Development and validation of risk prediction model for post-donation renal function in living kidney donors.

This study aimed to create and validate a predictive model for renal function following live kidney donation, using pre-donation factors. Accurately predicting remaining renal function post live kidney donation is currently insufficient, necessitating an effective assessment tool. A multicenter retrospective study of 2318 live kidney donors from two independent centers (May 2007-December 2019) was conducted. The primary endpoint was the reduction in eGFR to below 60 mL/min/m2 6 months post-donation. The primary endpoint was achieved in 14.4% of the training cohort and 25.8% of the validation cohort. Sex, age, BMI, hypertension, preoperative eGFR, and remnant kidney proportion (RKP) measured by computerized tomography (CT) volumetry were found significant in the univariable analysis. These variables informed a scoring system based on multivariable analysis: sex (male: 1, female: 0), age at operation (< 30: 0, 30-39: 1, 40-59: 2, ≥ 60: 3), preoperative eGFR (≥ 100: 0, 90-99: 2, 80-89: 4, < 80: 5), and RKP (≥ 52%: 0, < 52%: 1). The total score ranged from 0 to 10. The model showed good discrimination for the primary endpoint in both cohorts. The prediction model provides a useful tool for estimating post-donation renal dysfunction risk, factoring in the side of the donated kidney. It offers potential enhancement to pre-donation evaluations.

Necessity of induction agent modification for old age kidney transplant recipients.

Background: Immunosenescence gradually deteriorates the function of the immune system, making elderly patients susceptible to infection, while reducing rejection of organ transplants. Therefore, age-adaptive immunosuppression is necessary in the elderly. We evaluated clinical outcomes such as rejection and infection rate when using basiliximab and rabbit anti-thymocyte globulin (r-ATG) as induction agents in elderly and young organ transplant recipients. Methods: We retrospectively reviewed patients who underwent kidney transplantation (KT) between June 2011 and April 2019. We enrolled 704 adult KT patients and classified the patients into groups according to patient age. We compared the outcomes of infection and biopsy-proven acute rejection (BPAR) according to the type of induction agent (basiliximab and r-ATG [4.5 mg/kg]). Results: The patient group included 520 recipients (74.6%) in the younger recipient group and 179 recipients (25.4%) in the older recipient group. When r-ATG was used as an induction agent, BPAR within 6 months occurred less (p = 0.03); however, infections within 6 months were higher in older recipients. Deaths due to infection were more common in older recipients (p = 0.003). Conclusion: It may be necessary to use less intensive induction therapy for older recipients, of which dose reduction of r-ATG is one option.

Unveiling the inhibition mechanism of Clostridioides difficile by Bifidobacterium longum via multiomics approach.

Antibiotic-induced gut microbiota disruption constitutes a major risk factor for Clostridioides difficile infection (CDI). Further, antibiotic therapy, which is the standard treatment option for CDI, exacerbates gut microbiota imbalance, thereby causing high recurrent CDI incidence. Consequently, probiotic-based CDI treatment has emerged as a long-term management and preventive option. However, the mechanisms underlying the therapeutic effects of probiotics for CDI remain uninvestigated, thereby creating a knowledge gap that needs to be addressed. To fill this gap, we used a multiomics approach to holistically investigate the mechanisms underlying the therapeutic effects of probiotics for CDI at a molecular level. We first screened Bifidobacterium longum owing to its inhibitory effect on C. difficile growth, then observed the physiological changes associated with the inhibition of C. difficile growth and toxin production via a multiomics approach. Regarding the mechanism underlying C. difficile growth inhibition, we detected a decrease in intracellular adenosine triphosphate (ATP) synthesis due to B. longum-produced lactate and a subsequent decrease in (deoxy)ribonucleoside triphosphate synthesis. Via the differential regulation of proteins involved in translation and protein quality control, we identified B. longum-induced proteinaceous stress. Finally, we found that B. longum suppressed the toxin production of C. difficile by replenishing proline consumed by it. Overall, the findings of the present study expand our understanding of the mechanisms by which probiotics inhibit C. difficile growth and contribute to the development of live biotherapeutic products based on molecular mechanisms for treating CDI.

Multiomics analysis reveals the biological effects of live Roseburia intestinalis as a high-butyrate-producing bacterium in human intestinal epithelial cells.

