Microvascular and tubulointerstitial injury associated with chronic hypoxia-induced hypertension

BACKGROUND: Rats submitted to chronic hypoxia develop hypertension that persists despite cessation of the hypoxia or correction of the hematocrit. We examined whether chronic hypoxia might induce subtle renal injury since studies in other animal models of hypertension suggest this may cause persistent hypertension. METHODS: Chronic hypoxia was induced in rats by placement in a hypobaric chamber for up to 24 days. Blood pressure and kidney biopsies were performed at baseline, 6 hours, 24 hours, and 24 days of hypoxia. RESULTS: Chronic hypoxia induced hypertension and erythrocytosis at 24 days. Acute hypoxia was associated with endothelial cell swelling in arterioles (6 and 24 hours), followed by thickening of the arterioles at 24 days. Subtle tubulointerstitial injury and inflammation occurred and was progressive. The influx of macrophages increased steadily over the 24 days and was associated with a progressive increase in interstitial collagen III deposition. Hypoxia was associated with increased tubular expression of osteopontin as early as 6 hours, the same period when an increase of proximal tubular cell proliferation occurred. Interstitial cell proliferation peaked twice, at 6 hours and at 24 days. Glomerular hypertrophy was manifest at 24 days. CONCLUSION: Both afferent arteriolar disease and subtle tubulointerstitial inflammation and injury occur early in hypoxic rats. These changes may predispose these animals to persistent hypertension.     

Coexistence of late spondyloepiphyseal dysplasia and congenital megaloblastic anemia with proteinuria in the same family

A case of spondyloepiphyseal dysplasia tarda was noted in a dwarf (130 cm tall) 18 years old boy associated with congenital megaloblastic anemia and proteinuria. His two sisters and a cousin are also suffering from similar hematologic disorder. One of his brothers, 145 cm tall, is also involved by spondyloepiphyseal dysplasia, but there is no known hematologic abnormalities. Review of family history revealed that two aunts from mother's side were deceased in adulthood following a chronic anemic disease. The findings in this anemia are compatible with Imerslund-Grasbech syndrome and coexistence of these two rare genetic disorders in a single family has not been reported previously.     

A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43)

We report a novel mutation in the amyloid precursor protein gene (APP I716V) which probably leads to familial early onset Alzheimer's disease with an onset age in the mid 50s. Cells transfected with cDNAs bearing this mutation produce more A beta 1-42(43) than those transfected with wild-type APP and this effect is additive with that of the previously reported APP V717I mutation thus providing a novel approach for further increasing A beta 1-42(43) in model systems.      

Effects of Experimental Hemosiderosis on Pancreatic Tissue Iron Content and Structure

The effects of iron overload on pancreatic ironcontent and morphology were investigated. Sprague-Dawleyrats were randomized into an iron-overloaded group,which received a single subcutaneous injection of 1.2 g/kg elemental iron as iron-dextrancomplex, and placebo-treated pair-fed controls. Animalswere studied after a 10-month observation period. Tissuenonheme iron content was measured, and histologic examination was carried out. Chroniciron-overloaded animals showed significant increases intissue iron content. There was a statisticallysignificant increase in stainable iron in perivascular,parenchymal, and lymphoid tissue in the iron-overloadedgroup. Although pancreatic fibrosis was present in theiron-overload group, it was not statisticallysignificant. The iron-overloaded animals showed someislet cell destruction. In contrast, no significantislet cell destruction was seen in the control group.However, the difference was not statisticallysignificant. Moreover, the serum glucose levels were the same in both groups, suggesting that there wasno significant impairment of pancreatic endocrinefunction. Thus, chronic experimental iron overload inrats leads to significant increases in tissue iron content, but no significant morphologicalterations of the pancreas with the dose and route ofiron administered in this animal model.     

Inhibition of delayed-type contact hypersensitivity in mice deficient in both E-selectin and P-selectin

Leukocyte rolling and emigration in response to inflammatory stimuli appears to involve both E-selectin- and P-selectin-dependent adhesion, which suggests that these molecules have overlapping functions. To clarify their relative contributions in chronic inflammation, we examined delayed-type contact hypersensitivity (DTH) responses in P- selectin, E-selectin, and E-/P-selectin-deficient mice. Oxazolone- induced increases in ear thickness and ear weight were equivalent in wild-type mice and in P-selectin and E-selectin mutants, but were significantly reduced in E-/P-selectin mutants. The number and area of microabscesses on the ears of E-/P-deficient mice were decreased by 72% and 93%, and the number of leukocytes invading the subdermal ear tissue was reduced. T cells from E-/P-deficient mice transferred oxazolone reactivity into naive wild-type mice. However, when donor T cells from wild-type mice were transferred into E-/P-selectin-deficient mice, the DTH response was significantly impaired. These results show that leukocyte recruitment into a subacute inflammatory reaction can occur when either P-selectin or E-selectin is present, but is significantly reduced when both selectins are absent. Both P- and E-selectin are likely to play important roles in the development and maintenance of inflammatory diseases.     

