Risk of malignant disease among 1525 adult male US Veterans with Gaucher disease

BACKGROUND: Some, but not all, reports suggest that patients with Gaucher disease are at increased risk of developing malignancies, particularly hematopoietic tumors. The aim of this study was to assess the pattern of Gaucher disease and subsequent malignancies among male veterans admitted to US Veterans Affairs hospitals. METHODS: Among 832 294 African American and 3 668 983 white male veterans with at least 1 hospital admission in US Veterans Affairs hospitals and up to 27 years of follow-up, we identified a total of 1525 patients with Gaucher disease; 11.7% were African Americans. We used Poisson regression methods for cohort data to estimate relative risks (RRs) and 95% confidence intervals (CIs) after adjusting for attained age and calendar year, race, number of hospital visits, and latency. RESULTS: When patients with Gaucher disease were compared with patients without Gaucher disease, the RR of any cancer was 0.91 (95% CI, 0.76-1.08 [n = 137]). When we stratified our analyses by race, risks were similar for whites (RR, 0.89; 95% CI, 0.74-1.07 [n = 120]) and African Americans (RR, 1.00; 95% CI, 0.61-1.64 [ n = 17]). Patients with Gaucher disease had an elevated risk for non-Hodgkin lymphoma (RR, 2.54; 95% CI, 1.32-4.88 [n = 9]), malignant melanoma (RR, 3.07; 95% CI, 1.28-7.38 [n = 5]), and pancreatic cancer (RR, 2.37; 95% CI, 1.13-4.98 [n = 7]). Among the remaining 19 cases involving defined solid tumors and 7 other hematologic malignancies, we found no statistical association with Gaucher disease. CONCLUSION: We found 2- to 3-fold risks of non-Hodgkin lymphoma, malignant melanoma, and pancreatic cancer in patients with Gaucher disease, but no significant association between Gaucher disease and cancer in general or with other specific malignancies such as multiple myeloma.     

Placental transfer of quetiapine in relation to P-glycoprotein activity

Atypical antipsychotic drugs are well tolerated and thus often preferred in women of fertile age; yet the information on their placental transfer and use during the prenatal period is limited. The aim of this study was to study the placental transfer of quetiapine, a widely used atypical antipsychotic, with special reference to the role of the placental transporter protein, P-glycoprotein (P-gp). This was performed in 18 dually perfused placentas, using the well established P-gp inhibitors PSC833 (valspodar) and GG918 to inhibit the function of P-gp. We also aimed to clarify the significance of two potentially functional ABCB1 single nuclear polymorphisms (SNPs), 2677G>T/A and 3435C>T, on the transplacental transfer (TPT) of quetiapine. The placental transfer of quetiapine in the control group as measured by TPT(AUC) % (absolute fraction of the dose crossing placenta) was 3.7%, which is 29% less than the transfer of the freely diffusible antipyrine, which was 5.2%. The P-gp inhibitors had no significant effect on the transfer of quetiapine as measured by TPT(AUC) % (P = 0.77). No correlation was found between the transplacental transfer of quetiapine (TPT(AUC) %) and placental P-gp expression (P = 0.61). The 3435T allele in exon 26 was associated with significantly higher placental transfer of quetiapine (P = 0.04). We conclude that quetiapine passes the human placenta but that the blood-placental barrier partially limits the transplacental transfer of quetiapine. Administration of P-gp inhibiting drugs with quetiapine is not likely to increase fetal exposure to quetiapine, although the ABCB1 C3435T polymorphism may contribute to inter-individual variation in fetal exposure to quetiapine.     

