Restricted treatments, inducements, and research participation

In this paper, I support the claim that placing certain restrictions on public access to possible new treatments is morally problematic under some exceptional circumstances. Very ill patients may find that all available standard treatments are unacceptable, either because they are ineffective or have serious adverse effects, and these patients may understandably be desperate to try something new even if this means stepping into the unknown. Faced with certain death, it is rational to want to try something new and to chance a dire outcome. Restricting possible new treatments to research trials may put these treatments scientifically, geographically or economically out of reach of these patients. For those who can get access, research restrictions could weaken, though not necessarily eliminate, the value of consent participants of such trials are able to give. Some participants may therefore be exploited for scientific purposes in the name of public interest. There are nonetheless compelling reasons for keeping some restrictive regulation in this area.     

Majority of Actinomadura clinical isolates from sputa or bronchoalveolar lavage fluid in Japan belongs to the cluster of Actinomadura cremea and Actinomadura nitritigenes, and the description of Actinomadura chibensis sp. nov

In Japan during 1996-2004, 21 actinomycete strains that have madurose as the diagnostic cell-wall sugar and show true branching in their substrate and aerial mycelia were isolated from sputa or bronchoalveolar lavage (BAL) fluid of patients with pulmonary infections or who were suspected of having related infections. Chemotaxonomic studies showed that all the isolates belong to the genus Actinomadura. Among them, six and seven strains were classified respectively into clusters of Actinomadura nitritigenes and Actinomadura cremea based on 16S rDNA analyses because their 16S rDNA similarities to those respective species were greater than 99.5%. To our knowledge, this is first report that strains of above two species were isolated from clinical specimens. Neither Actinomadura madurae nor Actinomadura pelletieri strain was isolated, and one new species, Actinomadura chibensis, was proposed; the remaining seven strains were not assigned into any known species, suggesting the presence of another new Actinomadura species.     

Mouth cavity base defect treated with biosynthetic graft

The use of in vitro prepared biosynthetic grafts can considerably improve the patient’s quality of life. This work reports on the use of an autologous graft prepared from a patient’s preputial cells cultivated on biodegradable polymeric membrane. Coladerm membrane is based on the chemically modified polyelectrolyte complex of atelocollagen and hyaluronan. The graft was used to cover a defect in the mouth cavity base and tongue after reconstruction surgery performed at this site in the past. The presented clinical case showed that the autologous biosynthetic graft prepared from foreskin cells can be successfully used for covering of medium-size defects in mouth cavity base resulting in the regeneration of target mouth structures with significant improvement of patient’s quality of life.     

Superoxide dismutase activity of Helicobacter pylori per se from 158 clinical isolates and the characteristics

We investigated the correlation between the SOD activity of Helicobacter pylori (H. pylori) and gastroduodenal diseases and the characteristics of strains exposed to oxidative stress. Two sequenced strains, 26695 and J99, and clinical isolates from 156 Japanese patients with gastroduodenal diseases such as gastric cancer (n= 59) and non-cancer (n= 97) were used. SOD activities of all 158 isolates were measured and were divided into three groups: high-SOD activity (>0.22, n= 2), moderate-SOD activity (0.15≦≦0.22, n= 16) and low-SOD activity (<0.15, n= 140). Expressions of H. pylori Fe-SOD were examined by western blotting with anti-H. pylori Fe-SOD antibody prepared inhouse, and the profiles of Fe-SOD activity were investigated by zymogram with activity staining in native-PAGE. The characteristics of strains from high-SOD and low-SOD groups were examined under oxidative stress by paraquat. The average of H. pylori SOD activity was significantly higher in the cancer group than in the non-cancer group (P < 0.05). However, irrespective of SOD activity level, the amount of Fe-SOD expressed was variable among individual strains. Zymogram revealed a single band in moderate-SOD and low-SOD strains, but multiple bands in high-SOD strains were observed. These bands were confirmed as H. pylori Fe-SOD. Under oxidative stress with paraquat, low-SOD strains were drastically eliminated without inducible SOD activity; however, high-SOD strains were still viable with increased SOD activity. This study is the first to exhibit the characteristics of high-SOD activity strains representing multiple bands in zymograms and the correlation between H. pylori SOD activity and gastric cancer.     

Evaluation of the efficacy of two mouthrinses formulated for the relief of xerostomia of diverse origin in adult subjects

doi: 10.1111/j.1741‐2358.2012.00626.x Evaluation of the efficacy of two mouthrinses formulated for the relief of xerostomia of diverse origin in adult subjects Objective: To evaluate the efficacy of two new mouthrinses in the reduction of xerostomía‐associated symptomatology. Background: Xerostomia is a common chronic health condition that affects a great number of adults and significantly deteriorates quality of life, such that treatment is necessary. Materials and methods: Sixty‐seven adult subjects of both sexes presenting xerostomia of diverse origin were selected. Mouthrinses were tested using a double‐blind, randomized, cross‐over clinical trial with an intervining wash out period. Results: The 100% of subjects presented sensation of dry mouth, and 86% stated sensation of thick saliva. Burning tongue sensation, need to drink liquids to swallow and the sensation of swallowing difficulty were recorded in more than 50% of the patients. The most frequent pathologies in the sample were depression, arthritis, and arterial hypertension. Results of the clinical tests showed that mouthrinse 1 relieves sensation of dry mouth, need to drink liquids, and swallowing difficulty. In contrast, mouthrinse 2 relieves only latter two symptoms. Both rinses were more effective in relieving xerostomía‐associated symptomatology in patients taking 3 or more medicines simultaneously. Conclusion: Both mouthrinses were effective in relieving various xerostomia symptoms, could be distributed at a low cost, thereby improving the quality of life of population affected.     

