The role of interstitial macrophages in nephropathy of type 2 diabetic db/db mice

Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-beta1, and collagen I-alpha1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy.     

Loss of nuclear p21(Cip1/WAF1) during neoplastic progression to metastasis in gamma-irradiated p21 hemizygous mice

p21(Cip1/WAF1) localizes to the nucleus in response to gamma-irradiation induced DNA damage and mediates a G(1) checkpoint arrest. Although gamma-irradiated p21(+/-) mice develop a broad spectrum of tumors, gamma-irradiated p21(-/-) mice develop significantly more metastatic cancers. To evaluate the expression of p21 in tissues prone or resistant to tumorigenesis as a function of gamma-irradiation, and to determine whether phenotypic loss of p21 heterozygosity occurs during tumor progression in p21(+/-) mice, tissues and tumors from gamma-irradiated mice were evaluated immunohistochemically. The percentage of tumors in p21(+/-) mice that were nuclear p21-positive declined with progression to metastasis (p<0.0001). Benign tumors were more often p21-positive and comprised of larger subsets of nuclear p21-positive cells than were malignant tumors of the same histopathological type, while metastatic cancers were nuclear p21-negative (p=0.0003). Even when a primary cancer was comprised of a subset of nuclear p21-positive cells, the metastatic foci of that same cancer were nuclear p21-negative. Mesenchymal tumors, though rare, were more likely metastatic than were epithelial tumors (p=0.0004), and these were invariably nuclear p21-negative. Prepubescent epithelial tissues from which most tumors later originated in mice with reduced p21 gene dosage (i.e., harderian gland, ovary, small intestine, and lung) were p21 expressive within 4 h of gamma-irradiation (p=0.0625), so that p21/Ki67 ratios increased post-gamma-irradiation (p=0.03). In contrast, p21 did not localize to nuclei of cortical thymocytes, a tissue where tumorigenesis was not augmented by reduced p21 gene dosage. Cellular subclones of malignant tumors, especially those of mesenchymal cell origin, which lack nuclear p21 may more readily acquire the genetic alterations of the metastatic phenotype.     

Potential correlates of burnout among general practitioners and residents in Hungary: the significant role of gender,age, dependant care and experience

Background

Burnout is increasingly prevalent among general practitioners (GPs) in Hungary, which may lead to functional impairment and, subsequently, to poor quality of patient care. However, little is known about potential predictors of burnout among GPs. The aim of this study was to explore psychosocial correlates of burnout among GPs and residents in Hungary.

Methods

We collected socio-demographic and work-related data with self-administered questionnaires in a cross-sectional study among GPs (N?=?196) and residents (N?=?154). We assessed burnout with the Maslach Burnout Inventory Human Services Survey (MBI-HSS) and calculated the mean level of burnout and the proportion of physicians suffering from low, intermediate and high degree of burnout. To identify potential socio-demographic and work-related correlates of burnout among physicians, we determined Spearman’s and Mann-Whitney U correlation coefficients and conducted stepwise linear regression analyses. We deployed Mann-Whitney U test to explore gender disparity in the level of burnout between female and male physicians and between general practitioners and residents.

Results

The prevalence of moderate to high level emotional exhaustion, depersonalisation, and impaired personal accomplishment was 34.7, 33.5 and 67.8% as well as 41.0, 43.1, and 71.1% among GPs and residents, respectively. Residents reported significantly lower level of personal accomplishment vs GPs. We identified a significantly higher level of depersonalization among male physicians compared to female physicians. Age correlated negatively with emotional exhaustion and depersonalization and positively with personal accomplishment among GPs. Dependant care was positively associated with burnout among female GPs. Female residents were more likely to report depersonalization. High workload was positively correlated with depersonalization among female GPs. Younger age emerged as the strongest predictor of emotional exhaustion. Male gender and fewer years of experience predicted depersonalization best, and male gender showed a significant predictive relationship with low personal accomplishment.

Conclusion

We identified specific socio-demographic and work-related correlates of burnout, which may guide the development of specific and effective organizational decisions to attenuate occupational stress and subsequent burnout as well as functional impairment among GPs, and thus, may improve the quality of patient care.

     

Controlled study of lactoperoxidase gel on oral flora and saliva in irradiated patients with oral cancer

The aim of this study was to determine if radiotherapy induces hyposalivation altering oral microbial flora. The purpose of this placebo-controlled, single-blind study was to determine beneficial effects of a saliva substitute and an oral hygiene product on irradiated patients with oropharyngeal cancer. Eighteen patients were assigned to the test group (Biotène Oral Balance gel [Lacléde Incorporated Healthcare Products, Gardena, CA] and toothpaste used daily), and another 18 were put on a conventional daily regimen (carboxymethylcellulose gel and Oral-B toothpaste [Laclede Pharmaceuticals, Gardena, CA]). Cultures for identifying and quantitating microorganisms, whole unstimulated saliva, and visual analog measurements for comfort were obtained before mucositis occurred and after treatment. Daily use of Biotène products enhanced control of microbial flora, improved salivary flow, and increased oral comfort as compared with control subjects. Four weeks after mucositis, some aerobic isolates disappeared in the test group; periodontal-associated bacteria were markedly decreased in the test group; and candidal species were significantly lowered in the test group. Although baseline saliva was lower in the test group (P = 0.001), after 4 weeks, no difference between groups existed; comfort was greater in the test group (P = 0.007). Use of enzyme-engineered Biotène products that assist in control of the oral microbial flora as well as supporting oral comfort through lubrication appear to be useful aids for irradiated patients with oropharyngeal cancer.     

Mortality and Long-Term Outcome of Neonates with Congenital Heart Disease and Acute Perinatal Stroke: A Population-Based Case-Control Study

Objective: Neonates with congenital heart disease (CHD) and perinatal stroke have high mortality and survivors are at risk for poor long-term neurodevelopmental outcome. The aim of this study was to assess the risk factors and outcome of neonates with both CHD and MRI-confirmed perinatal stroke (Study Group) and compare those to the risk factors and outcome of infants matched for CHD without stroke (Control-1) and of infants matched for MRI-confirmed stroke without CHD (Control-2). Methods: We conducted a population-based case-control study enrolling 28 term neonates with CHD and MRI-confirmed acute perinatal stroke born between 2007–2017 in the Central-Hungarian Region. Each of the control groups included 56 infants. The Bayley Scales of Infant Development-II, the Brunet-Lézine test and the Binet Intelligence scales-V were used for neurodevelopmental follow-up at a median age of 61 months. Results: Mortality was highest in the Study Group (25% compared to 5% and 2%, respectively, p = 0.001). Adverse neurodevelopmental outcome was prevalent in the Study (53%) and Control-2 Groups (52%, p = 0.03). Significantly different parameters among the three groups included Apgar scores, mode of delivery, gestational age at birth, cardiac interventions and twin pregnancy. In a multivariable regression analysis adjusted for clinically relevant parameters, patients in the Study Group had significantly higher odds for mortality compared to patients in the Control-1 Group (OR: 6.5 95% CI: 1.1–39.4). Conclusions: Neonates with perinatal stroke and CHD are at a higher risk for dying compared to neonates with CHD without stroke. In addition, the stroke-associated direct insult to the brain likely plays an important role in the development of neurodevelopmental morbidity in these patients.     

Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.