Diffusion Studies of Nanometer Polymersomes Across Tissue Engineered Human Oral Mucosa

Purpose  To measure the diffusion of nanometer polymersomes through tissue engineered human oral mucosa. Methods   In vitro models of full thickness tissue engineered oral mucosa (TEOM) were used to assess the penetration properties of two chemically different polymersomes comprising two of block copolymers, PMPC-PDPA and PEO-PDPA. These copolymers self-assemble into membrane-enclosed vesicular structures. Polymersomes were conjugated with fluorescent rhodamine in order to track polymersome diffusion. Imaging and quantification of the diffusion properties were assessed by confocal laser scanning microscopy (CLSM). Results  TEOM is morphologically similar to natural oral mucosa. Using CLSM, both formulations were detectable in the TEOM within 6 h and after 48 h both penetrated up to 80 μm into the TEOM. Diffusion of PMPC-PDPA polymersomes was widespread across the epithelium with intra-epithelial uptake, while PEO-PDPA polymersomes also diffused into the epithelium. Conclusions  CLSM was found to be an effective and versatile method for analysing the level of diffusion of polymersomes into TEOM. The penetration and retention of PMPC-PDPA and PEO-PDPA polymersomes means they may have potential for intra-epithelial drug delivery and/or trans-epithelial delivery of therapeutic agents.     

A prospective study of tobacco and alcohol use as risk factors for pharyngeal carcinomas in Singapore Chinese

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare disease in most populations; however, in areas of Southeast Asia and North Africa and in the Arctic, undifferentiated NPC is the most frequent pharyngeal malignancy. Although smoking and alcohol have been established firmly as synergistic risk factors for other pharyngeal carcinomas, previous studies on the association between these risk factors and NPC have not been consistent. Therefore, the authors analyzed this relation in a cohort of Singapore Chinese, which is a population with a high incidence of NPC. METHODS: From 1993 to 1998, a population-based cohort of 61,320 Singapore Chinese ages 45 years to 74 years who were free of cancer completed a comprehensive interview on living conditions and dietary and lifestyle factors. By linkage to Singapore population-based registries, the cohort was followed through 2005, and cancer occurrence was determined. The relative risk of NPC and other oropharyngeal carcinomas in the cohort was investigated by using a Cox proportional hazards model. RESULTS: In total, 173 NPCs and 75 other oropharyngeal carcinomas were observed during 601,879 person-years of follow-up. Smoking for >40 years was associated with a doubled risk of NPC (relative risk, 2.0; 95% confidence interval, 1.2-3.3), whereas smoking intensity, age at smoking initiation, and alcohol consumption were not associated with NPC risk. In contrast, smoking duration, smoking intensity, age at smoking initiation, and alcohol consumption all were associated with an increased risk of other oropharyngeal carcinoma (P for trend, <.0001). CONCLUSIONS: Smoking and alcohol influenced the risk of NPC and other oropharyngeal carcinomas differently in a high-incidence NPC population. Long-term smoking was a risk factor for NPC, but alcohol consumption was not.     

Chronic obstructive pulmonary disease and asthma-associated Proteobacteria,but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology

Recent studies of healthy human airways have revealed colonization by a distinct commensal bacterial microbiota containing Gram-negative Prevotella spp. However, the immunological properties of these bacteria in the respiratory system remain unknown. Here we compare the innate respiratory immune response to three Gram-negative commensal Prevotella strains (Prevotella melaninogenica, Prevotella nanceiensis and Prevotella salivae) and three Gram-negative pathogenic Proteobacteria known to colonize lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma (Haemophilus influenzae B, non-typeable Haemophilus influenzae and Moraxella catarrhalis). The commensal Prevotella spp. and pathogenic Proteobacteria were found to exhibit intrinsic differences in innate inflammatory capacities on murine lung cells in vitro. In vivo in mice, non-typeable H. influenzae induced severe Toll-like receptor 2 (TLR2)-independent COPD-like inflammation characterized by predominant airway neutrophilia, expression of a neutrophilic cytokine/chemokine profile in lung tissue, and lung immunopathology. In comparison, P. nanceiensis induced a diminished neutrophilic airway inflammation and no detectable lung pathology. Interestingly, the inflammatory airway response to the Gram-negative bacteria P. nanceiensis was completely TLR2-dependent. These findings demonstrate weak inflammatory properties of Gram-negative airway commensal Prevotella spp. that may make colonization by these bacteria tolerable by the respiratory immune system.     

