Does enalapril prevent peritoneal fibrosis induced by hypertonic (3.86%) peritoneal dialysis solution?

OBJECTIVE: Peritoneal fibrosis (PF) is one of the most serious causes of failure in continuous ambulatory peritoneal dialysis (PD). Although the underlying mechanism responsible for the genesis of PF is still unknown, transforming growth factor beta (TGFbeta1) has been shown to be associated with PF. Angiotensin converting enzyme inhibitors have been shown to prevent the stimulating effect of growth factors. The aim of the present study was to investigate the effect of enalapril on peritoneal function and morphology in a rat model of experimental PF. METHODS: Twenty-one albino Wistar rats were divided into three groups: (1) the control group (C) received 10 mL isotonic saline intraperitoneally (i.p.), (2) the dextrose (Dx) group 10 mL 3.86% dextrose PD solution i.p., and (3) the enalapril-treated group (ENA) 10 cc 3.86% dextrose PD solution i.p. plus 100 mg/L enalapril in drinking water. After 4 weeks, a 1-hour peritoneal equilibration test was performed with 20 mL 2.27% dextrose PD solution. Dialysate-to-plasma urea ratio (D/P urea), glucose reabsorption (D1/D0 glucose), ultrafiltration (UF) volume, and levels of dialysate protein, TGFbeta1, and cancer antigen 125 (CA125) were determined. The parietal peritoneum was evaluated histologically by light microscopy. RESULTS: Administration of enalapril resulted in preserved UF (-0.2 +/- 0.7 mL vs 1.7 +/- 0.3 mL, p < 0.05), protein loss (2.3 +/- 0.5 g/L vs 1.6 +/- 0.2 g/L, p > 0.05), and peritoneal thickness (77 +/- 7 microns vs 38 +/- 5 microns, p < 0.001). D/P urea increased significantly in the Dx group (p< 0.05). Both higher levels of TGFbeta1 (undetectable vs 298 +/- 43 pg/mL, p < 0.001) and lower levels of CA125 in dialysate effluent (0.94 +/- 0.5 U/L vs 0.11 +/- 0.1 U/L, p > 0.05) were determined in the Dx group. CONCLUSION: These findings show that peritoneal morphology and function tests were dramatically deranged in the Dx group. The same properties were partially preserved in the ENA group. The production of TGFbeta1 was significantly reduced but peritoneal thickness was not completely inhibited. In conclusion, by inhibiting the production of TGFbeta1, enalapril can preserve peritoneal histology, peritoneal function, and remodeling of mesothelial cells.     

Clevudine therapy with vaccine inhibits progression of chronic hepatitis and delays onset of hepatocellular carcinoma in chronic woodchuck hepatitis virus infection

We examined a rational approach to therapy of chronic hepatitis B virus (HBV) infection that utilized the reduction of viral load combined with appropriately timed immune modulation/stimulation. In a placebo-controlled study, chronic woodchuck hepatitis virus (WHV) carrier woodchucks received clevudine (L-FMAU), previously shown to have especially potent and sustained antiviral activity in woodchucks, for 32 weeks followed by WHV surface antigen (WHsAg) alum-adjuvanted vaccine at 32, 36, 40 and 48 weeks. Clevudine induced significant reductions in viraemia, surface antigenaemia, hepatic WHV nucleic acids, and hepatic core and surface antigens. Viral replication markers remained markedly suppressed in 75% of the clevudine-treated woodchucks following drug withdrawal, but remained at high levels in the vaccine monotherapy and placebo groups. Combination drug and vaccine therapy had benefits based on sustained reduction of viraemia, antigenaemia, and hepatic WHV DNA and RNA; inhibition of progression of chronic hepatitis; reduced frequency of chronic liver injury; and delayed onset of hepatocellular carcinoma (HCC). Combination therapy contributed to prevention of HCC in up to 38% of treated carriers, although the growth rate of established HCC was not affected. This study demonstrates enhanced benefits of combination chemo-immunotherapy against viral load and disease progression in chronic hepadnaviral infection, and provides a platform for further development of such treatment regimens.     

