Sleep quantity and quality as a predictor of injuries in a rural population

This study aimed to assess the association of sleep disturbance and injuries in a rural population of Iowa. Study participants were 1345 adults who were enrolled in the KCRHS. Sleep problems were assessed based on self-reports at the beginning of the study. Injury information was collected by telephone interviews an average of every 6 months from August 1999 to June 2004. Sleeping for less than 7.5 hours increased the risk for injuries by 61% (rate ratio, 1.61; 95% confidence interval, 1.21-2.15) compared with sleeping for 7.5 to 8.5 hours (reference). Snoring frequency/severity and daytime fatigue/sleepiness were not significant in predicting the risk for injuries. Alcohol consumption of 1 to 2 or more drinks per day increased the risk for injuries among those who had sleep problems. Having adequate hours of sleep is important in preventing injuries. Avoiding alcohol consumption would be especially helpful in reducing injuries among people with sleep disturbance.     

Toxicity and biodistribution of a first-generation recombinant adenoviral vector, encoding aquaporin-1, after retroductal delivery to a single rat submandibular gland

Before conducting a phase 1/2 clinical trial of a serotype 5 adenovirus encoding human aquaporin-1 (AdhAQP1) for the treatment of radiation-damaged salivary glands, we have conducted a detailed toxicity and biodistribution study in adult rats. AdhAQP1 (2x108-2x1011 particles) was delivered to a single submandibular gland by retroductal cannulation. Administration of this vector resulted in no animal mortality or morbidities, and no adverse signs of clinical toxicity. In addition, over the 92-day time course of the study, with both male and female rats, there were no consistent treatment-related changes in serum indicators of hepatic, renal, and cardiac functions. Importantly, we also observed no vector-associated effects on either water consumption by, or hematocrit levels in, study animals. However, three suggestive mild gender-related response differences were seen. Female, but not male, rats exhibited small reductions in food consumption (10-15%) and body weight gain (5-10%), and evidence of persistent inflammation, after vector treatment. These were vector, but not dose, related. Three days after delivery of 2x1011 particles of AdhAQP1, vector was detected primarily in the targeted gland; 9 of 10 samples from the targeted gland were positive, whereas only 5 of 90 nonoral samples were positive. There was no evidence of the generation of replication-competent adenovirus in saliva or blood samples. In aggregate, these findings show that localized delivery of AdhAQP1 to salivary glands appears to occur without significant toxicity.     

Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation

Bardet-Biedl syndrome (BBS) is an inherited ciliopathy generally associated with severe obesity, but the underlying mechanism remains hypothetical and is generally proposed to be of neuroendocrine origin. In this study, we show that while the proliferating preadipocytes or mature adipocytes are nonciliated in culture, a typical primary cilium is present in differentiating preadipocytes. This transient cilium carries receptors for Wnt and Hedgehog pathways, linking this organelle to previously described regulatory pathways of adipogenesis. We also show that the BBS10 and BBS12 proteins are located within the basal body of this primary cilium and inhibition of their expression impairs ciliogenesis, activates the glycogen synthase kinase 3 pathway, and induces peroxisome proliferator-activated receptor nuclear accumulation, hence favoring adipogenesis. Moreover, adipocytes derived from BBS-patients' dermal fibroblasts in culture exhibit higher propensity for fat accumulation when compared to controls. This strongly suggests that a peripheral primary dysfunction of adipogenesis participates to the pathogenesis of obesity in BBS.     

The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1

IL-33 is a chromatin-associated cytokine of the IL-1 family that has recently been linked to many diseases, including asthma, rheumatoid arthritis, atherosclerosis, and cardiovascular diseases. IL-33 signals through the IL-1 receptor-related protein ST2 and drives production of pro-inflammatory and T helper type 2-associated cytokines in mast cells, T helper type 2 lymphocytes, basophils, eosinophils, invariant natural killer T cells, and natural killer cells. It is currently believed that IL-33, like IL-1β and IL-18, requires processing by caspase-1 to a mature form (IL-33_112–270) for biological activity. Contrary to the current belief, we report here that full-length IL-33_1–270 is active and that processing by caspase-1 results in IL-33 inactivation, rather than activation. We show that full-length IL-33_1–270 binds and activates ST2, similarly to IL-33_112–270, and that cleavage by caspase-1 does not occur at the site initially proposed (Ser₁₁₁), but rather after residue Asp₁₇₈ between the fourth and fifth predicted β-strands of the IL-1-like domain. Surprisingly, the caspase-1 cleavage site (DGVD₁₇₈G) is similar to the consensus site of cleavage by caspase-3, and IL-33 is also a substrate for this apoptotic caspase. Interestingly, we found that full-length IL-33, which is constitutively expressed to high levels by endothelial cells in most normal human tissues, can be released in the extracellular space after endothelial cell damage or mechanical injury. We speculate that IL-33 may function, similarly to the prototypical alarmins HMGB1 and IL-1α, as an endogenous danger signal to alert cells of the innate immune system of tissue damage during trauma or infection.     

