Balneotherapy in dermatology

Balneotherapy and spa therapy emerged as an important treatment modality in the 1800s, first in Europe and then in the United States. Balneotherapy involves immersion of the patient in mineral water baths or pools. Today, water therapy is being practiced in many countries. Examples of unique and special places for balneotherapy are the Dead Sea in Israel, the Kangal hot spring in Turkey, and the Blue Lagoon in Iceland. Bathing in water with a high salt concentration is safe, effective, and pleasant for healing and recovery. This approach needs no chemicals or potentially harmful drugs. There are almost no side effects during and after treatment, and there is a very low risk to the patient's general health and well-being. Mineral waters and muds are commonly used for the treatment of various dermatologic conditions. The major dermatologic diseases that are frequently treated by balneotherapy with a high rate of success are psoriasis and atopic dermatitis. The mechanisms by which broad spectrums of diseases are alleviated by spa therapy have not been fully elucidated. They probably incorporate chemical, thermal, mechanical, and immunomodulatory effects. The major importance of balneotherapy and spa therapy both individually and as complements to other therapies lies in their potential effectiveness after standard medical treatments have failed to give comfort to these patients.     

Variable Phenotypes of Knockin Mice Carrying the M712T Gne Mutation

GNE myopathy is a recessive adult onset, slowly progressive distal and proximal myopathy, caused by mutations in the GNE gene. The most frequent mutation in GNE myopathy patients is the Middle Eastern founder mutation M712T. We have generated Gne ^M712T/M712T knockin mice. A high mortality rate in the first generation due to renal failure was recorded (as previously described). However, the following Gne ^M712T/M712T offspring generations could be classified into 3 phenotypic categories: severe, mild and without apparent phenotype. By further crossing between mice with no apparent phenotype, we were able to establish a colony of Gne ^M712T/M712T knockin mice with a high- and long-term survival rate, lacking any renal phenotype. These mice did not present any muscle phenotype (clinical or pathological) for up to 18 months. No correlation was found between the expression of any of the two mRNA Gne isoforms in muscle and the mouse genotype or phenotype. However, the expression of isoform 2 mRNA was significantly higher in the kidney of Gne ^M712T/M712T kidney affected mice compared with control. In contrast, the expression of UPR markers Bip, Chop and of the spliced form of XBP1, was upregulated in muscle of Gne ^M712T/M712T mice compared with controls, but was unchanged in the affected kidney. Thus, Gne defects can affect both muscle and kidney in mouse, but probably through different mechanisms.     

Blunted HPA axis response to stress influences susceptibility to posttraumatic stress response in rats.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with low levels of circulating cortisol, and recent studies suggest that cortisol administration may reduce PTSD symptoms. This study investigated the role of cortisol in the manifestation of anxiety- and fear-like symptoms in an animal model of PTSD. METHOD: Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in three strains of rats exposed to predator stress, with and without prior corticosterone treatment. Extreme behavioral changes in both paradigms implied an extreme behavioral response (EBR), representing PTSD-like symptoms. RESULTS: Lewis rats exhibited greater baseline anxiety-like behaviors and greater stress-induced increases in anxiety-like behaviors than Fischer F344 or Sprague-Dawley rats, with only minor corticosterone increases following stress. Prevalence of EBR was 50% among Lewis rats compared with 10% of Fischer F344 and 25% of Sprague-Dawley rats. Administering corticosterone 1 hour before stress exposure reduced the prevalence of EBR from 50% to 8% in the Lewis rats. CONCLUSIONS: These results suggest that a blunted HPA response to stress may play a causal role in this model of PTSD and that this susceptibility may be prevented by administration of cortisol before stress exposure.     

Diagnostic utility of array-based comparative genomic hybridization in a clinical setting

Array-based comparative genomic hybridization is a recently introduced technique for the detection of submicroscopic genomic imbalances (deletions or duplications) across the entire genome. To assess the potential utility of a widely available array-based comparative genomic hybridization platform that targets specific, clinically relevant, loci across the genome for cytogenetic diagnosis in a clinical setting, we reviewed the medical records of all 373 patients at Children's Hospital Boston who had normal chromosomal analysis and were tested with this targeted array-based comparative genomic hybridization over a 1-year period from November 1, 2004 to October 31, 2005. These patients were tested because of a suspicion of chromosomal abnormalities based on their clinical presentation. Thirty-six patients (9.7%) had abnormal array-based comparative genomic hybridization results. Twenty patients (5.4%) had potentially pathogenetic genomic imbalances and 16 patients (4.3%) had copy number variations that are not believed to be pathogenetic. Thirteen of 234 patients (5.6%) with mental retardation/global developmental delay, 10/114 patients (8.8%) with facial dysmorphism, 5/58 patients (8.6%) with multiple congenital anomalies, and 4/35 patients (11.4%) with both facial dysmorphism and multiple congenital anomalies had potentially pathogenetic genomic imbalances. Targeted array-based comparative genomic hybridization is a clinically available test that is useful in the evaluation of patients suspected of having chromosomal disorders. However, it is best used as an adjunct to chromosomal analysis when a clear genetic diagnosis is unavailable.     

