Selective elimination of alloreactive donor T cells attenuates graft-versus-host disease and enhances T-cell reconstitution.

Impaired T-cell immune reconstitution is a major complication after allogeneic bone marrow transplantation (BMT) and is particularly exacerbated in the setting of graft-versus-host disease (GVHD). Conventional approaches to reduce GVHD, such as T-cell depletion or pharmacologic immunosuppression, typically fail to enhance T-cell immunity and often further exacerbate this problem. An alternative strategy to mitigate GVHD severity is the selective elimination of graft-versus-host-reactive donor T cells by using an incorporated thymidine kinase suicide gene. This approach has been shown to effectively reduce GVHD, although the effect of this strategy on T-cell reconstitution is unresolved. We addressed this question in a murine BMT model (C57BL/6 [H-2(b)] --> AKR/J [H-2(k)]) in which donor and recipient differ at major and minor histocompatibility antigens. Lethally irradiated AKR recipients transplanted with T cell-depleted bone marrow plus thymidine kinase-positive T cells followed by post-BMT ganciclovir (GCV) administration had more prompt and complete normalization of the T-cell repertoire than phosphate-buffered saline-treated GVHD control animals. By 60 days after transplantation, mice administered GCV had T-cell repertoires that were virtually indistinguishable from those of mice that underwent transplantation with T cell-depleted bone marrow alone (no GVHD controls) when assayed by T-cell receptor (TCR) spectratyping. In contrast, phosphate-buffered saline-treated animals had persistent skewing in most Vbeta families. T cells obtained from GCV-treated mice also had significantly higher in vitro proliferative responses after posttransplantation inoculation with ovalbumin than GVHD animals, indicating that CD4(+) T-cell responses against a nominal antigen were better preserved in these chimeras. Finally, GCV-treated mice had augmented immune reconstitution in response to exogenous interleukin-7 administration, as evidenced by increased overall spleen cellularity and absolute numbers of T and B cells. This was in contrast to GVHD control animals, which had a blunted response to interleukin-7 administration. These data indicate that GVHD severity can be significantly reduced by selective elimination of alloreactive donor T cells without compromise of T-cell immunity. Moreover, in light of previous studies demonstrating that this strategy can reduce GVHD without loss of alloengraftment and antileukemia reactivity, further examination of this approach in humans seems warranted.     

Mesothelial/monocytic incidental cardiac excrescence.

Mesothelial/monocytic incidental cardiac excrescence (MICE) is a very uncommon lesion. Diagnosis is incidental and may simulate thrombotic lesions. One of the hypotheses with regard to the etiology of this lesion is a previous cardiac procedure especially mitral valve repair or commissurotomy. Herein, we describe a MICE incidentally found in a patient who underwent mitral valve replacement, as a thrombotic lesion on the left atrial auricle. Histopathologic examination suggested MICE lesions and immunohistochemical stains confirmed it.     

Age-dependent changes in CXC chemokine ligand 10 serum levels in euthyroid subjects.

Circulating levels of cytokines are deeply influenced by aging, and few data about serum chemokines are available. The aim of this study was to evaluate the influence of aging on circulating CXCL10. One hundred forty healthy subjects (70 males and 70 females), 10-79 years of age, underwent fasting plasma glucose, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride, and CXCL8 serum assay. Thyroid hormone testing for thyroid-stimulating hormone (TSH), antithyroglobulin (AbTg), and antithyroperoxidase (AbTPO) autoantibodies and thyroid ultrasonography were performed in all subjects to exclude the presence of clinical or subclinical thyroid disease. Serum CXCL10 levels were assayed in all subjects and found to be increased in 14 of 70 females (20%) and in 4 of 70 males (5.7%) (p = 0.01). In a multiple linear regression model including age, body mass index (BMI), systolic and diastolic blood pressure, glycemia, total cholesterol, HDL, LDL, triglycerides, TSH, AbTPO, AbTg, and CXCL8, only age was significantly related to CXCL10 [C.R. 1.30 (0.28-2.33), p = 0.001]. No relationship was present between CXCL8 serum levels and age, suggesting a specificity of CXCL10 elevation as a function of age. Results of this study, performed in healthy subjects on an age gradient, demonstrate an increase in serum CXCL10 with advancing age overall in females, supporting the hypothesis of enhanced Th1 immune responses in aging.     

