Enhancement of transdermal delivery of 6-beta-naltrexol via a codrug linked to hydroxybupropion.

Naltrexone (NTX) is a potent opioid antagonist used in the treatment of alcohol dependence and heroin abuse. Compared with naloxone, NTX has a longer duration of action largely attributed to its major active metabolite, 6-beta-naltrexol. The purpose of this study was to increase the delivery of 6-beta-naltrexol across human skin in vitro via a novel codrug. A carbonate codrug of 6-beta-naltrexol linked to hydroxybupropion was synthesized and evaluated. In vitro human skin permeation rates were measured using a flow-through diffusion cell system. The drug melting points, solubilities, chemical stability, and skin disposition were determined. The carbonate codrug was hydrolyzed on passing through skin and appeared as a combination of intact codrug and parent drugs, 6-beta-naltrexol and hydroxybupropion, in the receiver solution. The codrug provided a significantly (p<0.05) higher 6-beta-naltrexol flux across human skin than 6-beta-naltrexol base. The extent of parent drug regeneration in the skin ranged from 56 to 86%. A higher stratum corneum partition coefficient and rapid bioconversion of the carbonate codrug in the skin correlated with increased 6-beta-naltrexol delivery rates.     

Antigen-induced T cell death is regulated by CD4 expression

Activation induced cell death (AICD) is a major physiologic pathway that regulates T cell homeostasis. In CD4 T cells, AICD is mediated mainly through Fas/FasL interactions. Although TCR occupancy triggers AICD, the contribution of its tightly associated CD4 coreceptor to the process that leads to AICD is not known. Here we show that CD4 molecule plays an essential regulatory role of TCR dependent AICD. Loss of CD4 rendered activated 5kc T cell hybridoma resistant to AICD. The resistance of CD4 negative 5kc T cells to AICD was due to selective inhibition of FasL expression and it could be reversed by addition of recombinant FasL. Furthermore, a direct functional link between CD4 and FasL was demonstrated by induction of FasL upon CD4 crosslinking in a TCR independent fashion. The importance of CD4 interaction with MHC/peptide complex in mediating AICD was also evident in normal T cells that could survive chronic stimulation with anti-CD3 but died after short period of proliferation after stimulation with MHC/peptide. Thus it appears that AICD is controlled by the CD4 molecule via regulation of FasL expression. These findings have important implications for our understanding of mechanisms of peripheral tolerance as well as pathogenesis of autoimmune diseases.     

ASO Visual Abstract: Will It Play in Peoria? A Pilot Study of a Robotic Skills Curriculum for Surgical Oncology Fellows

Annals of Surgical Oncology -     

Desensitization of guanylyl cyclases in cultured human airway smooth-muscle cells

We previously showed that cultured human airway smooth-muscle cells (HASMC) contain soluble and particulate guanylyl cyclases (GCs). We studied the desensitization of soluble and particulate GCs in HASMC. Homologous desensitization of soluble GC occurred after incubation with S-nitroso-N-acetyl pencillamine (SNAP). SNAP-dependent desensitization was blocked by hemoglobin, a nitric oxide (NO) scavenger, suggesting that it was due to NO release. Cross-desensitization between SNAP and sodium nitroprusside (SNP) and the lack of thiol reduction after SNAP or SNP treatment suggested that thiol depletion was not involved. Assays for soluble GC activity and experiments using protein synthesis inhibitors suggested that SNAP-dependent desensitization was due to reduced soluble GC. Homologous desensitization of particulate GC occurred after pretreatment with atrial natriuretic peptide (ANP) accompanied by reduced particulate GC activity. Recovery required protein synthesis, suggesting that it was due to reduction in particulate GC. Homologous desensitization to either SNAP or ANP was not altered by phosphodiesterase (PDE) inhibitors, suggesting that increased PDE activity was not involved. Cross-desensitization experiments using SNAP and ANP and experiments using zaprinast to elevate cyclic guanosine monophosphate showed no evidence of heterologous desensitization. Our results suggest that pretreatment of HASMC with SNAP or ANP causes homologous, but not heterologous, desensitization of soluble and particulate GCs, respectively.     

GENDER AND AGE DIFFERENCES IN ANEMIA PREVALENCE DURING THE LIFECYCLE IN KUWAIT

Anemia remains a significant worldwide public health problem. Most studies of anemia and iron deficiency, the major cause of anemia, have targeted small children and reproductive age women. Much less is known about anemia in other lifecycle groups, especially preschool age children, prepubertal boys and girls, or in older adults. Yet recent studies indicate that anemia may increase the risk for chronic diseases and accelerate declining function in older adults. We examined anemia throughout the lifecycle in Kuwait by analyzing data from the 2002 Kuwait Nutrition Surveillance Program. Over 13,000 individuals of both sexes representing all ages were studied. The prevalence of anemia was higher in females than males between 6 months and 3 years. From age 4 to 14 years, there was a reversal with males having a higher rate of anemia. Older females had a lower prevalence of anemia than younger females. These results imply certain policy options.     