A comprehensive method for determination of fatty acids in the initial oral biofilm (pellicle)

The acquired pellicle is a tenacious organic layer covering the surface of teeth, protecting the underlying dental hard tissues. Lipids account for about one quarter of the pellicle's dry weight and are assumed to be of considerable importance for their protective properties. Nevertheless, only preliminary information is available about the nature of lipids in the pellicle. Gas chromatography coupled with electron impact ionization mass spectrometry was used to establish a convenient analytical protocol in order to obtain a qualitative and quantitative characterization of a wide range of FAs (C(12)-C(22)). In situ biofilm formation was performed on bovine enamel slabs mounted on individual splints carried by 10 subjects. A modified Folch extraction procedure was adopted to extract the lipids from the detached pellicle, followed by transesterification to fatty acid methyl esters using methanol and concentrated hydrochloric acid. Tridecanoic and nonadecanoic acid were used as internal standards suitable and reliable for robust, precise and accurate measurements. The present study demonstrates, for the first time, a procedure based on a combination of innovative specimen generation and convenient sample preparation with sensitive GC-MS analysis for the determination of the fatty acid profile of the initial oral biofilm.     

PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty

Peroxisome proliferator-activated receptor γ (PPAR-γ) is a key regulator of fatty acid metabolism, promoting its storage in adipose tissue and reducing circulating concentrations of free fatty acids. Activation of PPAR-γ has favorable effects on measures of adipocyte function, insulin sensitivity, lipoprotein metabolism, and vascular structure and function. Despite these effects, clinical trials of thiazolidinedione PPAR-γ activators have not provided conclusive evidence that they reduce cardiovascular morbidity and mortality. The apparent disparity between effects on laboratory measurements and clinical outcomes may be related to limitations of clinical trials, adverse effects of PPAR-γ activation, or off-target effects of thiazolidinedione agents. This review addresses these issues from a clinician's perspective and highlights several ongoing clinical trials that may help to clarify the therapeutic role of PPAR-γ activators in cardiovascular disease.     

Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk

Human and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass transfers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor dalcetrapib, which raises HDL levels less effectively than torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibitors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of torcetrapib.     

Recurrent Herpetic Stromal Keratitis in Mice,a Model for Studying Human HSK

Herpetic eye disease, termed herpetic stromal keratitis (HSK), is a potentially blinding infection of the cornea that results in over 300,000 clinical visits each year for treatment. Between 1 and 2 percent of those patients with clinical disease will experience loss of vision of the infected cornea. The vast majority of these cases are the result of reactivation of a latent infection by herpes simplex type I virus and not due to acute disease. Interestingly, the acute infection is the model most often used to study this disease. However, it was felt that a recurrent model of HSK would be more reflective of what occurs during clinical disease. The recurrent animal models for HSK have employed both rabbits and mice. The advantage of rabbits is that they experience reactivation from latency absent any known stimulus. That said, it is difficult to explore the role that many immunological factors play in recurrent HSK because the rabbit model does not have the immunological and genetic resources that the mouse has. We chose to use the mouse model for recurrent HSK because it has the advantage of there being many resources available and also we know when reactivation will occur because reactivation is induced by exposure to UV-B light. Thus far, this model has allowed those laboratories using it to define several immunological factors that are important to this disease. It has also allowed us to test both therapeutic and vaccine efficacy.     

Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD

The aim of our study was to identify relationships between epigenetic parameters correlating with a relaxed chromatin state of the DUX4 promoter region and clinical severity as measured by a clinical severity score or muscle pathologic changes in D4Z4 contraction-dependent (FSHD1) and –independent (FSHD2) facioscapulohumeral muscular dystrophy patients. Twenty primary fibroblast (5 control, 10 FSHD1 and 5 FSHD2) and 26 primary myoblast (9 control, 12 FSHD1 and 5 FSHD2) cultures originating from patients with FSHD and controls were analyzed. Histone modification levels were determined by chromatin immunoprecipitation. We examined correlations between the chromatin compaction score (ChCS) defined by the H3K9me3:H3K4me2 ratio and an age corrected clinical severity score (CSS) or muscle pathology score (MPS). Possible relationships were investigated using linear regression analysis and significance was tested by Pearson’s product-moment coefficient.   We found a significant difference of the ChCS between controls and patients with FSHD1 and between controls and patients with FSHD2. Tissue specific differences in ChCS were also observed. We also found a near-significant relationship between ChCS and the age corrected CSS in fibroblasts but not in myoblasts. Surprisingly, we found a strong correlation between the MPS of the vastus lateralis and the CSS. Our results confirm the D4Z4 chromatin relaxation previously shown to be associated with FSHD in a small number of samples. A possible relationship between clinical and epigenetic parameters could be established in patient fibroblasts, but not in myoblasts. The strong correlation between the MPS of the vastus lateralis and the CSS suggests that this muscle can be used to study for surrogate markers of overall disease severity.