Butyrate-producing bacteria play a key role in human health, and recent studies have triggered interest in their development as next-generation probiotics. However, there remains limited knowledge not only on the identification of high-butyrate-producing bacteria in the human gut but also in the metabolic capacities for prebiotic carbohydrates and their interaction with the host. Herein, it was discovered that Roseburia intestinalis produces higher levels of butyrate and digests a wider variety of prebiotic polysaccharide structures compared with other human major butyrate-producing bacteria (Eubacterium rectale, Faecalibacterium prausnitzii, and Roseburia hominis). Moreover, R. intestinalis extracts upregulated the mRNA expression of tight junction proteins (TJP1, OCLN, and CLDN3) in human intestinal epithelial cells more than other butyrate-producing bacteria. R. intestinalis was cultured with human intestinal epithelial cells in the mimetic intestinal host-microbe interaction coculture system to explore the health-promoting effects using multiomics approaches. Consequently, it was discovered that live R. intestinalis only enhances purine metabolism and the oxidative pathway, increasing adenosine triphosphate levels in human intestinal epithelial cells, but that heat-killed bacteria had no effect. Therefore, this study proposes that R. intestinalis has potentially high value as a next-generation probiotic to promote host intestinal health.

Graft-recipient-weight ratio and lowered immunosuppression is important for the success of adult liver retransplantation.

This study analyzed the risk of liver retransplantation and factors related to better outcome. Adult liver transplantations performed during 1996-2021 were included. Comparison between first transplantation and retransplantation were performed. Among retransplantation cases, comparison between whole liver and partial liver graft was performed. Multivariable Cox analyses for analyzing risk factors for primary graft and overall patient survival were performed for the entire cohort as well as the subgroup of patients with retransplantation. A total 2237 transplantations from 2135 adults were included and 103 cases were retransplantation. A total of 44 cases (42.7%) were related to acute graft dysfunction while 59 cases (57.3%) were related to subacute or chronic graft dysfunction. Retransplantation was related poor primary graft (HR 3.439, CI 2.230-5.304, P < 0.001) and overall patient survival. (HR 2.905, CI 2.089-4.040, P < 0.001) Among retransplantations, mean serum FK506 trough level ≥ 9 ng/mL was related to poor primary graft (HR 3.692, CI 1.288-10.587, P = 0.015) and overall patient survival. (HR 2.935, CI 1.195-7.211, P = 0.019) Graft-recipient-weight ratio under 1.0% was related to poor overall patient survival in retransplantations. (HR 3.668, CI 1.150-11.698, P = 0.028). Retransplantation can be complicated with poor graft and patient survival compared to first transplantation, especially when the graft size is relatively small. Lowering the FK506 trough level during the first month can be beneficial for outcome.

Improved recurrence-free survival in patients with HCC with post-transplant plasma exchange.

Total plasma exchange (TPE) can play a role in cancer treatment by eliminating immune checkpoint inhibitors. This study investigated whether TPE improved oncological outcomes in patients with HCC who underwent ABO-incompatible living donor liver transplantation (LT). The study included 152 patients who underwent ABO-incompatible living donor LT for HCC between 2010 and 2021 at Samsung Medical Center. Overall survival was analyzed using the Kaplan-Meier curve, whereas HCC-specific recurrence-free survival (RFS) was analyzed using the cumulative incidence curve after propensity score matching. Cox regression and competing risks subdistribution hazard models were used to identify the risk factors associated with overall survival and HCC-specific RFS, respectively. The propensity score matching resulted in 54 matched pairs, grouped according to whether they underwent postoperative TPE [post-transplant TPE(+)] or not [post-transplant TPE(-)]. The 5-year HCC-specific RFS cumulative incidence was superior in the post-transplant TPE (+) group [12.5% (95% CI: 3.1%-21.9%)] compared with the post-transplant TPE(-) group [38.1% (95% CI: 24.4%-51.8%), p = 0.005]. In subgroup analysis for patients with microvascular invasion and those beyond the Milan criteria, the post-transplant TPE(+) group showed significantly superior HCC-specific survival. The multivariable analysis also showed that postoperative TPE had a protective effect on HCC-specific RFS (HR = 0.26, 95% CI: 0.10-0.64, p = 0.004) and that the more post-transplant TPE was performed, the better RFS was observed (HR = 0.71, 95% CI: 0.55-0.93, p = 0.012). Post-transplant TPE was found to improve RFS after ABO-incompatible living donor LT for HCC, particularly in advanced cases with microvascular invasion and beyond Milan criteria. These findings suggest that TPE may have a potential role in improving oncological outcomes in patients with HCC undergoing LT.

