastic proliferation of Langerhans-type dendritic cells associated with a reactive inflammatory infiltrate composed predominantly of lymphocytes and eosinophils. Only three cases of LCH mimicking periapical lesions have been reported in the English-language literature to date. Herein, we report a rare case of LCH involving the mandible of a 45-years-old woman mimicking microscopically and radiographically a residual cyst. The patient underwent enucleation and curettage of the lesion. Microscopically, the lesion showed fibrous tissue with an intense inflammatory infiltrate and histiocytes with irregular to elongated nuclei with prominent nuclear grooves. The tumor cells were positive for S-100 protein, CD1a, and CD207. After careful evaluation through imaging tests to rule out lesions in other anatomical locations, the diagnosis was solitary LCH of the mandible. After four years of follow-up, the patient remained with no evidence of recurrence. This case emphasizes the importance of a carefully clinical, radiographic, and microscopical evaluation of bone lesions, including periapical or residual cysts, since some neoplasms can mimic common benign lesions of the jaws. Although conservative approaches to treating solitary mandibular bone lesions of LCH can be employed, long-term follow-up is strongly recommended.


Methyl 3-Hydroxymyristate, a Diffusible Signal Mediating phc Quorum Sensing in Ralstonia solanacearum.
Ralstonia solanacearum, a plant pathogenic bacterium causing "bacterial wilt" on crops, uses a quorum sensing (QS) system consisting of phc regulatory elements to control its virulence. Methyl 3-hydroxypalmitate (3-OH PAME) was previously identified as the QS signal in strain AW1. However, 3-OH PAME has not been reportedly detected from any other strains, and this suggests that they produce another unknown QS signal. Here we identify (R)-methyl 3-hydroxymyristate [(R)-3-OH MAME] as a new QS signal that regulates the production of virulence factors and secondary metabolites. (R)-3-OH MAME was synthesized by the methyltransferase PhcB and sensed by the histidine kinase PhcS. The phylogenetic trees of these proteins from R. solanacearum strains were divided into two groups, according to their QS signal types--(R)-3-OH MAME or (R)-3-OH PAME. These results demonstrate that (R)-3-OH MAME is another crucial QS signal and highlight the unique evolution of QS systems in R. solanacearum.


Effect of a milk formula containing probiotics on the fecal microbiota of asian infants at risk of atopic diseases.
The fecal microbiota of 37 infants with (n = 20) or without (n = 17) probiotic administration was evaluated on D 3, and at 1, 3, and 12 mo by fluorescence in situ hybridization-flow cytometry (FISH-FC), PCR, and bacteriological culture methods. They represent consecutive subjects of an ongoing double-blind, placebo-controlled trial on a probiotic formula (LGG and Bifidobacterium longum) administered during the first 6 mo of life. Despite varying composition in each baby, there was a general bacterial colonization pattern in the first year. Bifidobacteria increased markedly (p = 0.0003) with a parallel decrease in Enterobacteriaceae (p < 0.001) and Bacteroides-Prevotella (p = 0.005) populations. Eubacterium rectale-Clostridium coccoides (p < 0.001) and Atopobium (p = 0.039) groups also gradually increased. This overall pattern was unaffected by probiotic administration (p > 0.05). B. longum (p = 0.005) and Lactobacillus rhamnosus (p < 0.001) were detected more frequently in probiotic group during supplementation, but no difference after supplementation had ceased (p > 0.05). Cultured lactic acid bacteria were also more numerous in the probiotic-administered babies during treatment period (log CFU/g 8.4 versus 7.4; p = 0.035). Our results indicate that supplemented strains could be detected but did not persist in the bowel once probiotic administration had ceased.