Bone geometry, density, and microarchitecture in the distal radius and tibia in adults with osteogenesis imperfecta type I assessed by high-resolution pQCT

Osteogenesis imperfecta (OI) is a hereditary disorder characterized by decreased biosynthesis or impaired morphology of type I collagen that leads to decreased bone mass and increased bone fragility. We hypothesized that patients with OI have altered bone microstructure and bone geometry. In this cross‐sectional study we compared patients with type I OI to age‐ and gender‐matched healthy controls. A total of 39 (13 men and 26 women) patients with OI, aged 53 (range, 21–77) years, and 39 controls, aged 53 (range, 21–77) years, were included in the study. Twenty‐seven of the patients had been treated with bisphosphonates. High‐resolution peripheral quantitative computed tomography (HR‐pQCT) at the distal radius and distal tibia and dual‐energy X‐ray absorptiometry of total hip, femoral neck, trochanteric region, and the lumbar spine (L1–L4) were performed. The patients were shorter than the controls (159 ± 10 cm versus 170 ± 9 cm, p < 0.001), but had similar body weight. In OI, areal bone mineral density (aBMD) was 8% lower at the hip (p < 0.05) and 13% lower at the spine (p < 0.001) compared with controls. The trabecular volumetric bone mineral density (vBMD) was 28% lower in radius (p < 0.001) and 38% lower in tibia (p < 0.001) in OI compared with controls. At radius, total bone area was 5% lower in OI than in controls (p < 0.05). In the tibia, cortical bone area was 18% lower in OI (p < 0.001). In both radius and tibia the number of trabeculae was lower in patients compared to the controls (35% and 38%, respectively, p < 0.001 at both sites). Furthermore, trabecular spacing was 55% higher in OI in both tibia and radius (p < 0.001 at both sites) when compared with controls. We conclude that patients with type I OI have lower aBMD, vBMD, bone area, and trabecular number when compared with healthy age‐ and gender‐matched controls. © 2012 American Society for Bone and Mineral Research.     

A Spectrum of Basaloid Morphology in a Subset of EBV-Associated “Lymphoepithelial Carcinomas” of Major Salivary Glands

Nasopharyngeal carcinomas of the undifferentiated or lymphoepithelial type are most commonly seen in South East Asians. Identical tumors have also been described at a variety of other sites including lung, skin and salivary gland and have been referred to by a number of names including lymphoepithelial carcinoma (LEC). LECs of major salivary gland are extremely rare. They are particularly common amongst the Inuit populations of the arctic region including Greenland (Denmark), Canada and Alaska, as well as South East Asians. Within the Inuit group, this tumor represents the majority of all salivary gland carcinomas. Amongst primary LEC of major salivary gland, most cases reported in the literature have represented typical nasopharynx-like tumors. Variants of Epstein–Barr Virus (EBV) associated LEC have not been described previously, to the best of our knowledge. In this report, we describe 4 EBV-associated major salivary gland LECs with prominent basaloid morphology, which represent 22 % of a cohort of 18 salivary LECs from an Inuit population in Greenland. The features described in these cases raise a differential diagnosis of other basaloid tumors, particularly in light of the salivary gland location. A basaloid variant of LEC in major salivary gland should be recognized, especially in highly prone populations, to avoid misdiagnosis of other more common salivary tumors.     

