Three-Component Synthesis of Quinoline-4-carboxylic Acids Based on Doebner Hydrogen-Transfer Reaction.

The Doebner hydrogen-transfer reaction has been developed for the synthesis of substituted quinolines from anilines possessing electron-withdrawing groups, which are known to give products in low yields when used in the conventional Doebner reaction. This reaction can be applied to not only anilines having electron-withdrawing groups but also those having electron-donating groups and can be used in the large-scale synthesis of bioactive molecules.

Occult bacteremia in living donor liver transplantation: a prospective observational study of recipients and donors.

PURPOSE: To investigate the incidence and clinical impact of occult bacteremia in liver transplantation (LT). METHODS: This prospective observational study involved a fixed-point observation for up to 2 weeks after living donor LT in 20 recipients, with 20 donors as comparison subjects. Bacteria in the blood samples were detected using the ribosomal RNA-targeted reverse-transcription quantitative polymerase chain reaction method. To identify the causality with the gut microbiota (GM), fecal samples were collected and analyzed simultaneously. RESULTS: Occult bacteremia was identified in four recipients (20%) and three donors (15%) before the operation, and in seven recipients (35%) and five donors (25%) after the operation. Clostridium leptum subgroup, Prevotella, Colinesella, Enterobacteriaceae, and Streptococcus were the main pathogens responsible. Although it did not negatively affect the donor post-hepatectomy outcomes, the recipients with occult bacteremia had a higher rate of infectious complications post-LT. The GM analyses showed fewer post-LT predominant obligate anaerobes in both the recipients and donors with occult bacteremia. CONCLUSIONS: Occult bacteremia is a common condition that occurs in both donors and recipients. While occult bacteremia generally remains subclinical in the healthy population, there is potential risk of the development of an apparent post-LT infection in recipients who are highly immunosuppressed.

Gut Microbiome and Microbiome-Derived Metabolites in Patients with End-Stage Kidney Disease.

The composition of the gut microbiome is altered in patients with chronic kidney disease (CKD). Dysbiosis leads to decreased levels of stool organic acids (OAs) and systemic inflammation, followed by accumulation of uremic toxins (UTs) and the development of end-stage kidney disease (ESKD). We assessed the relationship between the microbiome and UT levels or the development of ESKD by comparing patients undergoing hemodialysis (HD) and those with normal renal function (NRF). This cross-sectional study recruited 41 patients undergoing HD and 38 sex- and age-matched patients with NRF, and gut microbiome, levels of plasma UTs, inflammatory markers, and stool OAs were compared. The indices of beta-diversity differed significantly between patients with NRF and those undergoing HD, and between patients undergoing HD with and without type 2 diabetes. The levels of stool total OA, inflammatory markers, and UTs differed significantly between the patients with NRF and those undergoing HD. The combined main effects of type 2 diabetes and kidney function status were accumulation of indoxyl sulfate and p-cresyl sulfate. The relative abundances of Negativicutes and Megamonas were associated with development of ESKD and with the levels of UTs, even after adjustment for factors associated with the progression of ESKD. The present study indicates that the gut environment differs between patients with NRF and those undergoing HD and between patients undergoing HD with and without type 2 diabetes. Moreover, ESKD patients with diabetes accumulate more UTs derived from the gut microbiome, which might be associated with cardio-renal diseases and poor prognosis.

Dysbiosis and Depletion of Fecal Organic Acids Correlate With the Severity of Rejection After Rat Liver Transplantation.