Satisfaction of patients with mechanical neck disorders attended to by primary care physical therapists

Objective To describe the satisfaction and expectations of the patients with neck pain with relation to the physical therapy received and to analyse the relationship between the patient's characteristics and his degree of satisfaction and expectation. Design This study is performed in the setting of a random clinical trial. Participants Subjects between 18 and 60 years of age with subacute mechanical neck disorders. Main variables Patient's expectations and satisfaction with the received treatment (scale similar to Likert's Scale). Other variables Pain intensity, episodes of previous neck pain, depression and anxiety symptoms (Goldberg Scale), age and gender, physical disability, general state of health, duration of the present episode of neck pain, regular exercise and regular consumption of medicines. Results and conclusions A total of 90 patients were studied. The mean age was 40.1 years and 88.9% were female. Thirteen per cent of the subjects expected partial relief, 60% expected good recovery and 27% expected complete recovery. Those patients who have not suffered previous episodes of neck pain and those who have a higher score on the Goldberg Scale have a higher expectation of recovering after the treatment. About patients' satisfaction after the intervention, 2% totally unsatisfied, 1% very unsatisfied, 2% somewhat unsatisfied, 2% indifferent, 17% somewhat satisfied, 42% very satisfied and 30% totally satisfied. Those patients who experienced a greater decrease in pain were more satisfied. It would be interesting to study in depth the measurement of patients' satisfaction with the received physical therapy and to extend it to other pathologies.     

Effects of some 1,3,5-trisubstitued-2-pyrazoline derivatives on depression and anxiety parameters of mice

The aim of the present study was examining the effects of some 1,3,5-trisubstituted-2-pyrazoline derivatives on depression, anxiety and spontaneous locomotor activity parameters of mice. None of the compounds was effective at 50 mg/kg dose whereas at 100 and 200 mg/kg, pyrazoline-benzoxazole derivative test compound 4a and pyrazoline-benzimidazole derivative test compound 4d in the series were exhibited significant antidepressant effects in modified forced swimming tests. These two pyrazolines decreased the immobility and increased the swimming times of mice without any change in climbing durations suggesting the antidepressant-like effects of the test compounds. In spite of significant antidepressant effect, none of the compounds changed the exploratory parameters in hole-board tests or total numbers of spontaneous locomotor activities in activity cage measurements at any of the applied doses. In other words, neither anxiolytic nor sedative effects induced by the test compounds. The results obtained from this study supported the previous findings reporting the antidepressant activities of pyrazoline derivative compounds. Exact mechanism of the antidepressant action exhibited in the present study need to be clarified with further detailed investigations.     

Dietary energy restriction-induced modulation of protein kinase C ζ isozyme in the hamster pancreas

Dietary restriction in experimental animals enhances life span, delays disease, inhibits immunological perturbations, and ameliorates cancer. Protein kinase C(a) isozymes mediate signals generated by hormones, growth factors, and neurotransmitters for cell proliferation and differentiation. The results of our study showed that a C-terminally directed anti-PKC ζ antibody detected an 81–kDa band in the pancreases of control and energy-restricted hamsters. Syrian golden hamsters were fed energy-restricted diets formulated such that the hamsters received 90%(10% energy restriction(a) ), 80%(20% ER), or 60%(40% ER) of the total energy consumed by control hamsters, with the energy reduced proportionally from fat and carbohydrate. ER decreased PKC ζ isozyme levels by 40–75% in hamsters fed 10, 20, and 40% ER diets for 8 wk. PKC ζ isozyme expression was decreased by 75–80% in hamsters fed ER diets for 15 wk. Although ER caused significant decreases in PKC ζ isozyme levels compared with those of control hamsters at both time points, the relative differences in PKC ζ levels between the dietary ER groups(10, 20, and 40%) were small and not significant. A significant decrease in the body weights of ER animals compared with those of controls was observed at both time points. No differences in tomato lectin and phytohemagglutinin reactivity were observed between control animals and animals fed 10, 20, and 40% ER diets. Furthermore, the cellular expression of PKC ζ in the hamster pancreas did not differ among hamsters fed the various ER diets. These observations may be important for understanding not only the role of dietary ER in pancreatic cancers but also PKC ζ signal transduction mechanisms in normal pancreatic physiology.© 1995 Wiley-Liss, Inc     