Sensitivity of prostate tumors to wild type and M protein mutant vesicular stomatitis viruses

Because of its potent ability to induce apoptosis, vesicular stomatitis virus (VSV) is an attractive candidate as an oncolytic virus for tumor therapy. Previous studies have suggested that VSV selectively infects tumor cells due to defects in their antiviral responses making them more susceptible to VSV infection than normal cells. We tested this hypothesis in the prostate tumor system by comparing LNCaP and PC-3 prostate tumor cells to benign human prostatic epithelial cells from patient prostatectomy specimens. We compared the cell killing ability of a recombinant virus containing a wild-type (wt) M protein (rwt) and an isogenic M protein mutant virus (rM51R-M) that induces interferon (IFN) in infected cells and should display a greater selectivity for tumor cells. Our results showed that in single-cycle infection experiments, LNCaP cells were sensitive to killing by both wt and mutant viruses, while PC-3 cells were highly resistant to VSV-induced cell killing. LNCaP and benign prostate cells were similarly susceptible to both viruses, indicating that normal prostate cells are not inherently resistant to killing by VSV. In each of the cell lines, the rM51R-M virus induced similar levels of apoptosis to rwt virus, showing that the M protein does not play a significant role in apoptosis induction by VSV in these cells. In multiple-cycle infection experiments, LNCaP cells were more sensitive than benign prostatic epithelial cells to virus-induced cell killing by rM51R-M virus, but not rwt virus. Both viruses were equally effective at reducing LNCaP tumor volume in vivo following intratumoral and intravenous inoculation in nude mice, while PC-3 tumors were resistant to VSV treatment. None of the mice treated with rM51R-M virus died as a result of virus infection, while 50-71% of mice treated with rwt virus succumbed to virus infection. Similarly, when inoculated by the more sensitive intranasal route, the rM51R-M virus was less pathogenic than the rwt virus from which it was derived. These results indicate that M protein mutant viruses are superior candidates as oncolytic viruses for therapies of prostate tumors, but future strategies for use of VSV will require testing individual tumors for their susceptibility to virus infection.     

Correlation between Karnofsky Performance Status Scale and Short-Form Health Survey in patients on maintenance hemodialysis

BACKGROUND: Assessment of quality of life is vital inmonitoring response to various treatment measures. Various instruments, which include both generic and disease-specific instruments, are used in the assessment of health-related quality of life (HRQOL). In this study, we compare two commonly used generic instruments. OBJECTIVES: The objective of this study was to compare two generic instruments, the Karnofsky Performance Status Scale and the SF-36 Health Survey in hemodialysis (HD) patients. The study also aims to find out the association (if any) between HRQOL scores using these two scales and various clinical and biochemical parameters. MATERIALS AND METHODS: Sixty-two maintenance HD patients were recruited after informed consents were obtained. Detailed sociodemographic data was obtained. They were assessed during their regular HD sessions. Serum chemistry (which included serum urea, creatinine, Na+, K+, HCO3-, Ca2+, Po4(2-)), albumin, globulin, total protein and hemoglobin (g/dl) were assessed in all the patients. Adequacy of HD was assessed using second-generation Daugirdais formula. HRQOL was assessed using the Karnofsky and SSF-36 instruments and the scores collated and compared. Data was analyzed using SPSS version 10. RESULTS: Fifty-five patients completed the study (27 males and 28 females, mean age 40.76 +/- 11.05 years and age range of 20-65 years). There was a significant positive correlation between Karnofsky scores and all eight SF-36 domains, but only physical functioning, social functioning and role limitation due to emotional problems maintained the significance on multiple regression analysis. The serum creatinine and hemoglobin postively correlated with physical function, bodily pain, social functioning and Karnofsky scores. Age of the patients correlated negatively with two SF-36 dimensions (physical functioning and role limitation due to physical fitness) and Karnofsky scores. CONCLUSION: This study revealed a good correlation between Karnofsky performance status scale and the short-form (SF36) health survey in this Egyptian population. Age, serum creatinine and hemoglobin significantly influence quality of life in this HD patient population.     

