Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study

BackgroundThe efficacy of recombinant human C1 inhibitor (rhC1INH) for the treatment of patients with acute hereditary angioedema (HAE) attacks has been demonstrated in 2 randomized, double-blind, placebo-controlled studies.ObjectiveTo assess the safety and efficacy of rhC1INH for repeated treatment of acute attacks of HAE.MethodsIn this open-label extension study, patients with eligible HAE attacks were treated with an intravenous 50-U/kg dose of rhC1INH with an option for an additional dose of 50 U/kg based on clinical response. Time to beginning of relief was assessed by patients using a 100-mm visual analogue scale (VAS). Safety evaluation was based on the clinical laboratory results and adverse events.ResultsSixty-two patients were treated for 168 attacks (range, 1-8 attacks per patient). A total of 90% of the attacks were treated with a single 50-U/kg dose of rhC1INH. Median times to beginning of symptom relief for the first 5 attacks were 37 to 67 minutes. More than 90% of attacks responded within 4 hours after treatment with rhC1INH. There was no requirement for increased dosing with successive treatments. Thirty-nine patients (63%) reported at least 1 treatment-emergent adverse event, with most events rated mild to moderate. Seven severe treatment-emergent adverse events were reported, and all were considered to be unrelated to treatment with rhC1INH.ConclusionThe results of this open-label extension support continued efficacy of rhC1INH after repeated treatments for subsequent HAE attacks. There was no increase in adverse event reporting after repeated exposure to rhC1INH.Trial Registrationclinicaltrials.gov Identifier: NCT00225147     

Inflammasomes and the microbiota—partners in the preservation of mucosal homeostasis

Seminars in Immunopathology - Inflammasomes are multiprotein complexes that serve as signaling platforms initiating innate immune responses. These structures are assembled upon a large array of...     

Validity of nodule palpation in a Simulium neavei-transmitted onchocerciasis area in Uganda

The objective of this study was to evaluate the prevalence of palpable nodules as a rapid indicator for onchocerciasis endemicity in at-risk communities where Simulium neavei s.s. is the transmitting vector. We used data collected from 13 villages in Uganda to determine the validity of this rapid assessment method. The prevalence of palpable nodules was closely associated with the microfilarial prevalence (R2 = 0.603, P = 0.002), with the community filarial load (R2 = 0.620, P = 0.001) and with the prevalence of onchodermatitis. Nodule palpation in males more than 20 years old, using a cut-off point of 40% and higher for the nodule prevalence, had a sensitivity of 92% and a specificity of 100% in correctly identifying communities in need of urgent intervention with ivermectin mass treatment. Cut-off points were based on World Health Organization recommendations. Thus, nodule palpation can replace skin snipping to identify communities at serious risk of S. neavei-transmitted onchocerciasis.     

Structure of a psychodiagnostic test battery for children

Compared principal component analysis with hierarchical cluster analysis of a psychodiagnostic test battery for children, which included the Wechsler Intelligence Scale for Children-Revised, the Raven Progressive Matrices, the Wide Range Achievement Test, the Wepman Auditory Discrimination Test, the Gates-MacGinitie Reading Test, the Gray Oral Reading Test and the Huelsman Word Discrimination Test. Two hundred and thirteen children (149 males and 64 females) with a mean age of 11.17 were tested. The results are discussed within a multidimensional framework of cognitive abilities. The structure of the battery of tests included general intelligence, auditory and visual learning, academic achievement, and auditory discrimination.     

Simulium neavei-transmitted onchocerciasis: HIV infection increases severity of onchocercal skin disease in a small sample of patients

Onchocercal skin disease was measured in 72 onchocerciasis patients from western Uganda, where Simulium neavei is the main transmitting vector of Onchocerca volvulus. The onchocerciasis patients who were HIV-positive had a higher onchocercal skin score compared with those who were HIV-negative (33.7 vs. 19.4, P < 0.001).     

