Intraepithelial lymphocytes in celiac disease

Coeliac disease (CD) is a permanent intolerance to gluten that provokes alterations in the mucosa of the small intestine. The disease can usually be controlled by excluding gluten from the diet. CD is immunologically-mediated, with a strong linkage to certain HLA alleles and a permanently altered intraepithelial lymphocytes (IEL) pattern. The development of a flow cytometric technique for the evaluation of IEL subsets has increased our understanding of these alterations and has prepared the ground for its clinical application. Our experience shows that this procedure has excellent sensitivity and specificity in the diagnosis of CD and that it is particularly useful in the evaluation of atypical presentations of the disease. The present article reviews our experience in the diagnosis of CD and discusses some of the hypotheses that have been put forward on the possible role of IEL in its pathogenesis.     

Exfoliated buccal mucosa cells as a source of DNA to study oxidative stress.

The extent of oxidative DNA damage is considered a biomarker of carcinogenic process and could be investigated in population studies using easily obtained cells. The oxidized DNA base adduct 8-hydroxy-2-deoxyguanosine (8-OHdG) released by enzymatic hydrolysis of DNA is commonly assayed by high performance liquid chromatography with electrochemical detection. It is expressed as a ratio of 8-OHdG to unoxidized deoxyguanosine. We modified and improved this method, determined the optimal time for harvesting buccal mucosa cells (BMC), assessed whether they mirror peripheral circulating blood cell DNA damage, and compared the anticoagulants, heparin, and EDTA for consistency in measurement of leukocyte 8-OHdG. Thirty-one healthy participants, randomized into two groups, donated BMC and blood samples. Samples were collected at baseline and either 3 or 7 days after baseline. Results showed no correlation between 8-OHdG/deoxyguanosine ratios in BMC and peripheral blood leukocytes at any time point regardless of harvest time. BMC had much higher oxidative DNA damage, but displayed a 25.6% reduction in the oxidized DNA adduct level (P < 0.04) at 3 days after baseline. Leukocytes collected in heparin and EDTA had similar 8OHdG/deoxyguanosine ratios; however, EDTA was preferred, as it produced a clean nuclear pellet without hemoglobin contamination, and the results were less variable. This improved assay shows within subject stability over time in both leukocyte and BMC DNA damage, increasing the probability that small intervention differences can be detected in healthy subjects. Buccal cells provide an accessible pool of epithelial cells that represents higher levels of DNA damage than circulating leukocytes.     

Air pollution mortality: harvesting and loss of life expectancy

This article concerns the interpretation of epidemiological studies of air pollution mortality and the choice of indicators for quantifying the impact, for communication with policymakers. It is shown that the total mortality impact (measured by cohort studies) can only be quantified in terms of loss of life expectancy (LLE), not number of premature deaths. Time-series (TS) studies of mortality observe only acute impacts, that is, deaths due to short-term exposure ("acute mortality"); they allow the estimation of a number of deaths without providing any information on the LLE per death. However, even if the average loss per death is as long as 6 mo, acute mortality is only a very small percentage of the total mortality attributable to air pollution. Estimates of the population-average LLE due to air pollution are provided, for acute mortality, total adult mortality, and infant mortality.     

Replicative fitness of historical and recent HIV-1 isolates suggests HIV-1 attenuation over time

BACKGROUND: Changes in virulence during an epidemic are common among pathogens, but still unexplored in the case of HIV-1. Here we used primary human cells to study the replicative fitness of primary HIV-1 isolates from untreated patients, comparing historical (1986-1989) and recent samples (2002-2003). METHODS: Head-to-head dual virus infection/competition assays were performed in both peripheral blood mononuclear cells and human dendritic cell/T-cell co-cultures with pairs of 12 carefully matched historical and recent HIV-1 isolates from untreated patients. Sensitivity to inhibition by lamivudine (3TC) and TAK-779 of historical and recent R5 HIV-1 isolates was measured in a subset of samples. RESULTS: Overall, the historical HIV-1 out-competed the recent HIV-1 isolates in 176 of 238 competitions and in 9 of 12 competitions carefully matched for CD4 cell count. The mean relative replicative fitness (W) of all historical HIV-1 strains was significantly greater than that of recent HIV-1 isolates (W(1986-1989) = 1.395 and W(2002-2003) = 0.545, P < 0.001 (t test)). The more fit viruses (mean W > 1) from 1986-1989 appeared less sensitive to TAK-779 and 3TC than did the less fit (mean W < 1) 2002-2003 viruses. CONCLUSIONS: These findings suggest that HIV-1 replicative fitness may have decreased in the human population since the start of the pandemic. This 'attenuation' could be the consequence of serial bottlenecks during transmission and result in adaptation of HIV-1 to the human host.     