Two-Week Protocol Biopsy in Renal Allograft: Feasibility, Safety, and Outcomes.

BACKGROUND: Protocol biopsy in renal allograft helps to early detect subclinical rejection (SCR) in patients who have no abnormal clinical and laboratory findings. Still, there are rare reports about the techniques and outcomes of two-week protocol biopsy. The aim of this study was to assess two-week protocol biopsy regarding the technical feasibility, procedure safety, and clinical outcomes. METHODS: A total of 894 protocol biopsies were performed in adult recipients between 2012 and 2019. Two-week and one-year protocol biopsies were guided with ultrasound in 842 and 399 patients by one of four radiologists with wide range of biopsy experience, respectively. These protocol biopsies were compared in terms of feasibility and safety. Standard references were clinico-laboratory findings and biopsy examinations. RESULTS: The median period of two-week and one-year protocol biopsies were 12 days (10-20 days) and 383 days (302-420 days), respectively. All protocol biopsies were technically successful and there was no difference between radiologists regarding technical success and complications (p = 0.453). Major complication (Clavien-Dindo grading II-IV) rates of two-week and one-year protocol biopsies were 0.3% (3/842) and 0.2% (1/399), respectively (p = 1.000). However, univariate analysis demonstrated that platelet count < 100 K/mL and blood urea nitrogen ≥ 40 mg/dL were associated with major complications in two-week protocol biopsy. The SCRs of these protocol biopsies were 15.4% (130/842) and 33.6% (134/399), respectively (p < 0.001). CONCLUSION: Two-week protocol biopsy is technically feasible and safe. It contributes to early detecting a substantial number of SCRs. Prior to the biopsy, platelet count and blood urea nitrogen should be carefully checked to predict major complications.

Clinical effectiveness of liraglutide on weight loss in South Koreans: First real-world retrospective data on Saxenda in Asia.

ABSTRACT: Among Asian countries, South Korea was the first to approve liraglutide as a treatment for obesity. Thus, the clinical effectiveness of liraglutide has not been studied in Asian populations.In this study, we retrospectively analyzed obese patients [body mass index (BMI) >27 kg/m2] who were treated with liraglutide between March 2018 and March 2019 in a single clinic. Weight, BMI, HbA1c, and clinical data were collected before liraglutide treatment. Changes in body weight and composition and their relationships with clinical variables were examined at re-prescription dates within 30, 60, 90, and 180 days.A total of 169 subjects were studied. The average age was 41.5 years, and 42% of the subjects were male. The average weight was 85.2 kg, and the average BMI was 30.8 kg/m2. Weight reduction was significant (-5.5 ±â€Š3.4 kg, 30 days: -3.2 ±â€Š1.8 kg, 60 days: -4.5 ±â€Š2.3 kg, 90 days: -6.3 ±â€Š2.6 kg, 180 days: -7.8 ±â€Š3.5 kg) during the follow-up period and increased with longer treatment time (P < .001). The percentages of subjects that showed ≥ 5% and ≥ 10% body weight reduction were 62.1% and 17.2%, respectively. In the body composition analysis, skeletal muscle weight loss was -3.56 ±â€Š29.7%, which was significantly smaller than fat weight loss of -11.06 ±â€Š10.4% (P = .03). Weight loss was not significantly related to age, sex, baseline BMI, baseline HbA1c, smoking status, alcohol consumption, coffee intake.In conclusion, Liraglutide treatment led to meaningful weight loss in South Korean patients, and fat mass reduction was prominent during treatment. Furthermore, liraglutide showed greater clinical effectiveness with longer treatment time.

Development of an in vitro coculture device for the investigation of host-microbe interactions via integrative multiomics approaches.