The impact of T cell-mediated rejection (TCMR) after liver transplantation (LT) on the alterations in the gut microbiota (GM) and associated intestinal environment represented by fecal organic acids (OAs) require further elucidation. A rat allogeneic LT model was prepared without immunosuppressants or antibiotics, and a syngeneic model was used as a control. Qualitative and quantitative analyses of fecal samples at fixed time points were performed. Correlation analyses were also performed between liver function and GMs and OA levels. In the allogeneic TCMR group, the number of predominant obligate anaerobes decreased as liver function declined. Clostridioides difficile, Enterobacteriaceae, Enterococcus, Streptococcus, and Staphylococcus were significantly increased. Regarding fecal OA concentration, short-chain fatty acid (SCFA) concentrations were depleted as liver function declined. In contrast, in the syngeneic group, GM and OAs exhibited only slight, transient, and reversible disturbances. In addition, alanine aminotransferase and total bilirubin were positively correlated with the number of Enterobacteriaceae and Enterococcus, and negatively correlated with the fecal concentration of SCFAs. The allogeneic TCMR model demonstrated distinct dysbiosis and depletion of fecal OAs as TCMR progressed after LT. The degree of graft injury was closely related to the number of specific bacterial strains and the concentrations of fecal SCFAs.

Comparison of the risk of appendiceal tumors in uncomplicated and complicated appendicitis.

BACKGROUND: Interval appendectomy or non-operative management is commonly performed for complicated appendicitis in adult patients. However, these treatments are still controversial because the incidence rate of appendiceal tumors recognized after interval appendectomy is reportedly higher than that after emergency appendectomy. Thus, this study aimed to compare the appendiceal tumor rates between uncomplicated and complicated appendicitis. METHODS: This study was a retrospective review of patients with appendicitis who underwent surgical removal at a single institution over 7.5 years. The primary objective was the comparison of the incidence rate of appendiceal tumors using propensity score matching, and the secondary objective was the same comparison among older patients, defined as patients aged ≥ 60 years. RESULTS: A total of 1277 patients were included. Of these patients, 297 (23.3%) were preoperatively diagnosed with complicated appendicitis. Moreover, 22 (1.7%) patients, including 14 cases of complicated appendicitis and 8 cases of uncomplicated appendicitis, were diagnosed with appendiceal tumors based on pathological examination. No significant difference was found in the incidence rate of appendiceal tumors between the two groups after matching for patients' background, including age, sex, and history of appendicitis by propensity score matching (P = 0.073). However, among patients aged ≥ 60 years, the incidence of appendiceal tumors was significantly higher in complicated than in uncomplicated appendicitis (P = 0.006). CONCLUSIONS: Although the overall risk of appendiceal tumors did not differ between complicated and uncomplicated appendicitis when analyzed by the propensity score matching, in older patients aged ≥ 60 years, the risk increased among those with complicated appendicitis. Therefore, although the incidence is low, complicated appendicitis, particularly, among older patients, should be examined carefully and be performed IA when unusual findings exist.

The Association of Bohler's Angle With Postoperative Pain and Gender for Displaced Intra-Articular Calcaneal Fracture, Multicenter Retrospective Study-TRON Study.

A relationship between Böhler angle (BA) before or after surgery and clinical outcomes remains unclear. This retrospective multicenter cohort study aimed to compare pain and functional outcomes between a group in which the reduction angle was preserved and a group in which the reduction angle was lost during follow-up, and to clarify the risk factors leading to loss of last follow-up BA. From 2014 to 2018, 271 cases of calcaneal fractures were surgically treated at ten facilities. We divided patients into Group L (lost reduction of fracture) and Group P (preserved reduction of fracture). We matched subjects between the 2 groups according to age, sex and BA before surgery and compared American Orthopedic Foot and Ankle Society (AOFAS) score between the groups. We investigated the correlation between the amount of BA loss and postoperative pain. The factors leading to loss of last follow-up BA were examined by logistic regression analysis. Ultimately, 112 patients were eligible. After matching, each group included 38 patients. There was no difference between the 2 groups in total AOFAS score. However, the pain component of AOFAS score at 6 months and 12 months were worse in group L than in group P (p = .011, p = .031, respectively). We also showed a weak correlation between the amount of BA loss and postoperative pain. Logistic regression analysis revealed that female and BA before surgery independently predicted loss of reduction (odds ratios: 4.66, 95% CI: 1.15-18.9 and odds ratios: 0.90, 95% CI: 0.82-0.99, respectively). We clarified that reduction and preservation of BA within its normal range should lead to decrease postoperative pain. Female and lower pre-BA were risk factors leading to loss of reduction of BA in operative treatment of calcaneal fractures.

