Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells

During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by “inertia.” We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma–associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.     

Blood Infections in Patients Treated at Transplantation Wards of a Clinical Hospital in Warsaw

Establishment of the etiology in blood infection is always advisable. The purpose of this study was to evaluate the proportion of different bacterial species, including aerobic and anaerobic bacteria in blood cultures of patients hospitalized in transplantation wards of a large clinical hospital between 2010 and 2012. A total of 1994 blood samples from patients who were treated at one of two transplantation wards of a large hospital in Warsaw were analyzed using an automated blood culture system, BacT/ALERT (bioMerieux, France). The 306 bacterial strains were obtained from the examined samples. The highest proportion were bacteria from the family Enterobacteriaceae (112 strains; 36.6%) with Escherichia coli (61 strains), Klebsiella pneumoniae (30 strains), and Enterobacter cloacae (10 strains) most commonly isolated. The non-fermenting bacilli constituted 21.6% (66 strains), with most common Stenotrophomonas maltophilia (31 strains), Pseudomonas aeruginosa (14 strains), Achromobacter spp. (12 strains), and Acinetobacter baumannii (3 strains). Most frequent Gram-positive bacteria were staphylococci (25.2%). Of 77 staphylococcal strains, 56 were coagulase-negative staphylococci and 21 Staphylococcus aureus. Other Gram-positive bacteria included enterococci (14 strains) and Streptococcus pneumoniae (1 strain). Obligatory anaerobic bacteria were represented by 19 strains (6.2% of total isolates). Among all Enterobacteriaceae, 49 isolates (43.7%) produced extended-spectrum ß-lactamases (ESBLs). Resistance to methicillin was detected in 62% of S aureus isolates and in 46% of coagulase-negative staphylococci. Of 14 enterococci cultured from blood samples, 2 strains (14.3%) were resistant to vancomycin. Both were Enterococcus faecium. Resistant strains of Gram-negative and Gram-positive bacteria are significant problems for patients in the transplantation ward.     

The supply and demand for guns to juveniles: Oakland’s gun tracing project

In response to Oakland, California’s high level of gun violence affecting young people, the East Oakland Partnership to Reduce Juvenile Gun Violence, a citywide collaboration, was formed in 1997. In 1999, the Partnership established the Oakland Gun Tracing Project to develop evidence-based policy recommendations aimed at reducing the supply of and demand for gun acquisition among urban youth. The advocacy project involved gathering, analyzing, and using police record and gun sale/registration data to inform policy and practice. Such data were collected for all gun crimes committed in Oakland, California between 1998 and 1999 in which a juvenile was either the suspect or the victim. The 213 cases involved 263 juveniles of which 170 were suspects/perpetrators and 93 were victims. Suspects as well as victims were predominantly male and African American. The 213 cases involved 132 recovered guns. Only 55% of the cases were traced to a federally licensed dealer. Three-quarters of the guns were purchased near Oakland, California. Successful traces, defined as the ability to identify federally licensed dealers and initial purchasers, were completed on only 52 of the 132 guns, demonstrating systemic tracing difficulties. Data gathered for the project was used to advocate for numerous policy changes. Recommended policy strategies include initiating a comprechensive gun tracing program so police can track all secondary sales, new laws requiring federal handgun registration which would track ownership changes, required reporting of stolen firearms, and providing effective intervention services to all juveniles the first time they enter the criminal justice system. Preliminary findings were reported in a presentation at the American Public Health Association Annual Meeting in Atlanta, Georgia, October 2001.     

Clinical Significance of Gastrointestinal Carriage of Klebsiella Pneumoniae-Producing Extended-Spectrum Beta-Lactamases in Kidney Graft Recipients

The burden of Klebsiella pneumoniae (KP) producing extended-spectrum beta-lactamases (ESBL+) urinary tract infections (UTIs) is a growing problem after kidney transplantation (KTX). The study was aimed at evaluating the incidence of KP ESBL+ gut colonization in KTX recipients and its correlation with clinical outcomes with special regard to UTIs.The study included all KTX patients hospitalized in our department between January 2014 and December 2016. During this period 2018 KTX patients were admitted: 605 in 2014, 750 in 2015, and 663 in 2016, respectively. Screening for drug-multiresistant Enterobacteriaceae gut carriage was performed in 104 patients (2014), 122 (2015), and 166 (2016).In 2014, 2015, and 2016, 18 (17.3%), 26 (21.3%), and 30 (18.1%) patients had positive test results, and 44 (42.3%), 36 (29.5%), and 45 (27.4%) KTX patients were diagnosed with KP ESBL+ UTI. In 2014, KP ESBL+ UTI was diagnosed in 30 (34.9%) cases with negative anal swab and in 14 patients (77.8%) with positive test result (P = .0008). In 2015, KP ESBL+ UTI was diagnosed in 21 patients (21.9%) with negative anal swab and in 15 (57.7%) with positive test result (P = .0004). In 2016, KP ESBL+ UTI was diagnosed in 24 patients (17.8%) with negative anal swab and in 21 (72.4%) with positive test result (P = .000001).In conclusion, we have revealed a strong association between gut K. pneumoniae colonization, female sex, and MPA intake and KP ESBL+ urinary tract infections in kidney transplant recipients. Our results indicate the very important role of KP ESBL+ screening, while strategies of identified carriers require further research.     