The commensal gut bacterium Akkermansia muciniphila is well known as a promising probiotic candidate that improves host health and prevents diseases. However, the biological interaction of A. muciniphila with human gut epithelial cells has rarely been explored for use in biotherapeutics. Here, we developed an in vitro device that simulates the gut epithelium to elucidate the biological effects of living A. muciniphila via multiomics analysis: the Mimetic Intestinal Host-Microbe Interaction Coculture System (MIMICS). We demonstrated that both human intestinal epithelial cells (Caco-2) and the anaerobic bacterium A. muciniphila can remain viable for 12 h after coculture in the MIMICS. The transcriptomic and proteomic changes (cell-cell junctions, immune responses, and mucin secretion) in gut epithelial cells treated with A. muciniphila closely correspond with those reported in previous in vivo studies. In addition, our proteomic and metabolomic results revealed that A. muciniphila activates glucose and lipid metabolism in gut epithelial cells, leading to an increase in ATP production. This study suggests that A. muciniphila improves metabolism for ATP production in gut epithelial cells and that the MIMICS may be an effective general tool for evaluating the effects of anaerobic bacteria on gut epithelial cells.

The Natural History of High-Grade Partial Thickness Rotator Cuff Tears: The Conversion Rate to Full Thickness Tears and Affecting Factors.

BACKGROUND: Information regarding the progression of high-grade partial thickness rotator cuff tears (PTRCTs) is scarce. We aimed to assess the clinical outcome and the conversion rate to full thickness tears in patients with high-grade PTRCTs who underwent nonoperative treatment and to determine the factors associated with tear progression. METHODS: A total of 52 patients with high-grade PTRCTs, which were detected by magnetic resonance imaging or ultrasonography (USG), were treated conservatively between 2010 and 2017. They were followed up with USG at 6- to 12-month intervals for a mean of 34 months (range, 12-105 months). The average patient age was 57 years (range, 34-70 years), and 34 patients were women. Age, sex, body mass index, arm dominance, symptom duration, subscapularis tendon involvement, tear location, and trauma history were compared between patients with and without conversion to full thickness tears. RESULTS: A substantial percentage of high-grade PTRCTs progressed to full thickness tears (16/52, 30.8%). According to Kaplan-Meier analysis, the full thickness conversion rate was 30.8% at 3 years and 64% at 4 years. The full thickness conversion rate was higher in patients with subscapularis tendon involvement (p = 0.012). CONCLUSIONS: A considerably large proportion of high-grade PTRCTs progressed to full thickness tears. Therefore, regular monitoring of tear progression should be considered after conservative treatment of high-grade PTRCTs, particularly in patients with subscapularis tendon involvement.

New quantified measurement of fatty infiltration of the rotator cuff muscles using magnetic resonance imaging.

BACKGROUND: The degree of fatty infiltration of the rotator cuff muscle is typically evaluated using the Goutallier-Fuchs grading system, but its consistency remains controversial. This study aimed to evaluate a new quantified measurement of fatty infiltration based on three-dimensionally reconstructed volumetric data obtained from magnetic resonance images of non-pathologic shoulders using open-source software. METHODS: Fourteen shoulder 3-T magnetic resonance images (8 men, 6 women) without lesions obtained between 2010 and 2017 were analysed. Slicer version 4.6.2 was used to semi-automatically reconstruct the three-dimensional volumetric data from T2 sagittal oblique images and to differentiate fat tissue from rotator cuff muscle using the difference in signal intensity. RESULTS: The cutoff value for dividing muscle and fat was 508.9. The inter-class and intra-class correlations of each rotator cuff muscle and fat tissue were >0.9 (all P < 0.001). The mean muscle volume of the supraspinatus, infraspinatus, teres minor, and subscapularis were 15.2, 20.9, 13.3, and 29.7 mL, respectively. The muscle volume of the men was greater than that of the women (all P < 0.001), and the fat infiltration ratio was positively correlated with body mass index (all P < 0.05). CONCLUSIONS: The semi-automated quantified measurement of fatty infiltration of the rotator cuff muscles using magnetic resonance imaging and Slicer software presented excellent consistency. This technique could be an alternative measurement to complement the weak consistency of the Goutallier-Fuchs grading system. However, to reduce the error of measurement, this study evaluated non-pathologic shoulders. Therefore, further study using magnetic resonance imaging of pathologic shoulders is necessary for actual clinical application. LEVEL OF EVIDENCE: Level IV, case series, diagnostic study.

Corneal nerve healing after in situ laser nerve transection.