Plate fixation through the lateral extensile approach versus cannulated screw fixation through the sinus tarsi approach for calcaneal fracture: a multicenter, propensity score-matched TRON study.

PURPOSE: For calcaneal fracture, plate fixation through lateral extensive approach (LEP) is the most common procedure performed to achieve anatomic reduction. However, wound complications sometimes occur after LEP. To reduce complications, minimally invasive operative methods with cannulated screw fixation through sinus tarsi approach (STS) were developed. The aim of this multicenter propensity-matched study was to compare the clinical and radiographic outcomes of LEP to those of STS for calcaneal fracture and to evaluate the incidence of postoperative complications including surgical site infection (SSI). METHODS: We extracted 271 patients with calcaneal fracture undergoing surgery between January 2014 and March 2019 from our multicenter TRON database. We assessed the American Orthopedic Foot and Ankle Society (AOFAS) score at the final follow-up as the clinical outcome. We obtained the Bohler and Preis angles as radiographic parameters and also recorded the complications. We divided the subjects into two groups: LEP group and STS group. To adjust for baseline differences between the groups, a propensity score matching algorithm was used in a 1:1 ratio. RESULTS: After matching, there were 32 fractures in each group. There was no significant difference between the LEP versus STS group in AOFAS score at final follow-up (90 vs 90 points, p = 0.98) and in the Bohler and Pries angles (19.2 vs. 18.0 degrees, p = 0.74 and 16.0 vs. 17.5 degrees, p = 0.47). The rate of SSI in the LEP group was higher than that in the STS group (21.9% vs. 0.0%, p = 0.01). CONCLUSION: For calcaneal fracture, STS provides similar fixation effectiveness and functional outcomes as LEP while reducing the likelihood of infection.

Generation of Elemental Fluorine through the Electrolysis of Copper Difluoride at Room Temperature.

The safe generation of F2 gas at room temperature by using simple cell configurations has been the "holy grail" of fluorine research for centuries. Thus, to address this issue, we report generation of F2 gas through the electrolysis of CuF2 in a CsF-2.45HF molten salt without the evolution of H2 gas. The CuF2 is selected through a series of thermodynamic and kinetic assessments of possible metal fluorides. Anode assessments on graphite and glass-like carbon demonstrate the effect of the absence of the anode during generation of F2 gas owing to stabilized operations at room temperature. Although the Ni anode dissolves during electrolysis in the conventional medium-temperature cell, herein, it facilitates stable electrolysis over 100 h, achieving an F2 gas purity of over 99 % with the potential to operate using one-compartment electrolysis. This work presents a safe and propitious method for the generation of high-purity F2 gas for small-scale lab and industrial applications.

Heteroaggregation between Charged and Neutral Particles.

Experimentally determined heteroaggregation rates between charged and neutral colloidal particles are reported for the first time. Different positively and negatively charged polystyrene latex particles are investigated. The neutral particles are obtained through adsorption of an appropriate amount of oppositely charged additives, such as aliphatic oligoamines, iron cyanide complexes, or alkyl sulfates. Heteroaggregation rates were measured with time-resolved multiangle light scattering. One observes that heteroaggregation between charged and neutral particles is always fast and diffusion controlled. These experimental values are compared with calculations of the Derjaguin, Landau, Verwey, and Overbeek (DLVO) theory, whereby one finds that this heteroaggregation process is highly sensitive to charge regulation conditions. The comparison with experiments shows unambiguously that the surface of the neutral particles regulates strongly and probably behaves close to a constant potential surface. This observation is in line with direct force measurements on similar systems and further agrees with the fact that for neutral surfaces the capacitance of the diffuse layer is expected to be much smaller than the one of the inner layer.

Nanobubble Retention in Saturated Porous Media under Repulsive van der Waals and Electrostatic Conditions.