Partial Agonists of the ��3��4* Neuronal Nicotinic Acetylcholine Receptor Reduce Ethanol Consumption and Seeking in Rats

Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3–CHRNA5–CHRNB4 encoding the α3, α5, and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the α3, and β4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at α3β4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations, suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs. Furthermore, the selective α4β2^* nAChR antagonist, DHβE, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs.     

Recent trends and predictors in immediate breast reconstruction after mastectomy in the United States

Introduction

Immediate breast reconstruction after mastectomy has increased in frequency during the past decade, but the socioeconomic and patient factors have yet to be fully identified.

Methods

Data were analyzed from the Nationwide Inpatient Sample from 1999 to 2003 using International Classification of Disease-9 codes to identify patients undergoing immediate breast reconstruction. Regression analyses were used to examine predictive variables for immediate breast reconstruction after mastectomy.

Results

Between 1999 and 2003, 469,832 patients underwent mastectomy. Immediate breast reconstruction occurred in 110,878 patients, yielding a 5-year average rate of 23.6% (range of 22.2% to 25.3%). Independent predictors of immediate breast reconstruction after mastectomy include private insurance, hospital in an urban location, teaching hospital, white race, hospital region in the south, age between the 3rd and 6th decades, and low number of comorbidities.

Conclusions

Immediate breast reconstruction after mastectomy is still not commonly performed in the United States. Socioeconomic and geographic factors play a significant role in whether patients undergo immediate reconstruction.     

Varenicline: new treatment with efficacy in smoking cessation

Smoking is a significant public health problem, and existing treatments have demonstrated only moderate efficacy in assisting smokers to quit. Varenicline, recently approved by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products as an aid to smoking cessation treatment, has a novel mechanism of action, targeting the specific nicotinic acetylcholine receptor (nAChR) associated with nicotine-induced behaviors (alpha4beta2 nAChR). It has both agonistic and antagonistic properties that together are believed to account for reduction of craving and withdrawal as well as blocking the rewarding effects of smoking. The clinical efficacy and tolerability of varenicline has been demonstrated in phase III clinical trials involving more than 2,000 cigarette smokers. At the end of the treatment period in two 12-week, multicenter, randomized, double-blind, placebo-controlled studies, patients receiving varenicline (1 mg twice daily) experienced an increase in the odds of quitting smoking by nearly fourfold compared with those receiving placebo, and almost twofold compared with the odds for patients receiving 150 mg bupropion SR (sustained release) twice daily. In these two trials where patients were randomized to either varenicline or bupropion, the efficacy of varenicline was consistently superior at 12 weeks; this result sustained significance at 24 weeks in both studies and up to 52 weeks in one study. Nausea, a common adverse event reported in clinical trials, led to few treatment discontinuations. Its targeted mechanism of action, superior efficacy and excellent tolerability make varenicline a welcome and useful addition to the therapeutic options for smoking cessation.     

Estimating HIV incidence in voluntary counseling and testing clients in Uganda (1992-2003)

OBJECTIVES: To estimate HIV incidence from first-time testers among voluntary counseling and testing (VCT) clients in Uganda. METHODS: Data on 203,000 VCT clients tested from 1992 through 2003 were adjusted for temporal changes in the testing population. Differential mortality rates by HIV status were used to derive expected prevalence at future times from baseline prevalence within 5-year birth cohorts. Incidence was computed as the proportion of HIV-uninfected persons who seroconverted divided by the proportion negative at baseline. RESULTS: Annual HIV incidence per 100 uninfected persons increased from 0.9 (95% confidence interval [CI]: 0.8 to 1.1) in 1993 to 2.3 (95% CI: 2.2 to 2.5) in 2003 (chi test for trend, P < 0.001). Prevalence decreased from 23% to 13% in 1999 to 2000 and increased to 15% in 2003. Women had a higher incidence. Peak incidence shifted to older age groups over time. CONCLUSIONS: Estimating incidence from routine data presents a practical way of tracking HIV incidence and is a useful tool in targeting and evaluating the impact of prevention programs. Our analysis reveals a new phase of the HIV epidemic in Uganda: decreasing prevalence and increasing incidence, especially among middle-aged persons. These findings support the need for intensified prevention interventions among middle-aged persons in Uganda.