Management of maxillary impacted canines: A prospective study of orthodontists' preferences

BackgroundMaxillary canines are considered the most commonly impacted teeth, after the third molars. Orthodontists have different preferences on how to approach maxillary impacted canines (MIC). The objective of this article was to investigate orthodontists’ approach to managing MIC.Material and methodsA cross-sectional study comprising a comprehensive survey with 22 questions was sent to practicing orthodontists. This study explored the preferred diagnostic measures, surgical techniques, materials, and mechanics utilized to manage MIC;104 responses were returned.ResultsPalatal impaction was reported to be encountered more often than labial impaction by 60% of the respondents. In 62% of the respondents, an oral and maxillofacial surgeon was the specialist preferred to perform the surgical exposure. In 66%, the choice of required surgical techniques was reported as a joint decision between orthodontists and other specialists who perform the surgery. Cone-beam computed tomography (CBCT) was reported to be the diagnostic x-ray of choice. The gold button with a chain was the preferred bonded attachment in 86% of cases. Less than half of the respondents bonded the attachments themselves during surgical exposure. A clear plastic retainer was the preferred retainer in 61% of the respondents, and 43% of the respondents tended to use a closed exposure technique. Coe-pak^TM was the preferred surgical pack for orthodontists who prefer an open exposure technique. Piggyback (double wire) was the preferable mechanic to move a palatally impacted canine.ConclusionOur findings indicate that there are variations among orthodontists on how to manage MICs in terms of diagnostic methods, surgical management, materials, and mechanics.     

Activity restrictions after gynecologic surgery: is there evidence?

Many surgeons recommend rest and restricting activities to their patients after surgery. The aim of this review is to summarize the literature regarding types of activities gynecologic surgeons restrict and intra-abdominal pressure during specific activities and to provide an overview of negative effects of sedentary behavior (rest). We searched PubMed and Scopus for years 1970 until present and excluded studies that described recovery of activities of daily living after surgery as well as those that assessed intra-abdominal pressure for other reasons such as abdominal compartment syndrome and hypertension. For our review of intra-abdominal pressure, we excluded studies that did not include a generally healthy population, or did not report maximal intra-abdominal pressures. We identified no randomized trial or prospective cohort study that studied the association between postoperative activity and surgical success after pelvic floor repair. The ranges of intra-abdominal pressures during specific activities are large and such pressures during activities commonly restricted and not restricted after surgery overlap considerably. There is little concordance in mean peak intra-abdominal pressures across studies. Intra-abdominal pressure depends on many factors, but not least the manner in which it is measured and reported. Given trends towards shorter hospital stays and off work intervals, which both predispose women to higher levels of physical activity, we urge research efforts towards understanding the role of physical activity on recurrence of pelvic organ prolapse and urinary incontinence after surgery.     

Approaching a decade of cryo catheter ablation for type 1 atrial flutter—a meta-analysis and systematic review

Purpose  

Despite increasingly widespread use of cryo catheter ablation (CCA) in clinical practice, current ACC/AHA/ESC guidelines for management of supraventricular arrhythmias cite only radiofrequency catheter ablation (RFCA) as first-line treatment for type 1 atrial flutter (AFL). We performed a meta-analysis of efficacy and procedure outcomes from randomized controlled clinical trials comparing CCA with RFCA for type 1 AFL. A systematic review of non-randomized, single-arm clinical studies of CCA for type 1 AFL was also done.     

Autochthonous hepatitis E in Southwest England: natural history, complications and seasonal variation, and hepatitis E virus IgG seroprevalence in blood donors, the elderly and patients with chronic liver disease

AIMS: To report the natural history of autochthonous hepatitis E and hepatitis E virus (HEV) IgG seroprevalence in Southwest England. METHODS: Patients with unexplained hepatitis were tested for hepatitis E and cases followed until recovery or death. Five hundred blood donors, 336 individuals over the age of 60 years and 126 patients with chronic liver disease were tested for HEV IgG. RESULTS: Forty cases of autochthonous hepatitis E (genotype 3) were identified. Hepatitis E was anicteric in 25% of cases and usually caused a self-limiting hepatitis predominantly in elderly Caucasian males. Six of 40 had a significant complication and three patients died, two of who had previously undiagnosed cirrhosis. Hepatitis E shows a seasonal variation with peaks in the spring and summer and no cases in November and December. HEV IgG prevalence increases with age, is more common in men and is 16% in blood donors, 13% in patients with chronic liver disease and 25% in individuals over 60 years. CONCLUSION: Autochthonous hepatitis E is more common than previously recognized, and should be considered in the differential diagnosis in patients with hepatitis, whatever their age or travel history. It carries a significant morbidity and when seen in the context of chronic liver disease carries an adverse prognosis.     

Facile complexation reactions for the selective spectrofluorimetric determination of albendazole in oral dosage forms and spiked human plasma

Two simple, sensitive, and rapid spectrofluorimetric methods were developed and validated for the determination of albendazole. The first method (method I) was based on the quenching effect of albendazole on the native fluorescence of erythrosine B. The fluorescence intensity was measured at 554 nm after extraction at 527 nm. In the second method (method II) the drug was reacted with lanthanum(iii) ions to form a metal complex, which was measured at 340 nm after excitation at 295 nm. The suitable pH was 3.4 (Teorell–Stenhagen buffer) and pH 5.5 (phosphate buffer solution), for method I and II, respectively. The influence of experimental factors on the fluorescence intensity of the reaction products was investigated and optimized. The linear concentration ranges were 0.2–3.5 and 0.06–0.90 μg mL⁻¹, with detection limits of 0.049 and 0.019 μg mL⁻¹ for method I and II, respectively. ICH guidelines were followed for validation of the developed procedures, and the results were acceptable. The Gibb''s free energy change of the reactions was −24.6 and −27.5 kJ mol⁻¹ for method I and II, respectively. These negative values indicated the high feasibility of these reactions at ambient temperature. The proposed procedures were applied successfully for the determination of albendazole in commercial dosage forms and spiked human plasma. The results showed high precision, accuracy and recovery of the reported methods without any significant interference from pharmaceutical excipients or plasma components.

Complexation of albendazole with erythrosine B quench the native fluorescence of the dye while complexation of the drug with lanthanum (iii) ions enhance the fluorescence of the drug.