PURPOSE: We have previously reported that lamellar dissection of the cornea transects stromal nerves, and that regenerating neurites form a dense net along the surgical plane. In these experiments, we have disrupted the stromal nerve trunks in situ, without incising the cornea, to determine the regeneration events in the absence of a surgical plane. METHODS: Thy1-YFP mice were anesthetized and in vivo images of the corneal nerves were obtained with a wide-field stereofluorescent microscope. A far infrared XYRCOS Laser attached to 20X objective of an upright microscope was used to perform in situ transection of the stromal nerves. 3 types of laser transections were performed (n = 5/group): (i) point transection (a single cut); (ii) segmental transection (two cuts enclosing a segment of nerve trunk); and (iii) annular transection (cuts on all nerve trunks crossing the perimeter of a 0.8 mm diameter circular area centered on the corneal apex). Mice were imaged sequentially for 4 weeks thereafter to assess nerve degeneration (disappearance or weakening of original fluorescence intensity) or regeneration (appearance of new fluorescent fronds). Beta-3-tubulin immunostaining was performed on corneal whole-mounts to demonstrate nerve disruption. RESULTS: The pattern of stromal nerves in corneas of the same mouse and in corneas of littermates was dissimilar. Two distinct patterns were observed, often within the same cornea: (i) interconnected trunks that spanned limbus to limbus; or (ii) dichotomously branching trunks that terminate at the corneal apex. Point transections did not cause degeneration of proximal or distal segment in interconnected trunks, but resulted in degeneration of distal segment of branching trunks. In segmental transections, the nerve segment enclosed within the two laser cuts degenerated. Lack of beta-3 tubulin staining at transection site confirmed nerve transection. In interconnected trunks, at 4 weeks, a hyperfluorescent plaque filled the gap created by the transection. In annular transections, some nerve trunks degenerated, while others regained or retained fluorescence. CONCLUSIONS: Interconnected stromal nerves in murine corneas do not degenerate after in situ point transection and show evidence of healing at the site of disruption. Presence or absence of a surgical plane influences corneal nerve regeneration after transection.

Delamination Does Not Affect Outcomes After Arthroscopic Rotator Cuff Repair as Compared With Nondelaminated Rotator Cuff Tears: A Study of 1043 Consecutive Cases.

BACKGROUND: Limited information is available regarding the characteristics of delaminated rotator cuff tears as compared with nondelaminated tears. Furthermore, there is conflicting information regarding the effects of delamination on the anatomic healing of repaired cuffs. PURPOSE: To evaluate the characteristics and anatomic outcomes of delaminated rotator cuff tears in comparison with nondelaminated tears to determine whether delamination is a negative prognostic factor affecting rotator cuff repair outcomes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between 2010 and 2014, 1043 patients were enrolled in the study to assess the prevalence of delamination. Among them, the findings from 531 patients who underwent magnetic resonance imaging or computed tomographic arthrography at least 1 year after surgery were included to determine whether delamination was a negative prognostic factor affecting the anatomic outcomes of arthroscopic rotator cuff repair. Delamination was assessed intraoperatively and defined by distinguishable edge cleavage tearing or interstitial horizontal gap between the articular and bursal surfaces of the torn tendon. One of 3 repair techniques (modified Mason Allen, single row, or double row) was used according to tear configuration and tendon mobilization. The authors evaluated visual analog scale scores for pain and satisfaction and American Shoulder and Elbow Surgeons scores to quantify clinical outcomes. RESULTS: The incidence of delamination was 42.9% (447 of 1043). As compared with those with nondelaminated tears, patients with delaminated tears were older ( P < .001) and had longer symptom duration ( P = .019), larger tear sizes and retractions ( P < .001 for both), higher grades of fatty infiltration of the rotator cuff muscles (all P < .001), and poorer tendon quality ( P < .001). The overall healing failure rate was 19.0% (101 of 531). In univariate analysis, the rate of healing failure for the repaired cuffs was significantly higher in the delaminated group (delaminated tears, 60 of 238, 25.2%; nondelaminated tears, 41 of 293, 14.0%; P = .001). However, results of subgroup and multivariate analyses showed that the presence of delamination was ultimately not an independent risk factor for the failure of cuff healing. Between the delaminated and nondelaminated groups, there was no significant difference in postoperative functional outcomes. CONCLUSION: The results suggest that delaminated rotator cuff tears might represent chronic degenerative tears of longer symptom duration, with larger tear sizes and higher grades of fatty infiltration in older patients. It appears that delamination could be a confounding factor, not an independent prognostic factor, affecting rotator cuff healing.