Desloratadine relieves nasal congestion and improves quality-of-life in persistent allergic rhinitis

Background:  Symptoms of allergic rhinitis (AR), particularly nasal congestion, can impair quality-of-life (QoL). However, only a modest correlation exists between these symptoms and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, suggesting that both be evaluated for a complete assessment of health.
Methods:  Subjects with a ≥2-year history of moderate-to-severe AR to dust mite or cat dander were randomized to desloratadine 5 mg/day ( n  =   293) or placebo/day ( n  =   291) for 28 days. Primary endpoint was change from baseline in a.m./p.m. nasal congestion score. Secondary outcomes included change from baseline in total nasal symptom score, individual symptom scores and RQLQ scores (completed on days 1, 7, and 28).
Results:  The Allergic Rhinitis and its Impact on Asthma criteria for persistent allergic rhinitis (PER) were fulfilled by 99% of subjects in the placebo arm. Between-treatment difference in a.m./p.m. nasal congestion score, observed from day 8 onward, significantly favored desloratadine ( P  =   0.0003). Desloratadine significantly improved a.m./p.m. nasal congestion and RQLQ scores after 1 week and at treatment end ( P  <   0.05). Improvements in 5 of 7 RQLQ domain scores exceeded the minimal important difference. On days 7 and 28, desloratadine was also significantly superior to placebo in mean change from baseline in a.m./p.m. total nasal symptom score and rhinorrhea score (both P  ≤   0.01). Symptomatic benefit was primarily driven by improvement in nasal congestion and rhinorrhea.
Conclusions:  Desloratadine 5 mg/day significantly improved symptoms associated with PER, including nasal congestion, and provided significant improvement in QoL after 1 week of treatment.     

Dmu expression causes enrichment of MZ B cells, but is non permissive for B cell maturation in Rag2-/- mice even if combined with Bcl-2

Rearrangements in reading frame 2 promote the expression of a truncated heavy chain, the Dmu protein. Dmu can assemble into a pre-B cell receptor like complex that appears to induce a subset of signals elicited by full length mu, but cannot promote the pro-B to pre-B cell transition of Rag-/- B cells. In order to determine if this could stem from an impaired survival signal not properly induced by the Dmu protein, we introduced Bcl-2 into Dmu-transgenic, Rag2-/- mice. Despite the fact that the Bcl-2 transgene expression promoted some increase in the fraction of CD43- B cells, an identical increase was also observed in Rag2-/- mice. Moreover, whereas in mu-transgenic Rag2-/-Bcl-2+ mice, CD2 and CD25 expression were up regulated and c-Kit was down regulated, these markers were unaltered in Dmu-transgenic Rag2-/- Bcl-2+ mice compared to Rag2-/- Bcl-2+ mice, indicating that Dmu cannot support pre-B cell maturation despite extended survival of B cell precursors by Bcl-2. In addition, we observed that in Dmu-transgenic recombination competent mice, the Dmu induced partial block is permissive for marginal zone B cell development whereas the formation of follicular B cells is severely reduced. While the Dmu protein is expressed in peripheral B cells escaping the block, only a minor fraction of Dmu is exposed to the outer cell surface.     

Assessment of bleeding after concomitant administration of antiplatelet and anticoagulant agents in lower limb arthroplasty

In an analysis of the Melagatran Thrombosis Prophylaxis in Orthopedic Surgery (METHRO) III study, we evaluated whether concomitant administration of aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) with the direct thrombin inhibitor melagatran/ximelagatran or the low-molecular-weight heparin enoxaparin increased bleeding in patients undergoing major joint surgery. Further objectives were to compare the influence of the timing of initial postoperative administration of melagatran/ximelagatran on bleeding in orthopedic patients receiving ASA/NSAIDs and in comparison with the preoperative administration of enoxaparin. ASA or NSAIDs in conjunction with melagatran/ximelagatran or enoxaparin did not increase bleeding. Bleeding rates were not significantly different, irrespective of the timing of the initial postoperative dose of melagatran/ximelagatran (4-8 vs. 4-12 h) when compared with preoperative (12 h) administration of enoxaparin. Transfusion rates were significantly lower with administration of melagatran/ximelagatran compared with enoxaparin.     