The HIF-1α hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy

The tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived of oxygenation as confirmed by positron emission tomographic (PET) imaging. CD8 and CD4 tumor-infiltrating T lymphocytes (TIL) of transplanted colon carcinomas, melanomas, and spontaneous breast adenocarcinomas are CD137 (4-1BB)-positive, as opposed to their counterparts in tumor-draining lymph nodes and spleen. Expression of CD137 on activated T lymphocytes is markedly enhanced by hypoxia and the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Importantly, hypoxia does not upregulate CD137 in hypoxia-inducible factor (HIF)-1α-knockout T cells, and such HIF-1α-deficient T cells remain CD137-negative even when becoming TILs, in clear contrast to co-infiltrating and co-transferred HIF-1α-sufficient T lymphocytes. The fact that CD137 is selectively expressed on TILs was exploited to confine the effects of immunotherapy with agonist anti-CD137 monoclonal antibodies to the tumor tissue. As a result, low-dose intratumoral injections avoid liver inflammation, achieve antitumor systemic effects, and permit synergistic therapeutic effects with PD-L1/B7-H1 blockade. SIGNIFICANCE: CD137 (4-1BB) is an important molecular target to augment antitumor immunity. Hypoxia in the tumor microenvironment as sensed by the HIF-1α system increases expression of CD137 on tumor-infiltrating lymphocytes that thereby become selectively responsive to the immunotherapeutic effects of anti-CD137 agonist monoclonal antibodies as those used in ongoing clinical trials.     

Fecal incontinence and radiation dose on anal sphincter in patients with locally advanced rectal cancer (LARC) treated with preoperative chemoradiotherapy: a retrospective,single-institutional study

Background

The objective of the study is to determine the correlations among the variables of dose and the sphincter function (SF) in patients with locally advanced rectal cancer treated with preoperative capecitabine/radiotherapy followed by low anterior resection (LAR) + TME.

Methods

We retrospectively reviewed 92 consecutive patients with LARC treated at our center with LAR from 2006 and more than 2 years free from disease. We re-contoured the anal sphincters (AS) of patients with the help of the radiologist. SF was assessed with the Wexner scale (0–20 points, being punctuation inversely proportional to annal sphincter functionality). All questionnaires were filled out between January 2010 and December 2012. Dosimetric parameters that have been studied include V ₂₀, V ₃₀, V ₄₀, V ₅₀, mean dose (D _mean), minimum dose (D _min), D ₉₀ (dose received by 90% of the sphincter) and D ₉₈.

Statistical analysis

The correlations among the variables of dose and SF were studied by the Spearman correlation coefficient. Differences in SF relating to maximum doses to the sphincter were assessed by the Mann–Whitney test.

Results

Mean Wexner score was 5.5 points higher in those patients with V ₂₀ > 0 compared to those for which V ₂₀ = 0 (p = 0.008). In a multivariate regression model, results suggest that the effect of V ₂₀ on poor anal sphincter control is independent of the effect of distance, with an adjusted OR of 3.42.

Conclusions

In order to improve the SF in rectal cancer treated with preoperative radiotherapy/capecitabine followed by conservative surgery, the maximum radiation dose to the AS should be limited, when possible, to <20 Gy.

     

Assaults with a sharp object in small children: a 16-year review

Injuries as a result of assaults with sharp object in small children are rare and data on them are scarce. The Red Cross War Memorial Children's Hospital is presently the only Children's Hospital in South Africa with a dedicated Level 1 trauma unit for children under the age of 13 years, and we have an annual trauma load of over 10,000 patients. A retrospective review was performed using the Data Base of the Child Accident Prevention Foundation of Southern Africa at the Red Cross War Memorial Children's Hospital in Cape Town. All children who were coded as an 'assault with sharp object' were included in this study. Five-hundred-and-fifty-one (551) patients were retrospectively reviewed, of which 373 (68%) were boys and 177 (32%) girls. The mean age of the children was 7 years. The majority of children (51%) sustained injuries at the head or neck region, 26% sustained an injury at the trunk and 26% at the extremities. The majority of children sustained minor injuries (62%), thirty-three (33%) moderate and 5% severe injuries. Three children died. The most commonly recorded object used in the assault was glass or (broken) bottles (33%) and knives (18%). Other objects recorded included sticks, stones, pens, pencils, scissors, machetes and nails. The majority of perpetrators were known to the child. Assaults with a sharp object in small children are relatively rare and represent only 0.328% of all paediatric trauma patients. Although rare, these injuries carry a significant morbidity and even mortality. The majority of injuries occurred at home. Prevention programmes, specifically targeting the caretakers, should be implemented to prevent these tragic injuries.