The Effects of Permeation Enhancers on the Surface Morphology of the Rat Nasal Mucosa: A Scanning Electron Microscopy Study

A rat model has been developed to compare relative morphological changes in the nasal mucosa after exposure to potential membrane permeation enhancers. Scanning electron microscopy was used to characterize gross structural and specific cellular changes following exposure. Micrographs of the rat nasal mucosa were scored in four categories: (1) mucosal surface integrity, (2) ciliary morphology, (3) mucus/extracellular debris, and (4) presence of red blood cells. The order of increasing morphological damage resulting from a 5-min exposure to each surfactant was 0.5% Solulan C-24 0.5% Solulan C-24/0.5% sodium tauro-24,25-dihydrofusidate (STDHF) < 0.5% STDHF < 1.0% STDHF 1.0% Laureth-9 < 1.0% sodium taurodeoxycholate 1.0% sodium deoxycholate. The changes observed in the mucosal morphology after exposure to the various surfactants are in general agreement with data in the literature. This model is able to compare rapidly the relative morphological effects on the mucosal membrane of different nasal formulations.     

Genetics of hereditary vitreoretinal degenerations

The hereditary vitreoretinal disorders have variable vitreoretinal and other ocular and skeletal abnormalities. Some of these conditions represent a spectrum of clinical disease. This, along with the phenotypic variability, often leads to diagnostic difficulties. In this context, genetic testing is of valuable diagnostic value. Molecular genetic studies have helped distinguish conditions that were previously grouped together and proven others to represent spectrum of the same clinical entity. Accurate diagnosis is important in order to offer effective screening and genetic counseling and appropriate ophthalmological as well as systemic clinical surveillance.     

Current status of excision repair cross complementing-group 1 (ERCC1) in cancer

Cisplatin, carboplatin and oxaliplatin are some of the most widely used anti-cancer agents in solid tumours. The cytotoxicity of platinating agents is directly related to their ability to cause DNA intra-strand crosslinks that trigger a series of intracellular events that ultimately result in cell death. DNA intra-strand crosslinks are processed and repaired by the nucleotide excision repair pathway. It is now clear that nucleotide excision repair (NER) capacity may have a major impact on the emergence of resistance, normal tissue tolerance and patient outcomes. ERCC1 is a key player in NER. In this review, we provide an overview of mammalian NER and then focus on biochemical, structural and pre-clinical aspects of ERCC1. We then present current clinical evidence implicating ERCC1 as a predictive and prognostic marker in cancer. Early evidence also suggests that ERCC1 or the pathways involved in the regulation of ERCC1 expression may be attractive anti-cancer targets. Such agents are expected to potentiate the cytotoxicity of platinating agents and could have a major impact on cancer therapy.     

Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma

PURPOSE: Similar to other molecularly targeted agents, temsirolimus, an inhibitor of mammalian target of rapamycin, has shown promising activity in advanced renal cell carcinoma. However, only a subset of patients appears to derive significant tumor responses. In an effort to identify potential predictors of response to temsirolimus, tumor samples from a subset of patients within a randomized phase II trial of temsirolimus in advanced renal cell carcinoma were studied. PATIENTS AND METHODS: Paraffin-embedded tissue sections from patients who had received temsirolimus were immunostained with antibodies to carbonic anhydrase IX, phospho-S6, phospho-Akt (pAkt), and phosphotase and tensin homologue. Expression levels were correlated with objective response (partial response [PR], minor response [MR]) and clinical benefit (PR, MR, SD>or=4 cycles) to temsirolimus. In addition, von Hippel-Lindau (VHL) mutational analysis was performed and correlated with response. RESULTS: Tissue specimens were obtained from 20 patients who were evaluable for both tumor response and staining for phospho-S6 and carbonic anhydrase IX. In addition, 19 specimens were evaluable for pAkt, and 18 for phosphotase and tensin homologue. VHL mutational analysis was performed on 16 samples. Five patients achieved an objective response (1 PR/4 MRs) to temsirolimus. There was a positive association of phospho-S6 expression (P=.02) and a trend toward positive expression of pAkt (P=.07) with response to temsirolimus. No patient without high expression of either phospho-S6 or pAkt experienced an objective tumor response. There was no correlation of carbonic anhydrase IX and phosphotase and tensin homologue expression or VHL status with response to temsirolimus. CONCLUSION: These results suggest that phospho-S6 and pAkt expression are promising predictive biomarkers for response to temsirolimus that are worthy of further exploration for use in patient selection models for mammalian target of rapamycin inhibitors.     