Delivery and expression of pDNA embedded in collagen matrices.

Collagen matrices can be used as non-viral biocompatible gene carriers for localized implantable gene therapy. Collagen matrices embedding pDNA with enhanced binding through condensing agent linkage to the matrix or to the pDNA have been formulated, and characterized in various systems. pDNA and condensed pDNA were released intact from the matrices within 1-2 days. In vitro transfection with collagen matrices containing pDNA (luciferase encoding), pDNA in liposome (LIP), and pDNA with polyethylenimine (PEI) resulted in significantly higher expression levels in comparison to naked pDNA. pDNA-LIP matrices exhibited a dose response transfection of NIH 3T3, 293, MDA-MB-231 and smooth muscle cells (SMCs) in cell cultures. Subdermal implantations of collagen-polylysine-pDNA matrices in rats resulted in significantly higher gene expression levels in comparison to non-condensed pDNA matrices. Perivascular treatment with pDNA matrix and of naked pDNA solution in balloon-injured rat carotid arteries resulted in significant expression. In conclusion, a facile method for embedding cationic formulations of pDNA in collagen matrices was developed. These bioactive matrices seem to be suitable for tissue engineering and local gene therapy strategies.     

Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection.

The cultured T-cell line TIL1200, established from the tumor-infiltrating lymphocytes (TILs) of a patient with advanced metastatic melanoma, recognized an antigen on most HLA-A2+ melanomas and on all HLA-A2+ cultured neonatal melanocytes in an HLA-A2 restricted manner but not on other types of tissues or cell lines tested. A cDNA encoding an antigen recognized by TIL1200 was isolated by screening an HLA-A2+ breast cancer cell line transfected with an expression cDNA library prepared from an HLA-A2+ melanoma cell line. The nucleotide and amino acid sequences of this cDNA were almost identical to the genes encoding glycoprotein gp100 or Pmel17 previously registered in the GenBank. Expression of this gene was restricted to melanoma and melanocyte cell lines and retina but was not expressed on other fresh or cultured normal tissues or other types of tumor tested. The cell line transfected with this cDNA also expressed antigen recognized by the melanoma-specific antibody HMB45 that bound to gp100. A synthetic 10-amino acid peptide derived from gp100 was recognized by TIL1200 in the context of HLA-A2.1. Since the administration of TIL1200 plus interleukin 2 resulted in regression of metastatic cancer in the autologous patient, gp100 is a possible tumor rejection antigen and may be useful for the development of immunotherapies for patients with melanoma.     

Being PRO-ACTive: What can a Clinical Trial Database Reveal About ALS?

Advancing research and clinical care, and conducting successful and cost-effective clinical trials requires characterizing a given patient population. To gather a sufficiently large cohort of patients in rare diseases such as amyotrophic lateral sclerosis (ALS), we developed the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) platform. The PRO-ACT database currently consists of >8600 ALS patient records from 17 completed clinical trials, and more trials are being incorporated. The database was launched in an open-access mode in December 2012; since then, >400 researchers from >40 countries have requested the data. This review gives an overview on the research enabled by this resource, through several examples of research already carried out with the goal of improving patient care and understanding the disease. These examples include predicting ALS progression, the simulation of future ALS clinical trials, the verification of previously proposed predictive features, the discovery of novel predictors of ALS progression and survival, the newly identified stratification of patients based on their disease progression profiles, and the development of tools for better clinical trial recruitment and monitoring. Results from these approaches clearly demonstrate the value of large datasets for developing a better understanding of ALS natural history, prognostic factors, patient stratification, and more. The increasing use by the community suggests that further analyses of the PRO-ACT database will continue to reveal more information about this disease that has for so long defied our understanding.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0336-z) contains supplementary material, which is available to authorized users.     

Wild-type p53 can inhibit oncogene-mediated focus formation.

Mutant forms of the p53 cellular tumor antigen elicit neoplastic transformation in vitro. Recent evidence indicated that loss of normal p53 expression is a frequent event in certain types of tumors, raising the possibility that such loss provides transformed cells with a selective growth advantage. Thus, it was conceivable that the mutants might contribute to transformation by abrogating normal p53 function. We therefore studied the effect of plasmids encoding wild-type (wt) p53 on the ability of primary rat embryo fibroblasts to be transformed by a combination of mutant p53 and ras. It was found that wt p53 plasmids indeed caused a marked reduction in the number of transformed foci. Furthermore, wt p53 plasmids also suppressed the induction of transformed foci by combinations of bona fide oncogenes, such as myc plus ras or adenovirus E1A plus ras. On the other hand, plasmids carrying mutations in the p53 coding region totally failed to inhibit oncogene-mediated focus induction and often even slightly stimulated it. Hence, such mutations completely abolished the activity of wt p53 that is responsible for the "suppressor" effect. The latter fact is of special interest, since similar mutations in p53 are often observed in human and rodent tumors. The inhibitory effect of p53 was most pronounced when early-passage cells were used as targets, whereas established cell lines were less sensitive. These data support the notions that wt p53 expression may be restrictive to neoplastic progression and that p53 inactivation may play a crucial role in tumorigenesis.