An understanding of nanobubble (NB) migration in porous media is needed for potential environmental applications. The solution chemistry is well known to be a critical factor in determining interactions of other colloids and nanoparticles with surfaces. However, little quantitative research has examined the influence of solution chemistry on NB transport. One-dimensional column experiments were therefore conducted to investigate the transport, retention, and release of NBs in glass beads under different solution chemistry conditions. NB concentrations in the effluent were reduced with an increase in ionic strength (IS) or a decrease in pH due to a reduction in the repulsive force between the glass surface and NBs, especially when the solution contained Ca2+ as compared to Na+ and for larger NBs. This result was somewhat surprising because electrostatic and van der Waals interactions for NBs were both repulsive on a homogeneous glass bead surface. NB retention on the surface was explained by ubiquitous nanoscale roughness on the glass beads that significantly lowered the energy barrier and localized attractive charge heterogeneity and/or hydrophobic interactions. In contrast to Na+, adsorbed Ca2+ ions produced charge heterogeneity that enhanced NB retention and inhibited release with IS reduction.

Wakayama Medical University Hospital perinatal helicopter ambulance service: 14 year review.

BACKGROUND: In 2003, a perinatal helicopter air ambulance service was introduced for remote areas of Wakayama and Mie prefectures, Japan, but its long-term impact on perinatal medicine has not yet been analyzed. METHODS: A retrospective observational study was conducted on helicopter air ambulance cases recorded between January 2003 and December 2016 at Wakayama Medical University Hospital (WMUH). RESULTS: During that period, 61 pregnant mothers were transferred by helicopter air ambulance to WMUH. Between 2003 and 2009, the mean period from transfer to birth was 0.6 weeks, whereas between 2008 and 2016, this increased to 1.6 weeks, and the survival rate of infants born after transfer did not differ significantly (84.2%, 32/38 versus 82.1%, 23/28). Seventy-three neonates were transferred. The number transferred between 2003 and 2009 was 46, whereas this decreased to 27 between 2010 and 2016. The neonatal mortality rate in south Wakayama plus south Mie gradually decreased. The reasons for the longer period from transfer to birth, and the decrease in the rate of very low-birthweight infants after transfer may be due to development in the management of threatened premature labor, and the earlier transfer of such cases by regional obstetricians. The reasons for the decline in neonatal transfer may have included the development of fetal diagnostic techniques and improved efficiency of neonatal ground-transport in the South Wakayama region. CONCLUSION: The helicopter air ambulance is an important form of medical transportation in the south Kii peninsula.

Identification and characterization of PKCγ, a kinase associated with SCA14, as an amyloidogenic protein.

Amyloid assemblies are associated with a wide range of human disorders, including Alzheimer's and Parkinson's diseases. Here, we identify protein kinase C (PKC) γ, a serine/threonine kinase mutated in the neurodegenerative disease spinocerebellar ataxia type 14 (SCA14), as a novel amyloidogenic protein with no previously characterized amyloid-prone domains. We found that overexpression of PKCγ in cultured cells, as well as in vitro incubation of PKCγ without heat or chemical denaturants, causes amyloid-like fibril formation of this protein. We also observed that SCA14-associated mutations in PKCγ accelerate the amyloid-like fibril formation both in cultured cells and in vitro. We show that the C1A and kinase domains of PKCγ are involved in its soluble dimer and aggregate formation and that SCA14-associated mutations in the C1 domain cause its misfolding and aggregation. Furthermore, long-term time-lapse imaging indicates that aggregates of mutant PKCγ are highly toxic to neuronal cells. Based on these findings, we propose that PKCγ could form amyloid-like fibrils in physiological and/or pathophysiological conditions such as SCA14. More generally, our results provide novel insights into the mechanism of amyloid-like fibril formation by multi-domain proteins.

Heteroaggregation of oppositely charged particles in the presence of multivalent ions.

Time-resolved dynamic light scattering is used to measure absolute heteroaggregation rate coefficients and the corresponding stability ratios for heteroaggregation between amidine and sulfate latex particles. These measurements are complemented by the respective quantities for the homoaggregation of the two systems and electrophoresis. Based on the latter measurements, the stability ratios are calculated using Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. In monovalent salt solutions, the two types of particles investigated are oppositely charged. In the presence of multivalent ions, however, one particle type reverses its charge, while the charge of the other particle type is hardly affected. In this region, the heteroaggregation stability ratio goes through a pronounced maximum when plotted versus concentration. This region of slow aggregation is wider than the one observed in the corresponding homoaggregation process. One also finds that the onset of this region sensitively depends on the boundary conditions used to calculate the double layer force. The present results are more in line with constant potential boundary conditions.