The Rotator Cuff Healing Index: A New Scoring System to Predict Rotator Cuff Healing After Surgical Repair.

BACKGROUND: Scoring systems integrating possible prognostic factors and predicting rotator cuff healing after surgical repair could provide valuable information for clinical practice. PURPOSE: To determine the prognostic factors predictive of rotator cuff healing after surgical repair and to integrate these factors into a scoring system. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The authors reviewed the records of 603 patients who, at least 12 months after primary rotator cuff repair by a single surgeon, had magnetic resonance imaging or computed tomographic arthrography to assess repair integrity. The mean age at the time of surgery was 60 years (range, 39-81 years), and 378 patients were women (62.7%). Previous known or suggested factors affecting cuff integrity were analyzed through univariate and multivariate analyses. Factors identified in the multivariate analysis were integrated in a scoring system based on odds ratios (ORs). RESULTS: The overall healing failure rate was 24%. The following independent risk factors were identified in the multivariate analysis: age >70 years at the time of surgery ( P = .003, OR = 2.71), size of the tear in anteroposterior dimension ( P = .033, OR = 1.94) and retraction ( P = .000, OR = 4.56), fatty infiltration of infraspinatus exceeding grade 2 ( P = .001, OR = 2.91), low bone mineral density (T score ≤ -2.5, P = .04, OR = 1.95), and high level of work activity ( P = .036, OR = 2.18). A 15-point scoring system comprised the following: 4 points for retraction; 3 points for fatty infiltration of infraspinatus; and 2 points for anteroposterior tear size, age, bone mineral density, and work activity, weighted according to multivariate analysis ORs. Patients with ≤4 points had a 6.0% healing failure rate, and those with ≥5 and ≥10 points had 55.2% and 86.2% healing failure rates, respectively. CONCLUSION: A numerical scoring system including significant clinical and radiological factors was designed to predict healing of the rotator cuff after surgical repair. This scoring system helped predict the adequacy of the repair and assist in deciding the appropriate treatment options.

Effect of Sarcopenia on Postoperative Mortality in Osteoporotic Hip Fracture Patients.

BACKGROUND: Few studies have investigated the effects of sarcopenia on postoperative outcomes including mortality rates following surgery for osteoporotic hip fractures. The purpose of the present study was to determine the prevalence of sarcopenia and the relationship between sarcopenia and 1- and 5-year mortality rates in a consecutive series of patients with osteoporotic hip fractures. METHODS: Among patients who underwent hip surgery for osteoporotic hip fractures, this study included 91 patients subjected to abdominal computed tomography within 1 year of hip surgery. We defined sarcopenia using sex-specific cut-off points for the skeletal muscle index at the level of the third lumbar vertebra. All patients were divided into 2 groups according to the presence or absence of sarcopenia and the 1- and 5-year mortality rates were compared. To confirm factors affecting mortality in addition to sarcopenia, we examined patient age, sex, American Society of Anesthesiologists grade, location of fracture, type of surgery, and bone mineral density. RESULTS: The 1- and 5-year mortality rates were 20.9% and 67.2%, respectively. Among the 45 patients with sarcopenia, the 1- and 5-year mortality rates were 22.2% and 82.7%, respectively. Of the 46 patients without sarcopenia, the 1- and 5-year mortality rates were 19.6% and 52.7%, respectively. Results of the Kaplan-Meier analysis showed that sarcopenia did not affect the 1-year mortality rate (P=0.793), but had a significant effect on the 5-year mortality rate (P=0.028). Both perioperative sarcopenia (P=0.018) and osteoporosis (P=0.000) affected the 5-year mortality rate. CONCLUSIONS: Sarcopenia increases the risk of 5-year mortality in patients with osteoporotic hip fractures.

A novel series of enoyl reductase inhibitors targeting the ESKAPE pathogens, Staphylococcus aureus and Acinetobacter baumannii.