Probiotic Supplementation and High-Intensity Interval Training Modify Anxiety-Like Behaviors and Corticosterone in High-Fat Diet-Induced Obesity Mice

Evidence supports the role of exercise training and probiotics on reducing obesity. Considering the relationship between obesity and high-fat diet with anxiety indices, the aim of this study was to assess the effect of probiotic supplementation and high-intensity interval training (HIIT) on anxiety-like behaviors, corticosterone and obesity indices in high-fat diet (HFD)-induced obesity mice. Thirty male adult C57BL/6 mice were randomly divided into five groups: (1) Control with normal diet (CON), (2) High-fat diet (HFD), (3) HFD + exercise training (HT), (4) HFD + probiotics supplement (HP) and (5) HFD + exercise training +probiotics (HTP). Exercise training consisted of 8 weeks of high-intensity interval training (HIIT) programs. Probiotics supplement included 0.2 mL Lactobacillus rhamnosus GG. Anxiety-like behaviors were measured by open field (OF) and Elevated plus maze (EPM). OF and EPM tests, visceral fat mass (VFM) measurement, and blood sampling for corticosterone were performed after the intervention. Bodyweight was measured at different stages during the intervention. HFD regime in C57BL/6 mice increased bodyweight, VFM, and serum corticosterone levels and anxiety-like behaviors (p < 0.05). HIIT, probiotic and their combination, decreased bodyweight, VFM, and serum corticosterone levels and improved anxiety-like behavior in the HFD mice (p < 0.05). The effect of a combination of HIIT and probiotic on most of the anxiety indices was more than each one separately (p < 0.5). HIIT and probiotic supplements separately or above all in combination, may have beneficial effects in reducing obesity and anxiety indices.     

Effect of 940 nm laser diode irradiation prior to bonding procedure on postoperative sensitivity following class II composite restorations: a split-mouth randomized clinical trial

The aim of this study was to evaluate the effect of 940 nm laser diode on class II composite cavities prior to bonding and restoration process on the postoperative sensitivity (POS). Thirty patients with two bilateral premolars with mesio or disto-occlusal carious lesions were evaluated. In each patient, the teeth were randomly divided into the control and laser groups. After cavity preparation and isolation and before the bonding process, the laser group was subjected to 940 nm irradiation (Epic 10, Biolase, USA) by 400 μ tip continuously at 100 mW with 398 J/cm² energy density of tip, which was applied for 5 s at a distance of 2 mm on the axial wall of the cavity. In the control group, irradiation was performed by using the aiming beam. Access cavity was then restored with a composite resin. Cold sensitivity was measured using a cold spray application on the middle third of teeth buccal surface at baseline (before the intervention), 1, 14, and 30 days after the restoration by visual analog scale (VAS) criteria. The mean Friedman and Wilcoxon signed-rank tests were used for data analysis. It was shown that in both laser and control groups, the VAS was significantly decreased at all times compared to the baseline (p ≤ 0.05). There was no statistically significant difference between the mean VAS of two groups at baseline and first day (p ≤ 0.05), but at 14 and 30 days after the intervention, it was significantly lower in the laser group (p ≤ 0.05). The results of this study demonstrated that the cavity pretreatment with laser diode (940 nm) effectively reduces the postoperative sensitivity in class II composite restorations.