Medical facility statistics in Japan.

Medical facility statistics provide essential information to policymakers, administrators, academics, and practitioners in the field of health services. In Japan, the Health Statistics Office of the Director-General for Statistics and Information Policy at the Ministry of Health, Labour and Welfare is generating these statistics. Although the statistics are widely available in both Japanese and English, the methodology described in the technical reports are primarily in Japanese, and are not fully described in English. This article aimed to describe these processes for readers in the English-speaking world. The Health Statistics Office routinely conduct two surveys called the Hospital Report and the Survey of Medical Institutions. The subjects of the former are all the hospitals and clinics with long-term care beds in Japan. It comprises a Patient Questionnaire focusing on the numbers of inpatients, admissions, discharges, and outpatients in one month, and an Employee Questionnaire, which asks about the number of employees as of October 1. The Survey of Medical Institutions consists of the Dynamic Survey, which focuses on the opening and closing of facilities every month, and the Static Survey, which focuses on staff, facilities, and services as of October 1, as well as the number of inpatients as of September 30 and the total number of outpatients during September. All hospitals, clinics, and dental clinics are requested to submit the Static Survey questionnaire every three years. These surveys are useful tools for collecting essential information, as well as providing occasions to implicitly inform facilities of the movements of government policy.

Surgical tricks of handling a needle and grasping forceps during laparoscopic percutaneous extraperitoneal closure (LPEC) for pediatric inguinal hernia.

INTRODUCTION: Laparoscopic percutaneous extraperitoneal closure (LPEC) is an alternative to open repair for pediatric inguinal hernias; however, its application for boys remains controversial. In this study, we developed a technique to enhance the safety and feasibility of LPEC. MATERIAL AND SURGICAL TECHNIQUE: In our technique, forceps are used to pull up the peritoneum ahead on the route, creating a space between the peritoneum and structures, including gonadal vessels and vas deferens. This potentially decreases the risk of perioperative injury of these structures. This technique also allows the needle to pass on the shortest course around the inguinal ring without crossing the vas deferens, possibly lowering the likelihood of injury and preventing excessively high ligation of the vaginalis process. DISCUSSION: Our technique diversifies the LPEC methods, thereby augmenting the feasibility and safety of the procedure.

Probiotics may alleviate intestinal damage induced by cardiopulmonary bypass in children.

OBJECTIVES: Intestinal ischaemia-reperfusion injury induced by cardiopulmonary bypass causes intestinal epithelial barrier dysfunction, leading to dysbiosis and bacterial translocation. We conducted a randomized prospective study with 2 objectives: (i) to investigate epithelial barrier dysfunction and bacterial translocation induced by cardiopulmonary bypass and changes in the gut microbiota and (ii) to verify whether probiotics can improve these conditions. METHODS: Between 2019 and 2020, patients 0-15 years old scheduled to undergo cardiac surgery using cardiopulmonary bypass were enrolled and randomly allocated to 2 groups: the intervention group received probiotics and the control group did not receive probiotics. We analysed the microbiota in faeces and blood, organic acid concentrations in faeces, plasma intestinal fatty acid-binding protein and immunological responses. RESULTS: Eighty-two patients were enrolled in this study. The characteristics of the patients were similar in both groups. The total number of obligate anaerobes was higher in the intervention group than in the control group after postoperative day 7. We identified 4 clusters within the perioperative gut microbiota, and cluster changes showed a corrective effect of probiotics on dysbiosis after postoperative day 7. Organic acid concentrations in faeces, incidence of bacterial translocation, intestinal fatty acid-binding protein levels and immunological responses, except for interleukin -17A, were not markedly different between the 2 groups. CONCLUSIONS: Administration of probiotics was able to correct dysbiosis but did not sufficiently alleviate the intestinal damage induced by cardiopulmonary bypass. More effective methods should be examined to prevent disturbances induced by cardiac surgery using cardiopulmonary bypass. CLINICAL TRIAL REGISTRATION NUMBER: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000037174 UMIN000035556.