Gender-related differences in the presentation, management, and outcomes among patients with acute coronary syndrome from Oman.
To assess gender-related differences in the presentation, management, and in-hospital outcomes among acute coronary syndrome (ACS) patients from Oman. Data were analyzed from 1579 consecutive ACS patients from Oman during May 8, 2006 to June 6, 2006 and January 29, 2007 to June 29, 2007, as part of Gulf RACE (Registry of Acute Coronary Events). Analyses were conducted using univariate and multivariate statistical techniques. In this study, 608 (39%) patients were women with mean age 62 ± 12 vs. 57 ± 13 years (p < 0.001). More women were seen in the older age groups (age <55 years: 25% vs. 43%, 55-74 years: 60% vs. 49% and >75 years: 15% vs. 8%; p < 0.001). Women had higher frequencies of diabetes, hypertension, hyperlipidemia, obesity, angina, and aspirin use, but less history of smoking. Women were significantly less likely to have ischemic chest pain, ST-elevation myocardial infarction (STEMI), non-STEMI and were more likely to have dyspnea, unstable angina, ST depression and left bundle branch block. Both groups received ACS medications and cardiac catheterization equally; however, women received anticoagulants (88% vs. 79%; p < 0.001), angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) (70% vs. 65%; p = 0.050) more and clopidogrel less (20% vs. 29%; p < 0.001). Women experienced more recurrent ischemia and heart failure but with similar in-hospital mortality (4.6% vs. 4.3%) even after adjusting for age (p = 0.500). Women admitted with ACS were older than men, had more risk factors, presented differently with no difference in hospital mortality. This is similar to Gulf RACE study except for mortality. Women received anticoagulants/ACEIs /ARBs more but were under-treated with clopidogrel.


Current progress of pig models for liver cancer research.
Preclinical trials play critical roles in assessing the safety and efficiency of novel therapeutic strategies for human diseases including live cancer. However, most therapeutic strategies that were proved to be effective in preclinical cancer models failed in human clinical trials due to the lack of appropriate disease animal models. Therefore, it is of importance and urgent to develop a precise animal model for preclinical cancer research. Liver cancer is one of the most frequently diagnosed cancers with low 5-year survival rate. Recently, porcine attracted increasing attentions as animal model in biomedical research. Porcine liver cancer model may provide a promising platform for biomedical research due to their similarities to human being in body size, anatomical characteristics, physiology and pathophysiology. In this review, we comprehensively summarized and discussed the advantages and disadvantages, rationale, current status and progress of pig models for liver cancer research.


A subset of high-grade pulmonary neuroendocrine carcinomas shows up-regulation of matrix metalloproteinase-7 associated with nuclear beta-catenin immunoreactivity, independent of EGFR and HER-2 gene amplification or expression.
Nuclear translocation of beta-catenin has been correlated with epidermal growth factor receptor (EGFR) overexpression/activation in non-small cell lung cancer. Less is known on beta-catenin transactivation in high-grade pulmonary neuroendocrine tumors and on the status of beta-catenin activating EGFR and human epidermal growth factor receptor 2 (HER-2) or beta-catenin target genes cyclin D1 and matrix metalloproteinase-7 (MMP-7). beta-catenin immunoreactivity was evaluated in 51 large-cell neuroendocrine carcinomas (LCNEC) and 45 small-cell lung carcinomas (SCLC). Nineteen cases were assessed for beta-catenin gene exon 3 mutations, expression of MMP-7, and expression/gene amplification of EGFR, HER-2, and cyclin D1. beta-catenin was expressed in all 96 high-grade neuroendocrine tumors, the vast majority (94%) showing >50% immunopositive cells. A disarrayed immunoreactivity, however, was commonly encountered consisting in variably altered membrane-associated patterns of staining along with progressive accumulation of cytoplasmic immunoreactivity. In LCNEC, but not in SCLC, the disarrayed patterns correlated with EGFR and HER-2 protein expression. beta-catenin nuclear accumulation was found in nine tumors, including seven LCNEC and two SCLC, and was always associated with disarrayed immunoreactivity and increased MMP-7, but not cyclin D1 expression. These cases, however, did not show beta-catenin gene mutations or EGFR and HER-2 gene amplification or expression. No association was found between nuclear beta-catenin and any clinicopathological variable including patients' survival. The subcellular compartmentalization of beta-catenin is profoundly altered in high-grade pulmonary neuroendocrine tumors. A minor subset of these tumors shows beta-catenin nuclear accumulation in association with increased expression of MMP-7, but not of cyclin D1, independent of EGFR and HER-2 gene amplification or expression.