Can cocaine use be evaluated through analysis of wastewater? A nation‐wide approach conducted in Belgium

Aims Cocaine is the second most‐used illicit drug world‐wide and its consumption is increasing significantly, especially in western Europe. Until now, the annual prevalence has been estimated indirectly by means of interviews. A recently introduced and direct nation‐wide approach based on measurements of the major urinary excreted metabolite of cocaine, benzoylecgonine, in wastewater is proposed. Design Wastewater samples from 41 wastewater treatment plants (WWTPs) in Belgium, covering approximately 3 700 000 residents, were collected. Each WWTP was sampled on Wednesdays and Sundays during two sampling campaigns in 2007–08. Samples were analysed for cocaine (COC) and its metabolites, benzoylecgonine (BE) and ecgonine methylester (EME) by a validated procedure based on liquid chromatography coupled with tandem mass spectrometry. Concentrations of BE were used to calculate cocaine consumption (g/day per 1000 inhabitants) for each WWTP region and for both sampling campaigns (g/year per 1000 inhabitants). Findings Weekend days showed significantly higher cocaine consumption compared with weekdays. The highest cocaine consumption was observed for WWTPs receiving wastewater from large cities, such as Antwerp, Brussels and Charleroi. Results were extrapolated for the total Belgian population and an estimation of a yearly prevalence of cocaine use was made based on various assumptions. An amount of 1.88 tonnes (t) per year [standard error (SE) 0.05 t] cocaine is consumed in Belgium, corresponding to a yearly prevalence of 0.80% (SE 0.02%) for the Belgian population aged 15–64 years. This result is in agreement with an earlier reported estimate of the Belgian prevalence of cocaine use conducted through socio‐epidemiological studies (0.9% for people aged 15–64 years). Conclusions Wastewater analysis is a promising tool to evaluate cocaine consumption at both local and national scale. This rapid and direct estimation of the prevalence of cocaine use in Belgium corresponds with socio‐epidemiological data. However, the strategy needs to be refined further to allow a more exact calculation of cocaine consumption from concentrations of BE in wastewater.     

Development of a gene transfer-based treatment for radiation-induced salivary hypofunction

A significant long-term side effect of radiation therapy for head and neck cancers is xerostomia, a dry mouth, due to salivary gland damage. Despite continuing efforts to eliminate this problem, many patients continue to suffer. This brief review describes our efforts to develop a gene transfer approach, employing the aquaporin-1 cDNA, to treat patients with existing radiation-induced salivary hypofunction. A Phase I/II clinical trial, using a recombinant adenoviral vector to mediate gene transfer, is currently underway.     

Evaluation of novel bifunctional chelates for the development of Cu-64-based radiopharmaceuticals

BackgroundCurrently available bifunctional chelates (BFCs) for attaching Cu-64 to a targeting molecule are limited by either their radiolabeling conditions or in vivo stability. With the goal of identifying highly effective BFCs, we compared the properties of two novel BFCs, 1-oxa-4,7,10-triazacyclododecane-S-5-(4-nitrobenzyl)-4,7,10-triacetic acid (p-NO₂-Bn-Oxo) and 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-S-4-(4-nitrobenzyl)-3,6,9-triacetic acid (p-NO₂-Bn-PCTA), with the commonly used S-2-(4-nitrobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid (p-NO₂-Bn-DOTA).Methodsp-NO₂-Bn-DOTA, p-NO₂-Bn-Oxo and p-NO₂-Bn-PCTA were each radiolabeled with Cu-64 under various conditions to assess the reaction kinetics and robustness of the radiolabeling. Stability of each Cu-64 BFC complex was evaluated at low pH and in serum. Small animal positron emission tomography imaging and biodistribution studies in mice were undertaken.Resultsp-NO₂-Bn-Oxo and p-NO₂-Bn-PCTA possessed superior reaction kinetics compared to p-NO₂-Bn-DOTA under all radiolabeling conditions; >98% radiochemical yields were achieved in <5 min at room temperature even when using near stoichiometric amounts of BFC. Under nonideal conditions, such as low or high pH, high radiochemical yields were still achievable with the novel BFCs. The radiolabeled compounds were stable in serum and at pH 2 for 48 h. The imaging and biodistribution of the Cu-64-radiolabeled BFCs illustrated differences between the BFCs, including preferential clearance via the kidneys for the p-NO₂-Bn-PCTA Cu-64 complex.ConclusionsThe novel BFCs facilitated efficient Cu-64 radiolabeling under mild conditions to produce stable complexes at potentially high specific activities. These BFCs may find wide utility in the development of Cu-64-based radiopharmaceuticals.     

Complete remission of gastric Burkitt's lymphoma after eradication of Helicobacter pylori

Burkitt's lymphoma is a highly aggressive non- Hodgkin lymphoma, often presenting in extra-nodal sites. It generally has a poor spontaneous outcome and needs aggressive treatment with systemic and intrathecal chemotherapy. Occurrence at the gastric site is rare. We report the case of a 39-year old woman who presented with a prominent ulcerated lesion of the antrum corresponding histologically to a Burkitt's lymphoma associated with Helicobacter pylori ( H pylori) infection. Interphase fluorescence in situ hybridization (FISH) demonstrated c-MYC gene rearrangement in tumour cells without BCL2 or BCL6 gene translocations.Ulcer healing and tumour regression with a complete histological response were obtained 8 wk after H pylor ieradication. In spite of this complete remission, taking into account the high risk of recurrence, the patient received systemic and intrathecal chemotherapy. Two years later, the patient remained in complete remission.This is the first report of a gastric Burkitt's lymphoma responding to H pylori eradication. These findings raise the question of the potential role of H pylori in the pathogenesis of some gastric Burkitt's lymphomas, and show the importance of searching for and eradicating the bacteria in combination with conventional chemotherapy regimens.