Early postoperative hepatic sonography as a predictor of vascular and biliary complications in adult orthotopic liver transplant patients

OBJECTIVE: Our objective was to quantitatively assess the value of early posttransplantation hepatic artery resistive indexes in predicting vascular and nonvascular complications in adult orthotopic liver transplant (OLT) patients. MATERIALS AND METHODS: Between 1999 and 2001, 110 consecutive adults received grafts. Doppler sonographic graft evaluations measured main, right, and left resistive indexes within 24 to 48 hr after surgery (normal resistive index cutoff, 0.6). Clinical, operative, procedural, and radiologic reports were reviewed for vascular and biliary complications. Frequency, Student's t test, logistic, and regression statistical analyses were performed. RESULTS: even patients (6.4%) had vascular complications, including two (1.8%) hepatic artery and two (1.8%) hepatic vein stenoses, one (0.9%) hepatic vein thrombosis, two (1.8%) portal vein thromboses, and one (0.9%) thrombosis and two (1.8%) stenoses of the inferior vena cava (IVC). In 19 patients (17.3%), biliary complications included anastomotic strictures and leaks 1 week to 18 months after transplantation. In 11 patients (10%), sonographically large hematomas required surgical evacuation. In grafts with vascular complications or large hematomas, the mean early posttransplant main, right, and left indexes were significantly lower (< or = 0.6) than without these complications (p < 0.01). In grafts with and without biliary complications, mean early posttransplant main, right, and left indexes did not differ significantly. CONCLUSION: In adult OLT patients, low early posttransplant hepatic artery resistive indexes were sensitive (100%) and specific (80%) predictors for vascular complications (e.g., hepatic artery, portal vein, hepatic vein, and IVC) but not for biliary complications. All patients with indexes less than 0.6 within 24-48 hr after surgery should be monitored closely for vascular complications.     

Two decades of HIV/AIDS in Hawaii: contrast with national trends

This paper describes the HIV/AIDS epidemic in Hawaii. Data indicate gradual but steady changes in characteristics of infected populations. Most significant are increases in cases among Asian Pacific Islanders, women, heterosexuals and younger age groups. Early harm reduction measures and low incidence among injection drug users relative to other parts of the U.S. may have played a significant role in containing the epidemic.     

Apathy predicts hedonic but not craving response to cocaine

Cocaine-induced craving has been implicated in the maintenance of ongoing cocaine use and is presumed to be mediated by enhanced synaptic availability of monoamines, including dopamine. Apathy is a neuropsychiatric syndrome that is associated with hypodopaminergic functioning and is neurobiologically distinct from depression. Apathy has been observed to be prevalent during the initial phases of abstinence in cocaine-dependent individuals. In the current report, we sought to investigate the relationship between apathy, depression, and craving in response to an acute intravenous administration of cocaine. To this end, sixteen non-treatment seeking volunteers were evaluated. Following acute administration of cocaine (40 mg, IV), patients with low apathy scores exhibited increased craving, whereas patients with high apathy scores exhibited decreased craving. In addition, patients with high apathy scores exhibited increased ratings of the subjective measure of "High", suggesting that high apathy predicts a greater hedonic response in dependence. Self-reported ratings of depression did not account for the observed differences. The data reveal that cocaine-induced craving is not ubiquitous, and may not play a critical role in the maintenance of cocaine dependence. Overall, the findings suggest that apathy predicts hedonic but not craving response to cocaine.     

Abdominal war wounds--experiences from Red Cross field hospitals

The traditional approach to abdominal war wounds consists of triage, eche-loned care, and mandatory laparotomy for penetrating abdominal injuries, and it remains valid in modern conventional wars with well-organized evacuation and surgical services. Expectant management of abdominal casualties can be considered under difficult circumstances with a high influx of patients exhausting the available resources. This can occur in regional conflicts associated with mass movements of people and with collapsed infrastructure. While always combined with adequate fluid resuscitation, antibiotic treatment, and other supportive care, the expectant approach in patients with penetrating abdominal injuries could be indicated for asymptomatic patients with multiple fragment wounds or for patients presenting several days post-injury in good condition. The focus of surgical resources and competence should be on the majority of patients with intestinal perforation only, who need surgery to save life--but not necessarily on an urgent basis--and who have a good chance of survival. The limited availability of blood products to correct blood loss and coagulation factor deficiencies, and the lack of sophisticated monitoring of hemodynamic variables that call into question the value of a damage-control approach for the most severely injured. Even if the bleeding could be temporarily controlled, the subsequent need for adequate resuscitation before returning the patient to the operating room could be difficult to achieve and would result in incompletely resuscitated patients being reoperated while acidotic, coagulopathic, and even hypothermic. Perhaps, in mass casualty situations these patients should be recognized during triage or at least early during operation, and aggressive surgery should be replaced with adequate expectant management with sedation and analgesics.     

Tolerance: is it worth the risk?

BACKGROUND: The success of orthotopic liver transplantation (OLT) has been limited by the adverse effects of immunosuppression. The purpose of this study was to determine the safety and feasibility of withdrawing immunosuppression in OLT recipients to achieve tolerance. METHODS: Eighteen adult OLT recipients in our steroid-free protocol without rejection were selected for this protocol. All patients chosen for this trial were on tacrolimus monotherapy with normal liver function tests (LFTs). Tacrolimus was weaned as long as LFTs remained stable. Weaning was halted for elevations of liver enzymes and tacrolimus was increased to the last dosage at which the patients had normal LFTs. Rejection was treated by increasing tacrolimus to levels of 10-15 ng/ml. Mycophenolate mofetil (MMF) or sirolimus was added if there was severe rejection by biopsy. Steroids were used if there was no improvement. RESULTS: One patient has been weaned off immunosuppression. Three additional patients were weaned completely off but had tacrolimus resumed because of mild elevations in LFTs. Eleven of 18 (61%) patients had rejection. Two patients required steroid therapy and one required rabbit antithymocyte globulin in addition to MMF and steroids. One of the patients with rejection developed diabetes and one patient had renal failure, which subsequently resolved. One patient died following a stroke. CONCLUSIONS: Clinical tolerance can be achieved in a minority of patients, even when being maintained on minimum immunosuppression. The potential benefit of achieving tolerance must be weighed against the risks of rejection therapy in patients doing well on low-dose immunosuppression.