     

Efficacy of allogeneic cord blood platelet gel on wounds of dystrophic epidermolysis bullosa patients after pseudosyndactyly surgery

Epidermolysis bullosa (EB) is a rare genetic disorder characterized by the formation of blisters and wounds in skin and mucous membranes; it is classified into four types and has various methods of treatment. Management of previous wounds and prevention of formation of new lesions are the most important strategies in the course of therapy to improve patient's quality of life; lack of wound management can lead to further complications such as infection. The current study investigated the therapeutic effects of allogeneic platelet gel (prepared from umbilical cord blood) in a group of children diagnosed with dystrophic epidermolysis bullosa (DEB) eligible for surgical correction of pseudosyndactyly in the hand. The post‐surgical clinical outcome in this group was compared with the clinical outcomes of DEB patients receiving the standard treatment (paraffin gauze wound dressing and topical antibiotics) after corrective surgery. The current study results showed an increase in the rate of recovery and promotion of tissue granulation, complete wound healing, and a decrease in pain level and treatment period. The application of cord blood platelet gel topical dressing was not a conventional method of treatment in patients with DEB wounds and blisters. However, the current study results demonstrated that this gel dressing could effectively accelerate epithelialization and healing of the wounds and decrease patients' pain and post‐surgical recovery period, which altogether leads to improvements in patients' overall quality of life.     

Transient association between semen exposure and biomarkers of genital inflammation in South African women at risk of HIV infection

IntroductionSemen induces mucosal changes in the female reproductive tract to improve pregnancy outcomes. Since semen‐induced alterations are likely short‐lived and genital inflammation is linked to HIV acquisition in women, we investigated the contribution of recent semen exposure on biomarkers of genital inflammation in women at high HIV risk and the persistence of these associations.MethodsWe assessed stored genital specimens from 152 HIV‐negative KwaZulu‐Natal women who participated in the CAPRISA 008 trial between November 2012 and October 2014. During the two‐year study period, 651 vaginal specimens were collected biannually (mean five samples per woman). Cervicovaginal lavage (CVL) was screened for prostate‐specific antigen (PSA) by ELISA, whereas Y‐chromosome DNA (YcDNA) detection and quantification were conducted by RT‐PCR, representing semen exposure within 48 hours (PSA+YcDNA+) and semen exposure within three to fifteen days (PSA−YcDNA+). Soluble protein concentrations were measured in CVLs by multiplexed ELISA. T‐cell frequencies were assessed in cytobrushes by flow‐cytometry, and vulvovaginal swabs were used to detect common vaginal microbes by PCR. Linear mixed models adjusting for factors associated with genital inflammation and HIV risk were used to assess the impact of semen exposure on biomarkers of inflammation over multiple visits.ResultsHere, 19% (125/651) of CVLs were PSA+YcDNA+, 14% (93/651) were PSA−YcDNA+ and 67% (433/651) were PSA−YcDNA−. Semen exposure was associated with how often women saw their partners, the frequency of vaginal sex in the past month, HSV‐2 antibody detection, current gonorrhoea infection and Nugent Score. Both PSA detection (PSA+YcDNA+) and higher cervicovaginal YcDNA concentrations predicted increases in several cytokines, barrier‐related proteins (MMP‐2, TIMP‐1 and TIMP‐4) and activated CD4+CCR5+HLA‐DR+ T cells (β = 0.050; CI 0.001 to 0.098; p = 0.046) and CD4+HLA‐DR+ T cells (β = 0.177; CI 0.016 to 0.339; p = 0.032) respectively. PSA detection was specifically associated with raised pro‐inflammatory cytokines (including IL‐6, TNF‐α, IP‐10 and RANTES), and with the detection of BVAB2 (OR = 1.755; CI 1.116 to 2.760; p = 0.015), P. bivia (OR = 1.886; CI 1.102 to 3.228; p = 0.021) and Gardnerella vaginalis (OR = 1.815; CI 1.093 to 3.015; p = 0.021).ConclusionsMore recent semen exposure was associated with raised levels of inflammatory biomarkers and the detection of BV‐associated microbes, which declined by three to fifteen days of post‐exposure. Although transient, semen‐induced alterations may have implications for HIV susceptibility in women.