Preclinical Pharmacokinetics and Pharmacodynamics and Content Analysis of Gnetol in Foodstuffs.
Studies were undertaken to evaluate the bioavailability in rats and content analysis of gnetol in Gnetum gnemon products reported to contain gnetol and to examine the pharmacological properties of gnetol in in vitro models including anti-inflammatory/analgesic, antidiabetic, anti-adipogenesis, and anticancer activity. Male Sprague-Dawley rats were cannulated and dosed either intravenously with gnetol (10 mg/kg) or orally (100 mg/kg). Various methanolic extractions of G. gnemon products were quantified. Gnetol's effect on cell viability in selected cell lines with or without inflammatory stimulus was assessed. α-Amylase and α-glucosidase inhibition was evaluated. Cyclooxygenase (COX)-1, COX-2, and histone deacetylase inhibition and adipogenesis inhibition were examined. After oral and intravenous administration, gnetol was detected in both serum and urine as the parent compound and as a glucuronidated metabolite. The bioavailability of gnetol was determined to be 6%. Gnetol is rapidly glucuronidated and is excreted in urine and via nonrenal routes. Gnetol was found to exist as an aglycone and as a glycoside in G. gnemon products. Gnetol showed concentration-dependent reductions in cell viability in cancer cell lines with greatest activity in colorectal cancer and potent COX-1, histone deacetylase, and weak COX-2 activities along with limited reduction in inflammation. Gnetol also possessed concentration-dependent alpha-amylase, alpha-glucosidase, and adipogenesis activities. Pretreatment of mice with gnetol was able to increase the latency period to response in analgesia models.


Single-Cell Analysis of Neonatal HSC Ontogeny Reveals Gradual and Uncoordinated Transcriptional Reprogramming that Begins before Birth.
Fetal and adult hematopoietic stem cells (HSCs) have distinct proliferation rates, lineage biases, gene expression profiles, and gene dependencies. Although these differences are widely recognized, it is not clear how the transition from fetal to adult identity is coordinated. Here we show that murine HSCs and committed hematopoietic progenitor cells (HPCs) undergo a gradual, rather than precipitous, transition from fetal to adult transcriptional states. The transition begins prior to birth and is punctuated by a late prenatal spike in type I interferon signaling that promotes perinatal HPC expansion and sensitizes progenitors to the leukemogenic FLT3ITD mutation. Most other changes in gene expression and enhancer activation are imprecisely timed and poorly coordinated. Thus, heterochronic enhancer elements, and their associated transcripts, are activated independently of one another rather than as part of a robust network. This simplifies the regulatory programs that guide neonatal HSC/HPC ontogeny, but it creates heterogeneity within these populations.


Patient Navigation to Improve Early Access to Supportive Care for Patients with Advanced Cancer in Resource-Limited Settings: A Randomized Controlled Trial.
The early integration of supportive care in oncology improves patient-centered outcomes. However, data are lacking regarding how to achieve this in resource-limited settings. We studied whether patient navigation increased access to multidisciplinary supportive care among Mexican patients with advanced cancer. This randomized controlled trial was conducted between August 2017 and April 2018 at a public hospital in Mexico City. Patients aged ≥18 years with metastatic tumors ≤6 weeks from diagnosis were randomized (1:1) to a patient navigation intervention or usual care. Patients randomized to patient navigation received personalized supportive care from a navigator and a multidisciplinary team. Patients randomized to usual care obtained supportive care referrals from treating oncologists. The primary outcome was the implementation of supportive care interventions at 12 weeks. Secondary outcomes included advance directive completion, supportive care needs, and quality of life. One hundred thirty-four patients were randomized: 67 to patient navigation and 67 to usual care. Supportive care interventions were provided to 74% of patients in the patient navigation arm versus 24% in usual care (difference 0.50, 95% confidence interval [CI] 0.34-0.62; p < .0001). In the patient navigation arm, 48% of eligible patients completed advance directives, compared with 0% in usual care (p < .0001). At 12 weeks, patients randomized to patient navigation had less moderate/severe pain (10% vs. 33%; difference 0.23, 95% CI 0.07-0.38; p = .006), without differences in quality of life between arms. Patient navigation improves access to early supportive care, advance care planning, and pain for patients with advanced cancer in resource-limited settings. The early implementation of supportive care in oncology is recommended by international guidelines, but this might be difficult to achieve in resource-limited settings. This randomized clinical trial including 134 Mexican patients with advanced cancer demonstrates that a multidisciplinary patient navigation intervention can improve the early access to supportive and palliative care interventions, increase advance care planning, and reduce symptoms compared with usual oncologist-guided care alone. These results demonstrate that patient navigation represents a potentially useful solution to achieve the adequate implementation of supportive and palliative care in resource-limited settings globally.


