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.     

Coxsackievirus B3 replication and persistence in intestinal cells from mice infected orally and in the human CaCo-2 cell line

Although the transmission of coxsackievirus B3 occurs mainly via the oral route, little is known about the primary replication and persistence of this agent in the intestine. To address this question, BALB/c mice were inoculated by gavage with coxsackievirus B3, Nancy strain. The mice were killed from 1 hr to 90 days after infection. The viral markers were detected in the small intestine using RT-PCR, cell culture and detection of VP1 protein. Coxsackievirus B3 was detected positive by the three methods from hr 2 to day 45 after infection. By using monoclonal antibodies directed towards VP1, CD40 and CD26, the virus was shown to be present in the lymphocytes of the mucosa as soon as 2 hr after infection; in contrast, no virus was detected in the epithelial cells lining the intestinal lumen. Further experiments were performed to evaluate the capacity of coxsackievirus B3 to establish a persistent infection in two intestinal cell lines. In contrast to HT29 cells, the CaCo-2 cells were shown to develop a persistent infection for up to 20 passages, as demonstrated by the detection of viral RNA and VP1 protein. This study provides further evidence that, after infection by the oral route, the viral particles are concentrated in the lymphocytes of the mucosal layer. In addition, the results suggest that coxsackievirus B3 is capable of establishing a persistent infection in the small intestine that may act as a reservoir of viral particles for the delayed spread of the virus to other target organs.     

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.     

Design and Mechanical Properties of a Novel Cerebral Flow Diverter Stent

Brain arterial aneurysms are localised dilatation in the wall of cerebral arteries that are common among adult population and associated with high incidence of morbidity and mortality. Using flow diverter stent alone to treat cerebral aneurysm is recognized as a safe and effective method. However, flow diverter stents currently available have limitations due to their braided structures. In this paper a novel flow diverter stent is proposed. It is made out of nitinol tubes that provide adequate radial stiffness and tailored surface coverage to overcome problems of currently available braided stents while retaining low porosity and excellent longitudinal flexibility. Finite element analysis using Abaqus has been conducted to investigate radial stiffness, longitudinal flexibility, and maximum strain during packaging of a series of novel stent designs with varied geometric parameters. Results show that porosity below 70% can be achieved and provides radial stiffness and longitudinal flexibility comparable to those of the Neuroform stent that is commonly used for stent assisted coiling. The novel flow diverter has showed great potential for direct treatment of cerebral aneurysms.     

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.