Exome sequencing identifies a novel INPPL1 mutation in opsismodysplasia.

Opsismodysplasia is an autosomal recessive skeletal disorder characterized by facial dysmorphism, micromelia, platyspondyly and retarded bone maturation. Recently, mutations in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1) are found in several families with opsismodysplasia by a homozygosity mapping, followed by whole genome sequencing. We performed an exome sequencing in two unrelated Japanese families with opsismodysplasia and identified a novel INPPL1 mutation, c.1960_1962delGAG, in one family. The mutation is predicted to result in an in-frame deletion (p.E654del) within the central catalytic 5-phosphate domain. Our results further support that INPPL1 is the disease gene for opsismodysplasia and that opsismodysplasia has genetic heterogeneity.

Anal function after ligation of the intersphincteric fistula tract.

BACKGROUND: Although the ligation of the intersphincteric fistula tract is a promising anal sphincter-saving procedure for fistula-in-ano, the objective assessment of the sphincter preservation remains unknown. OBJECTIVE: The primary end point was to measure the anal function before and after this procedure. The secondary end point measured was cure of the disease. DESIGN: This study is a prospective observational study. SETTING: This study was conducted at the Department of Surgery, Kameda Medical Center, Japan, from March 2010 to August 2012. PATIENTS: Twenty patients with transsphincteric or complex fistulas were evaluated. INTERVENTIONS: All patients underwent the ligation of the intersphincteric fistula tract with a loose seton for anal fistulas. MAIN OUTCOME MEASURES: Anal manometric study was performed before and 3 months after the procedure. Fecal incontinence was evaluated by using the fecal incontinence severity index. Failure was defined as nonhealing of the surgical wound or fistula. RESULTS: The median operation time was 42 minutes. No intraoperative complications were documented. The median follow-up duration was 18 (3-32) months. No patients reported any incontinence postoperatively. The median score of the fecal incontinence severity index before and 3 months after the procedure was 0. The median maximum resting pressure measured before and after operation were 125 (71-175) cm H2O and 133 (95-169) cm H2O. The median maximum squeeze pressure measured before and after operation were 390 (170-815) cm H2O and 432 (200-902) cm H2O. There were no significant postoperative changes in either the resting pressure or the squeeze pressure. Primary healing was observed in 19 (95%) patients, and the median healing time was 7 weeks; 1 wound remained incompletely healed. LIMITATIONS: Short-term follow-up may not justify the use of the term definitive cure. CONCLUSION: The ligation of the intersphincteric fistula tract with a loose seton showed no postoperative deterioration on anal sphincter function with favorable healing rates.

A randomized, prospective, double-blind, placebo-controlled trial of the effect of diltiazem gel on pain after hemorrhoidectomy.

BACKGROUND: Spasm of the internal anal sphincter is considered to be one of the causes of pain in anal diseases. We have evaluated the effects of topical diltiazem on postoperative pain after hemorrhoidectomy. METHODS: Sixty-two patients were randomly assigned to receive a 2 % diltiazem gel (n = 32) or a placebo gel (n = 30) after hemorrhoidectomy. Patients applied the gel to the anal region three times per day for 14 days. Pain both in the resting state and on defecation ranged from 0 to 10 on a numerical rating scale, and the number of prescribed loxoprofen tablets (Loxonin) were recorded and confirmed daily by telephone. Any morbidity during the follow-up period was recorded. RESULTS: Both pain scores during defecation and the number of analgesic tablets consumed tended to be lower in the diltiazem group, although they did not reach statistical significance (P = 0.09, P = 0.12, respectively). Total number of complications was significantly higher in the diltiazem group, but each incidence of complications, including itching sensation, headache, and dizziness was not statistically different. CONCLUSIONS: Perianal application of 2 % diltiazem gel after hemorrhoidectomy has the potential to reduce postoperative pain during defecation.