Liver-Resident NK Cells: The Human Factor.
Mouse liver contains two natural killer (NK) cell populations, one of which recirculates while the other is tissue resident. Following this discovery, several groups have sought to identify liver-resident NK (lrNK) cells in humans. Here, I present an overview of recent advances in the field.


Influence of football match time-motion parameters on recovery time course of muscle damage and jump ability.
We analysed the time course of recovery of creatine kinase (CK) and countermovement jump (CMJ) parameters after a football match, and correlations between changes in these variables and match time-motion parameters (GPS-accelerometry) in 15 U-19 elite male players. Plasma CK and CMJ height (CMJH), average concentric force (CMJCON) and average eccentric force (CMJECC) were assessed 2 h before and 30 min, 24 h and 48 h post-match. There were substantially higher CK levels 30 min, 24 h and 48 h (ES: 0.43, 0.62, 0.40, respectively), post-match. CMJECC (ES: -0.38), CMJH (ES: -0.35) decreased 30 min post, CMJCON (ES: -0.35), CMJECC (ES: -0.35) and CMJH (ES: -1.35) decreased 24 h post, and CMJCON (ES: -0.41) and CMJH (ES: -0.53) decreased 48 h post. We found correlations between distance covered at velocities ≤21 km · h(-1) and changes in CK at 24 h (r = 0.56) and at 48 h (r = 0.54) and correlations between CK and distance covered >14 km · h(-1) (r = 0.50), accelerations (r = 0.48), and decelerations (r = 0.58) at 48 h. Changes in CMJCON 30 min and 24 h post (both r = -0.68) correlated with impacts >7.1·G. Decelerations >2 m · s(-)(2) correlated with changes CMJCON (r = -0.49) at 48 h and CMJECC (r = -0.47) at 30 min. Our results suggest that match GPS-accelerometry parameters may predict muscle damage and changes in components of neuromuscular performance immediately and 24-48 h post-match.


Unusual degenerated forms of human sperms.
Many spheric bodies with radiating, needle-like filaments are present in semen of patients with fertility problems. These bodies are most likely degenerated sperm. The intermediate forms and a sequential series of degeneration are discussed.


Regulation of endothelial nitric oxide synthase activation in endothelial cells by S1P1 and S1P3.
Endothelial nitric oxide synthase (eNOS) plays a crucial role in vascular homeostasis. Lysophospholipid interaction with sphingosine 1-phosphat (S1P) receptors results in eNOS activation in different cells. In endothelial cells, eNOS activation via S1P1 or S1P3 was shown controversially. The aim of this study is to investigate the meaning of both S1P receptors for eNOS activation in human endothelial cells. Therefore, several S1P1 and S1P3 agonists in combination with antagonists and specific RNAi approach were used. eNOS activation was measured in human umbilical vein endothelial cells (HUVEC) via DAF2-DA-based fluorescence microscopy. For investigation of the signaling pathway, agonists/antagonist studies, RNAi approach, Luminex™ multiplex, and Western Blot were used. In HUVEC, both the S1P1 agonist AUY954 as well as the S1P1,3 agonist FTY720P induced eNOS activation in a time- and dose-dependent manner. Other S1P1 agonists activated eNOS to a lesser extent. The AUY954-induced eNOS activation was blocked by the S1P1 antagonist W146, the combination of W146 and the S1P3 antagonist CAY10444 and the S1P1,3 antagonist VPC23019, but not by CAY10444 indicating the meaning of S1P1 for the AUY954-induced eNOS activation. The FTY720P-induced eNOS activation was blocked only by the combination of W146 and CAY10444 and the combined S1P1,3 antagonist VPC23019, but not by W146 or CAY10444 indicating the importance of both S1P1 and S1P3 for FTY720-induced eNOS activation. These results were confirmed using specific siRNA against S1P1 and S1P3. The S1P1,3 activation results in Akt phosphorylation and subsequent activation of eNOS via phosphorylation at serine(1177) and dephosphorylation at threonine(495). Beside former investigations with rather unspecific S1P receptor activation these data show potent selective S1P1 activation by using AUY954 and with selective S1P receptor inhibition evidence was provided that both S1P1 and S1P3 lead to downstream activation of eNOS in HUVEC in the same experimental setting. Inhibition or knockdown of one of these receptor subtypes did not abolish the eNOS activation and subsequent NO production.