Anxiety disorders among Nigerian women in late pregnancy: a controlled study

Summary This study aimed to investigate the rate and type of anxiety disorders among Nigerian women in late pregnancy. Women in late pregnancy (n = 172) and a non-pregnant control group were assessed for DSM-IV anxiety disorders. The rate of any anxiety disorder in the pregnant women was 39.0% compared with 16.3% in the non-pregnant population (p < 0.001). Although all the anxiety disorders were more common, only the rate of social anxiety disorder was significantly higher among the pregnant than non-pregnant population. Correlates of anxiety disorder in the pregnant population include age less than 25 years (OR 4.62, 95% CI 2.39–8.92), primiparity (OR 3.90, 95% CI 2.00–7.59) and presence of medical conditions (OR 3.60, 95% CI 1.28–10.12). More research is needed in this field to ascertain the specific association between pregnancy and anxiety disorders.     

Motion sickness increases the risk of accidental hypothermia

Motion sickness (MS) has been found to increase body-core cooling during immersion in 28°C water, an effect ascribed to attenuation of the cold-induced peripheral vasoconstriction (Mekjavic et al. in J Physiol 535(2):619–623, 2001). The present study tested the hypothesis that a more profound cold stimulus would override the MS effect on peripheral vasoconstriction and hence on the core cooling rate. Eleven healthy subjects underwent two separate head-out immersions in 15°C water. In the control trial (CN), subjects were immersed after baseline measurements. In the MS-trial, subjects were rendered motion sick prior to immersion, by using a rotating chair in combination with a regimen of standardized head movements. During immersion in the MS-trial, subjects were exposed to an optokinetic stimulus (rotating drum). At 5-min intervals subjects rated their temperature perception, thermal comfort and MS discomfort. During immersion mean skin temperature, rectal temperature, the difference in temperature between the non-immersed right forearm and 3rd finger of the right hand (ΔT _ff), oxygen uptake and heart rate were recorded. In the MS-trial, rectal temperature decreased substantially faster (33%, P < 0.01). Also, the ΔT _ff response, an index of peripheral vasomotor tone, as well as the oxygen uptake, indicative of the shivering response, were significantly attenuated (P < 0.01 and P < 0.001, respectively) by MS. Thus, MS may predispose individuals to hypothermia by enhancing heat loss and attenuating heat production. This might have significant implications for survival in maritime accidents.     

Increased body mass index does not alter response to initial highly active antiretroviral therapy in HIV-1-infected patients

BACKGROUND: Body mass index (BMI) can influence drug metabolism, thus affecting efficacy and risk for toxicities. Hypothesizing that persons with an increased BMI and larger volumes of distribution may experience a suboptimal response to highly active antiretroviral therapy (HAART), we evaluated the effect of BMI on virologic and immunologic response in previously ART-naive patients initiating therapy. METHODS: Using data from the HIV Outpatient Study, we analyzed the statistical association of BMI and other selected demographic variables with achieving an undetectable viral load and experiencing a CD4 cell count increase of more than 100 cell/microL after 3 to 9 months of therapy among antiretroviral-naive patients initiating HAART. RESULTS: Among 711 patients included in analysis, 43% had a BMI of more than 25 (overweight-obese). Higher BMI was associated with being female, having black or Hispanic race/ethnicity, being heterosexual, and using injection drugs (all P<0.001). The patients in BMI groups did not differ significantly by baseline CD4 cell count or the duration of the initial HAART regimen. Although median baseline viral loads were significantly lower in obese participants (P=0.008), overweight or obese BMI did not significantly alter the likelihood of achieving an undetectable viral load and a CD4 cell count increase of more than 100 cells/microL compared with normal weight persons. CONCLUSION: A substantial proportion of HIV-infected outpatients in this cohort were overweight or obese. Increased BMI was not associated with decreased virologic and immunologic responses to initial HAART. Responses were equivalent and within expected ranges between normal weight patients, overweight patients, and obese patients at 3 to 9 months of observation.