Polymorphism of adhesion molecule CD31 is not a significant risk factor for graft-versus-host disease

Mismatch between bone marrow transplant (BMT) patient and donor for an amino acid polymorphism within the adhesion molecule CD31 has recently been reported to increase risk for the development of graft-versus-host disease (GVHD). We further examined this association in a larger series of 301 BMT patients (227 with grade III/IV GVHD and 74 with grade 0 GVHD) and their HLA-identical sibling donors. CD31 genotypes were determined by polymerase chain reaction and restriction endonuclease digestion. The role of mismatch at the CD31 locus in the development of GVHD was assessed by analyzing the extent of CD31 identity and CD31 compatibility among the grade 0 GVHD and grade III/IV GVHD sibling pairs. No significant association between CD31 mismatch and the development of severe GVHD was detected in our overall patient population. Sixty-three percent of grade III/IV GVHD sibling pairs and 69% of grade 0 GVHD sibling pairs had CD31 genotypes that were identical (P = .36, odds ratio = 1.30). In addition, neither the grade 0 GVHD group (P = .10) nor the grade III/IV GVHD group (P = .27) differed significantly from the expected probability of identity between sibling pairs. Mismatch at the CD31 polymorphism between recipients and donors showed no consistent association with the development of GVHD. Current evidence does not support the value of CD31 mismatch in the selection of BMT donors.     

Breast Cancer Chemoprevention among High‐risk Women and those with Ductal Carcinoma In Situ

Chemoprevention with the anti‐estrogens, tamoxifen, raloxifene, and aromatase inhibitors, reduce breast cancer incidence in high‐risk women; however, uptake has been poor (<5%) in the prevention setting. We assessed use of anti‐estrogens for breast cancer prevention, among high‐risk women seen at an academic breast center, to observe how uptake rates compare in this setting. We collected data on demographics, breast cancer risk factors, and health behaviors via self‐administered questionnaires and medical chart abstraction. Women eligible for chemoprevention with anti‐estrogens had a 5‐year predicted breast cancer risk according to the Gail model of ≥1.67%, history of lobular or ductal carcinoma in situ (LCIS/DCIS), and/or BRCA mutation. We dichotomized anti‐estrogen use as ever or never. Predictors of use were evaluated using multivariable log‐binomial regression. Of 412 high‐risk women enrolled, 316 (77%) were eligible for chemoprevention. Among eligible women, 55% were non‐Hispanic white, 29% Hispanic, 8% non‐Hispanic black, and 7% Asian. Women were grouped based upon their highest category of breast cancer risk (in descending order): BRCA mutation carriers (3%), DCIS (40%), LCIS (22%), and 5‐year Gail risk ≥1.67% (36%). Among those eligible for chemoprevention, 162 (51%) had ever initiated anti‐estrogen therapy (71% tamoxifen, 23% raloxifene, 5% aromatase inhibitor). Anti‐estrogen use was highest among women with DCIS (73%). In multivariable analysis, women with a 5‐year Gail risk ≥1.67% had approximately a 20% lower likelihood of anti‐estrogen use compared to women with DCIS (p = 0.01). In the primary prevention setting, excluding women diagnosed with DCIS, anti‐estrogen use was 37%. Multivariable analysis showed differences in uptake by education and potentially by race/ethnicity. Among high‐risk women seen at a breast center, anti‐estrogen use for chemoprevention was relatively high as compared to the published literature. Clinicians can support high‐risk women by effectively communicating breast cancer risk and enhancing knowledge about the risks and benefits of chemoprevention.     

The effects and effectiveness of electromotive drug administration and chemohyperthermia for treating non-muscle invasive bladder cancer

Introduction

Preliminary studies show that device assisted intravesical therapies appear more effective than passive diffusion intravesical therapy for the treatment of non-muscle invasive bladder cancer (NMIBC) in specific settings, and phase III studies are now being conducted. Consequently, we have undertaken a non-systematic review with the objective of describing the scientific basis and mechanisms of action of electromotive drug administration (EMDA) and chemohyperthermia (CHT).

Methods

PubMed, ClinicalTrials.gov and the Cochrane Library were searched to source evidence for this non-systematic review. Randomised controlled trials, systematic reviews and meta-analyses were evaluated. Publications regarding the scientific basis and mechanisms of action of EMDA and CHT were identified, as well as clinical studies to date.

Results

EMDA takes advantage of three phenomena: iontophoresis, electro-osmosis and electroporation. It has been found to reduce recurrence rates in NMIBC patients and has been proposed as an addition or alternative to bacillus Calmette–Guérin (BCG) therapy in the treatment of high risk NMIBC. CHT improves the efficacy of mitomycin C by three mechanisms: tumour cell cytotoxicity, altered tumour blood flow and localised immune responses. Fewer studies have been conducted with CHT than with EMDA but they have demonstrated utility for increasing disease-free survival, especially in patients who have previously failed BCG therapy.

Conclusions

It is anticipated that EMDA and CHT will play important roles in the management of NMIBC in the future. Techniques of delivery should be standardised, and there is a need for more randomised controlled trials to evaluate the benefits of the treatments alongside quality of life and cost-effectiveness.