S. aureus and A. baumannii are among the ESKAPE pathogens that are increasingly difficult to treat due to the rise in the number of drug resistant strains. Novel therapeutics targeting these pathogens are much needed. The bacterial enoyl reductase (FabI) is as potentially significant drug target for developing pathogen-specific antibiotics due to the presence of alternate FabI isoforms in many other bacterial species. We report the identification and development of a novel N-carboxy pyrrolidine scaffold targeting FabI in S. aureus and A. baumannii, two pathogens for which FabI essentiality has been established. This scaffold is unrelated to other known antibiotic families, and FabI is not targeted by any currently approved antibiotic. Our data shows that this scaffold displays promising enzyme inhibitory activity against FabI from both S. aureus and A. baumannii, as well as encouraging antibacterial activity in S. aureus. Compounds also display excellent synergy when combined with colistin and tested against A. baumannii. In this combination the MIC of colistin is reduced by 10-fold. Our first generation compound displays promising enzyme inhibition, targets FabI in S. aureus with a favorable selectivity index (ratio of cytotoxicity to MIC), and has excellent synergy with colistin against A. baumannii, including a multidrug resistant strain.

Use of fractional CO2 laser decreases the risk of skin cancer development during ultraviolet exposure in hairless mice.

BACKGROUND: Nonmelanoma skin cancers are caused mainly by prolonged ultraviolet (UV) exposure. There is a growing interest in the prevention of skin cancer and antiaging treatment because of aging of the population. Currently, ablative fractional photothermolysis (FP) laser treatment is actively being performed for facial rejuvenation. OBJECTIVE: The objective of this study was to prove the suppressive effect of CO2 fractional laser (FL) on skin cancer development. MATERIALS AND METHODS: Two groups of hairless mice were treated with either CO2 FL or nothing at 3-week intervals during the 20 weeks of UV exposure period. The number of tumors was subsequently counted every 2 weeks over the 30-week period to the termination of the experiment. At 30 weeks, representative tumors were evaluated for tumor type. The authors also determined the messenger RNA (mRNA) expression levels of the matrix metalloproteinase 13 (MMP-13) and Type 1 procollagen. RESULTS: At 30 weeks, the UV- and FL-treated group showed a significantly lower tumor occurrence rate and a more benign progression of tumors than the UV-only treated group. The UV- and FL-treated group presented a higher mRNA level of Type 1 procollagen and a lower level of MMP-13 than the UV-only treated group. CONCLUSION: The occurrence of UV-induced skin tumors can be decreased by multiple sessions of ablative FP with CO2 laser.

A Case of Common Bile Duct Cancer That Completely Responded to Combination Chemotherapy of Gemcitabine and TS-1.

Common bile duct (CBD) cancer is a relatively rare malignancy that arises from the biliary epithelium and is associated with a poor prognosis. Here, we report a case of advanced metastatic CBD cancer successfully treated by chemotherapy with gemcitabine combined with S-1 (tegafur+gimeracil+oteracil). A 65-year-old male presented with pyogenic liver abscess. After antibiotic therapy and percutaneous drainage, follow-up computed tomography (CT) showed an enhanced nodule in the CBD. Biopsy was performed at the CBD via endoscopic retrograde cholangiopancreatography, which showed adenocarcinoma. Additional CT and magnetic resonance imaging showed multiple small nodules in the right hepatic lobe, which were confirmed as metastatic adenocarcinoma by sono-guided liver biopsy. The patient underwent combination chemotherapy with gemcitabine and S-1. After nine courses of chemotherapy, the hepatic lesion disappeared radiologically. Pylorus-preserving pancreaticoduodenectomy was performed, and no residual tumor was found in the resected specimen. Three weeks after the operation, the patient was discharged with no complications. Through 3 months of follow-up, no sign of recurrence was observed on CT scan. Gemcitabine combined with S-1 may be a highly effective treatment for advanced cholangiocarcinoma.

ThinPrep Cytological Findings of Desmoplastic Small Round Cell Tumor with Extensive Glandular Differentiation: A Case Study.

Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive neoplasm. The cytological diagnosis of this tumor has only been reported in a few cases. In most of these cases, the diagnosis was made using fine-needle aspiration cytology. Most DSRCTs resemble disseminated carcinomatoses in their clinical manifestation as well as cytomorphologically, even in young-adult patients. These authors report a case of using peritoneal-washing and pleural-effusion ThinPrep cytology to diagnose DSRCT, with extensive glandular differentiation and mucin vacuoles. We found that fibrillary stromal fragment, clinical setting, and adjunctive immunocytochemical staining were most helpful for avoiding misdiagnosis.