Persistent hepatitis C virus (HCV) infection impairs HCV‐specific cytotoxic T cell reactivity through Mcl‐1/Bim imbalance due to CD127 down‐regulation

Summary. In persistent hepatitis C virus (HCV) infection, HCV‐specific cytotoxic T lymphocyte (CTL) reactivity is impaired and this affects HCV control. Interleukin‐7 receptor (CD127) expression on these cells could regulate CTL reactivity through Mcl‐1/Bim balance modulation. Bim is a pro‐apoptotic molecule blocked by the action of Mcl‐1. Mcl‐1/Bim expression and T cell reactivity on HCV‐specific CTLs were compared according to CD127 phenotype. Peripheral blood lymphocytes (PBL) from HLA‐A2⁺ HCV⁺ patients were obtained. HCV‐specific CTLs were visualized by staining PBL with anti‐CD8 and HLA‐A2/peptide pentameric complexes (pentamer). Mcl‐1/Bim/CD127 phenotype of HCV‐specific CTLs was tested by staining detectable CD8⁺/pentamer⁺ cells with anti‐Mcl‐1/Bim/CD127 antibodies. HCV‐specific CTL proliferation ability after specific in vitro challenge was tested in the presence and absence of pancaspase inhibitor z‐VAD‐fmk. All stained cells were analysed by flow cytometry. CD127^low‐expressing HCV‐specific CTLs associated with high HCV viraemia, while CD127^high correlated with undetectable viral loads (P < 0.001). Directly ex vivo, pentamer⁺ cell frequency was similar according to CD127 expression level. Nevertheless, CD127^low pentamer⁺ cell proliferation after specific in vitro challenge was impaired (P < 0.05), although this was corrected by z‐VAD‐fmk treatment (P < 0.05). Mcl‐1 expression was low directly ex vivo (P < 0.01), and Bim was up‐regulated after antigen encounter (P < 0.05) of CD127^low pentamer⁺ cells. The ex vivo difference between Mcl‐1 and Bim expression on pentamer⁺ cells correlated positively with CD127 expression level (P < 0.001) and with pentamer⁺ cell reactivity (P < 0.05). In summary, a low ex vivo Mcl‐1 expression and Bim up‐regulation after antigen encounter are involved in CD127^low HCV‐specific CTL hyporeactivity during chronic infection, but it can be overcome by apoptosis blockade.     

Solvent-induced chronic toxic encephalopathy

Chlorinated solvents, especially trichloroethylene, have been extensively used for metal degreasing since the beginning of this century. There have been case reports of cranial nerve damage and symptoms of acute and reversible encephalopathy. However, another issue during the last decade is the possible existence of a syndrome of chronic cerebral dysfunction. Our study deals with the risk of developing a state of psychoorganic syndrome after long-term exposure to solvents, mainly trichloroethylene. In this historical cohort study, 96 metal degreasers participated in a clinical medical and psychological examination. The risk of developing psychoorganic syndrome was proportional to the exposure duration, to increasing age, and to decreasing primary intellectual level. Using logistic regression analysis, there was a significantly increased risk of developing psychoorganic syndrome from solvent exposure. There was an odds ratio of 5.6 (0.93–34.3) for psychoorganic syndrome in the medium-exposed group. In the most highly exposed group, with a mean full-time exposure duration of 11 years, there was a significantly increased risk of psychoorganic syndrome, the adjusted odds ratio was 11.2 (1.9–66.6). None of four other potential confounders (arteriosclerotic disease, neurologic/psychiatric disease, alcohol abuse, and current solvent exposure) had any significant associations to psychoorganic syndrome. © 1993 Wiley-List, Inc.     

Intraocular foreign bodies. 297 consecutive cases

The records of 297 patients with intraocular foreign body (IOFB) injuries were analyzed in a retrospective study ranging from 1956 to 1985, and the data of the three decades were compared. 62% of the IOFB were located in the vitreous, 13.5% in the posterior sclera. There was no significant difference between Haab's and Hirschberg's methods in removing the IOFB. In 6.7% an enucleation followed the primary operation, half of these due to postoperative infection. The number of injuries with IOFB has declined. The postoperative improvement of visual acuity has doubled in the last decade compared to the first. The importance of removing the IOFB is stressed, as an unsuccessful attempt considerably worsens the prognosis. 5 of the 297 cases were female, which emphasizes the causative occupational factor. Hammering was the commonest cause of IOFB (80%). None were wearing protective goggles. The importance of wearing protective goggles should be stressed in health education programs.