All in the family: atypical Hsp70 chaperones are conserved modulators of Hsp70 activity.

Divergent relatives of the Hsp70 protein chaperone such as the Hsp110 and Grp170 families have been recognized for some time, yet their biochemical roles remained elusive. Recent work has revealed that these "atypical" Hsp70s exist in stable complexes with classic Hsp70s where they exert a powerful nucleotide-exchange activity that synergizes with Hsp40/DnaJ-type cochaperones to dramatically accelerate Hsp70 nucleotide cycling. This represents a novel evolutionary transition from an independent protein-folding chaperone to what appears to be a dedicated cochaperone. Contributions of the atypical Hsp70s to established cellular roles for Hsp70 now must be deciphered.

Environmental and behavioral risk factors for moderate or severe rotavirus diarrhea in children less than 24 months

On a global basis rotaviruses are the most important agents involved in childhood diarrhea. In developing countries they account for 6% of all diarrheas and 20% of all diarrhea related deaths of children under 5 years of age, with over 1 billion episodes and over 4 million deaths annually. Given the disease burden, there is a need for better understanding the risk factors involved in rotavirus disease, to identify areas of intervention. In order to provide this information, two areas were developed: a review of the literature, examining the causal evidence for rotavirus diarrhea and a case comparison study. The case comparison study analyzed two areas: identifying climate factors and, identifying environmental and behavioral risk factors. The literature review showed that few analytical studies have identified specific risk factors such as home environment, and a winter seasonal trend for temperate areas, but in key areas evidence is contradictory. The case comparison study for climate factors demonstrated that seasonality occurs in a tropical country like Venezuela and that a complex interplay between weather conditions contribute to the seasonal pattern. A positive association between rain fall (OR 4.1); dew point (OR 2.3) and temperature differential during the day (OR 1.4) and, an inverse association with temperature (OR 0.5) and relative humidity (OR 0.8) was found. This information is useful in understanding the seasonal pattern of rotavirus and for planning health care needs. The second analysis demonstrated that environmental variables such as crowding (OR 14.3), contact with someone with an infectious disease (OR 4.9) and animal ownership (OR 2.3) were important. Restricting the analysis to animal owners demonstrated that living In a rural settling (OR 13.8), defecating in inappropriate places (OR 7.2), crowding(4.2) and indoor animals (4.0) are of importance. Behavioral variables identified were: lack of breast feeding (OR 4.0) and visiting when someone was sick (OR 3.4). Biological and demographic variables of importance were: age, with a dose response relationship; undernurishment (OR 11.3) and household per capita monthly income less than US $ 16.30 (OR 8.5). Using a diarrhea compeer group we found that, although some of the previous variables were of importance, no major differences were found. These findings are important in identifying paths for prevention and further research. ^

Retrospective assesment of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and early endometrioid endometrial cancer

Objective: The primary objective of this project was to describe the efficacy of the Levonorgestrel Intrauterine Device (LIUD) for treatment of Complex Endometrial Cancer (CAH) and Grade 1 Endometrial Cancer (G1EEC) in terms of rate of Complete Response (CR) and Partial Response (PR) after 6 months of therapy. Finally, we assessed if any clinical or pathologic features were associated with response to the LIUD. ^ Methods: This study was a retrospective case series designed to report the response rate of patients with CAH or G1EEC treated with LIUD therapy. In addition, this study has a laboratory component to assess molecular predictors of response to LIUD therapy. Retrospective data already collected from patients diagnosed with CAH or EEC grade 1 and treated with LIUD therapy at MD Anderson Cancer Center (MDACC) were used for this study. Patients from all ethnic and race groups were included. A Complete Response (CR) was defined in patients diagnosed with CAH if pathologic report at 6 months demonstrated either no evidence of hyperplasia or no atypia in the setting of simple or complex hyperplasia. Partial Response (PR) was recorded if disease downgraded to only CAH from G1EEC. No Response (NR) was recorded if pathologic report demonstrates no change (Stable Disease, SD) or progression to cancer (Progressive Disease, PD). We calculated the proportion of patients with complete response to LIUD therapy with 95% confidence interval. We compared the response rates (CR/PR vs NR) by obesity status (Obese if BMI > 40 kg/m2 vs non-obese if BMI <= 40 kg/m2) as well as other clinical and pathologic factors, such as age, uterine size (median size), and presence of exogenous progesterone effect. ^ Results: There were 39 patients diagnosed with either CAH or G1EEC treated with the LIUD. Of 39 patients, 12 did not have pathological results of biopsy at 6months time period. Of 27 evaluable patients, 17 were diagnosed with CAH and 10 with G1EEC. Overall response rate (RR) was 78% (95% CI = 62-94%) at 6 months, 18 patients had CR (4 in G1EEC; 14 in CAH), 3 patients had PR (3 in G1EEC), 3 had SD (1 in CAH; 2 in G1EEC), 3 had PD (2 in CAH; 1 in G1EEC). After histology stratification, RR at 6 months was 82.35% (14/17; 95%CI = 67.4-97.3%) in CAH and 70% (7/10; 95% CI = 41-98.4%) in G1EEC. ^ There was no difference in response (R) and no response (NR) based on BMI (p=0.56). He observed a trend showing association between age with response (p=0.1). There was no association between uterine size and response to therapy (p=0.17). We recorded strong association between exogenous progesterone effect and response. ^ Conclusion: LIUD therapy for the treatment of CAH and G1EEC may be effective and safe. Presence of exogenous progesterone effect may predict the response to LIUD therapy at earlier time points. There is need of further studies with larger sample size to explore the relationship of response with other clinical and pathologic factors^