Can mesenchymal stem cells survive under normal impaction force in revision total hip replacements?

Impaction allograft as a scaffold for bone-forming cells is a tissue-engineering approach for filling bone defects that are commonly encountered during revision total joint replacement (THR). The purpose of this in vitro study is to assess the viability of mesenchymal stem cells (MSC) grown on allograft following impaction using forces similar to those measured during revision total hip replacements. Impaction forces of 0, 3, 6, and 9 kN were used representing normal and high impact. The results showed that the viability in the 3 and 6 kN groups was not significantly reduced compared with that of the 0 kN group, while the survival of the MSCs was significantly reduced after 9 kN impaction force. This study suggests that the addition of MSCs to the allograft scaffold will survive normal impaction force in revision THR.     

Progression of liver fibrosis among injection drug users with chronic hepatitis C

Although most hepatitis C virus (HCV) infections are acquired by injection drug use, prospective data on the progression of liver fibrosis are sparse. Baseline liver biopsies were obtained (1996-1998) on a random sample of 210 out of 1667 HCV-positive injection drug users (IDUs). Subjects were followed biannually, with a second biopsy offered to those eligible. Paired biopsies were scored 0 to 6 (modified Ishak score), significant fibrosis was defined as score 3 or greater, and progression of fibrosis was defined as an increase 2 or more units or clinical evidence of end-stage liver disease. Predictive values of blood markers [FibroSURE, aspartate aminotransferase-to-platelet-ratio index (APRI) and alanine aminotransferase (ALT)] were assessed for detection of contemporaneous and future liver fibrosis. Among 119 prospectively followed IDUs, 96% were African American; 97% HCV genotype 1a/b; 27% HIV-infected, and median age was 42 years. Most (90.7%) did not have significant liver fibrosis at first biopsy. Although predictive value for detecting insignificant fibrosis at first biopsy was greater than 95% for FibroSURE, APRI, and ALT, specificities were 88.9%, 72.7%, and 72.7%, respectively. After 4.2 years median follow-up, 21% had progression of fibrosis, which was significantly associated with serum level of HCV RNA and ALT. No serological test had predictive value greater than 40% for contemporaneous or future significant fibrosis. Even initial biopsy result had only a 30.4% value for predicting future significant fibrosis. In conclusion, significant liver fibrosis and progression were detected in some, but not most, IDUs in this cohort. In this setting with low fibrosis prevalence, FibroSURE, ALT, and APRI tests predict insignificant fibrosis; however, further work is needed to find noninvasive markers of significant liver fibrosis.     

A small outbreak of human cryptosporidiosis associated with calves at a dairy farm in Norway

Cryptosporidiosis is rarely diagnosed in Norway. This is the first report of a human outbreak in Norway and involved 3 calves and 5 people. Sequencing studies were performed. Although 4 of the people acquired their infections from the calves, the other probably became infected from other calves or contaminated pens.     

Why am I depressed?: An investigation of whether patients' beliefs about depression concur with their diagnostic subtype

We investigated whether patients' beliefs about the causes of their depression concurred with their diagnostic subtype. Depressed patients (N = 196) attending a tertiary referral clinic completed a questionnaire regarding putative biological and nonbiological causes of their depression. Subtyping diagnoses of melancholic or nonmelancholic depression were made. Patients with nonmelancholic depression were more likely to attribute nonbiological factors as the cause of their depression than those with melancholic depression, whereas patients with melancholic depression were no more likely to attribute biological factors as the cause of their depression. Patients can distinguish differing causes of depression. The implications of the findings for the current classificatory systems of depression are discussed.