Molecular Epidemiology of Vancomycin-Resistant Enterococcus Faecalis Among Patients of Transplantology Wards

Objective

Vancomycin-resistant enterococci (VRE) require epidemiological monitoring especially in transplantation wards. The aim of our work was to perform a molecular analysis of vancomycin-resistant Enterococcus faecalis (VREfl) strains among solid organ recipients during various years.

Materials and Methods

Strains were examined for the presence of different genes determining vancomycin resistance: vanA, vanB, vanD, or vanG by polymerase chain reaction (PCR). Restriction fragment length polymorphism (RFLP)-pulsed field gel electrophoresis (PFGE) was performed on bacterial DNA digested with SmaI enzyme.

Results

From 2003 to 2006, we isolated 12 strains of VREfl from 8 patients (2 liver and 6 kidney transplantations). All strains harbored the vanA gene. Among the strains, 5 displayed patterns similar to each other, despite being isolated from different patients, and were susceptible to ampicillin with high resistance to aminoglycosides.

Conclusions

These results suggested that a single strain of VREfl was present for 3 years in closely related hospital wards, but it disappeared in the following years.     

Description des caractéristiques,des projets de soins et du devenir des patients de plus 75 ans présentant une insuffisance rénale sévère (DFGe ≤ 20 mL/min/1,73 m2) : phase pilote du projet PSPA

In France, the incidence of dialysis patients is increasing in people over 75 years and represents 40% of incident patients. In these elderly patients with many comorbidities, the benefit of dialysis in terms of survival and quality of life remains controversial. Using data from REIN, determinants of early mortality were identified and a prognostic score was provided. This approach must now be adapted to elderly with end stage renal failure (ESRF) not on dialysis for which we have little data on their clinical characteristics, therapeutic projects and outcome. We report the results of a pilot study and the prospective study protocol that resulted. In four French nephrology department, 76 patients were studied with a mean age of 83 ± 5 years, with a MDRD estimated GFR (abbreviated MDRD) of 16 ± 4 mL/min/1.73 m². These patients were different from the population on dialysis recorded in REIN. This pilot study has shown the feasibility of a prospective study on a larger scale, which aims to build a valuable tool for decision making in elderly patients with ESRF not yet on dialysis.     

Comparison of bacteria isolated from urinary tract infections in patients on transplant versus urologic wards

Objective

Urinary tract infections (UTI) are the most common hospital infections. Complications include sepsis and shock. Immunosuppressed transplant surgery patients may experience loss of the graft due to UTI. The purpose of this study was to determine the main microorganisms responsible for UTIs among patients of transplant wards compared to urologic wards. Additionally, drug susceptibility profiles of the most frequent microorganisms were analyzed.

Materials and Methods

We analyzed the results of positive urine cultures from patients on 2 transplant versus 1 urologic ward in 2010.

Results

The most common pathogen in urine samples from all 3 wards was Escherichia coli. Often, other Gram-negative bacilli of the genus Klebsiella spp, were cultured as well as Gram-positive cocci (Enterococcus spp). Yeasts of the genus Candida were only found in urine of patients of transplant wards. The percentage of resistant bacteria was much higher among bacteria from transplant patients.

Conclusions

The high level of antimicrobial resistance of microorganisms isolated from the urine of transplant patients and the relatively high incidence of fungal infections, demand an especially quick, accurate microbiological diagnosis for this group of patients.     

Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site

Background Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs.Methods Different integration signatures were identified using HPV double capture followed by next-generation sequencing (NGS) in 272 CC patients from the BioRAIDs study [{"type":"clinical-trial","attrs":{"text":"NCT02428842","term_id":"NCT02428842"}}NCT02428842]. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed.Results Episomal HPV was much less frequent in CC as compared to anal carcinoma (p < 0.0001). We identified >300 different HPV-chromosomal junctions (inter- or intra-genic). The most frequent integration site in CC was in MACROD2 gene followed by MIPOL1/TTC6 and TP63. HPV integration signatures were not associated with histological subtype, FIGO staging, treatment or PFS. HPVs were more frequently episomal in PIK3CA mutated tumours (p = 0.023). Viral integration type was dependent on HPV genotype (p < 0.0001); HPV18 and HPV45 being always integrated. High HPV copy number was associated with longer PFS (p = 0.011).Conclusions This is to our knowledge the first study assessing the prognostic value of HPV integration in a prospectively annotated CC cohort, which detects a hotspot of HPV integration at MACROD2; involved in impaired PARP1 activity and chromosome instability.Subject terms: Oncology, Molecular medicine, Biomarkers, Molecular biology