Molecular basis and clinical management of Gaucher disease

Gaucher disease (GD) type I is an autosomal recessive disease caused by a genetic deficiency of lysosomal β-glucocerebrosidase that leads to accumulation of undergraded substrate glucocerebroside and other glycolipids, thus causing damage in different organs. GBA is the only gene in which mutations are known to cause GD. Nearly 300 mutations have been identified in GD patients, including frame-shift mutations, point mutations, deletions, insertions, splice site mutations and recombinants. The variety of phenotypes associated to GD shows imperfect correlation with mutations. GD encompasses a spectrum of clinical findings from a perinatal lethal form to an asymptomatic form. However the classification of GD by clinical subtype is still useful in describing the wide range of clinical findings and broad variability in presentation. Three major clinical types are delineated: type I (chronic nonneuropathic), type II (acute neuropathic), and type III (chronic neuropathic). Patients with type I GD present with visceromegaly, hematological complications, and bone disease. Cardiac and pulmonary complications are rare. Type I GD adult patients have elevated risk of malignancies, Parkinson’s disease or Parkinsonism. Neuropathic forms of GD are rare and clinically ranging from lethal perinatal form to very mild form limited to abnormalities of horizontal ocular saccades. Diagnosis of acid β-glucosylceramidase relies on enzyme activity in peripheral blood leukocytes or skin fibroblasts and/or identification of GBA mutations. Enzyme replacement therapy is an effective treatment for non-neuropathic GD. Substrate inhibitor is the alternative therapy for some patients with GD is miglustat, iminosugar inhibitor of glucocerebroside synthase

Multiple pyogenic granuloma of the penis in a four-year-old child: a case report

Pyogenic granulomas are common, acquired, benign vascular lesions of the skin and mucous membranes that can develop both spontaneously and traumatically. We present a unique case of a four-year healthy, uncircumcised boy with multiple pyogenic granuloma on the mucous face of the penis foreskin. Although penile multiple pyogenic granulomas have previously been described in adults, there are no reports of similar problems in children. In this patient, the pathogenesis of the lesions is probably trauma related as reported in the anamnesis. Therapeutic options are discussed

Atypical ulcers: Diagnosis and management

Atypical ulcers show atypical clinical features, histology, localization, and resistance to standard therapies. The persistence of a chronic ulcer despite treatment with standard therapies requires a more specific diagnostic investigation. Diagnosis involves obtaining the history and performing clinical examination and additional tests. A skin biopsy is frequently used to confirm unclear diagnosis. In difficult cases, microbiological and immunohistochem-ical examinations, laboratory blood tests, or instrumental tests should be evaluated. The treatment of atypical wounds is characterized by local systemic therapy and pain control. Our results highlight the need for early diagnosis, and standardized and targeted management by a multidisciplinary wound healing center

Dynamic markers based on blood perfusion fluctuations for selecting skin melanocytic lesions for biopsy

Skin malignant melanoma is a highly angiogenic cancer, necessitating early diagnosis for positive prognosis. The current diagnostic standard of biopsy and histological examination inevitably leads to many unnecessary invasive excisions. Here, we propose a non-invasive method of identification of melanoma based on blood flow dynamics. We consider a wide frequency range from 0.005 – 2 Hz associated with both local vascular regulation and effects of cardiac pulsation. Combining uniquely the power of oscillations associated with individual physiological processes we obtain a marker which distinguishes between melanoma and atypical nevi with sensitivity of 100% and specificity of 90.9%. The method reveals valuable functional information about the melanoma microenvironment. It also provides the means for simple, accurate, in vivo distinction between malignant melanoma and atypical nevi, and may lead to a substantial reduction in the number of biopsies currently undertaken

Paradoxical worsening of seizure activity with pregabalin in an adult with isodicentric 15 (IDIC-15) syndrome involving duplications of the GABRB3, GABRA5 and GABRG3 genes

Background: Isodicentric 15 syndrome (IDIC-15) is due to partial duplications of chromosome 15 that may includes the q11–13 region that includes genes encoding the α5 (GABRA5) and β3 - γ3 (GABRB3) receptor subunits. The disease causes intellectual and physical developmental delay, seizures, intellectual disability and behavioral disorders that may be related to abnormal GABA receptor function and morphology. Seizures are often severe and may be refractory to treatment. There are however no specific guidelines for the treatment of the seizures and it is unknown whether drugs that affect the GABAergic system have a different effect in IDIC-15 seizures. Case presentation: We report the case of an adult individual with IDIC-15 whose complex-partial seizures worsened dramatically after the introduction of pregabalin, with increased seizure frequency, frequent generalization, and appearance of new seizure pattern. Her cognitive function and verbal skills also worsened during treatment with pregabalin. Her seizures and cognitive skills quickly improved after pregabalin was discontinued and treatment with lacosamide started. Conclusion: As her genetic testing confirmed that her region of duplication included GABA receptor encoding genes, it is plausible that the worsening of seizures were due to induction of an abnormal GABAergic response to pregabalin.This case may help define proper therapeutic strategies for the treatment of IDIC-15 associated seizures

Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers

BACKGROUND: Many breast, pancreatic, colonic and non-small-cell lung carcinoma lines express CEACAM6 (NCA-90) and CEACAM5 (carcinoembryonic antigen, CEA), and antibodies to both can affect tumor cell growth in vitro and in vivo. Here, we compare both antigens as a function of histological phenotype in breast, pancreatic, lung, ovarian, and prostatic cancers, including patient-matched normal, primary tumor, and metastatic breast and colonic cancer specimens. METHODS: Antigen expression was determined by immunohistochemistry (IHC) using tissue microarrays with MN-15 and MN-3 antibodies targeting the A1B1- and N-domains of CEACAM6, respectively, and the MN-14 antibody targeting the A3B3 domain of CEACAM5. IHC was performed using avidin-biotin-diaminobenzide staining. The average score ± SD (0 = negative/8 = highest) for each histotype was recorded. RESULTS: For all tumors, the amount of CEACAM6 expressed was greater than that of CEACAM5, and reflected tumor histotype. In breast tumors, CEACAM6 was highest in papillary > infiltrating ductal > lobular > phyllodes; in pancreatic tumors, moderately-differentiated > well-differentiated > poorly-differentiated tumors; mucinous ovarian adenocarcinomas had almost 3-fold more CEACAM6 than serous ovarian adenocarcinomas; lung adenocarcinomas > squamous tumors; and liver metastases of colonic carcinoma > primary tumors = lymph nodes metastases > normal intestine. However, CEACAM6 expression was similar in prostate cancer and normal tissues. The amount of CEACAM6 in metastatic colon tumors found in liver was higher than in many primary colon tumors. In contrast, CEACAM6 immunostaining of lymph node metastases from breast, colon, or lung tumors was similar to the primary tumor. CONCLUSION: CEACAM6 expression is elevated in many solid tumors, but variable as a function of histotype. Based on previous work demonstrating a role for CEACAM6 in tumor cell migration, invasion and adhesion, and formation of distant metastases (Blumenthal et al., Cancer Res 65: 8809–8817, 2005), it may be a promising target for antibody-based therapy

Transcriptome Analysis of H2O2-Treated Wheat Seedlings Reveals a H2O2-Responsive Fatty Acid Desaturase Gene Participating in Powdery Mildew Resistance

Hydrogen peroxide (H2O2) plays important roles in plant biotic and abiotic stress responses. However, the effect of H2O2 stress on the bread wheat transcriptome is still lacking. To investigate the cellular and metabolic responses triggered by H2O2, we performed an mRNA tag analysis of wheat seedlings under 10 mM H2O2 treatment for 6 hour in one powdery mildew (PM) resistant (PmA) and two susceptible (Cha and Han) lines. In total, 6,156, 6,875 and 3,276 transcripts were found to be differentially expressed in PmA, Han and Cha respectively. Among them, 260 genes exhibited consistent expression patterns in all three wheat lines and may represent a subset of basal H2O2 responsive genes that were associated with cell defense, signal transduction, photosynthesis, carbohydrate metabolism, lipid metabolism, redox homeostasis, and transport. Among genes specific to PmA, ‘transport’ activity was significantly enriched in Gene Ontology analysis. MapMan classification showed that, while both up- and down- regulations were observed for auxin, abscisic acid, and brassinolides signaling genes, the jasmonic acid and ethylene signaling pathway genes were all up-regulated, suggesting H2O2-enhanced JA/Et functions in PmA. To further study whether any of these genes were involved in wheat PM response, 19 H2O2-responsive putative defense related genes were assayed in wheat seedlings infected with Blumeria graminis f. sp. tritici (Bgt). Eight of these genes were found to be co-regulated by H2O2 and Bgt, among which a fatty acid desaturase gene TaFAD was then confirmed by virus induced gene silencing (VIGS) to be required for the PM resistance. Together, our data presents the first global picture of the wheat transcriptome under H2O2 stress and uncovers potential links between H2O2 and Bgt responses, hence providing important candidate genes for the PM resistance in wheat

The Physiology and Proteomics of Drought Tolerance in Maize: Early Stomatal Closure as a Cause of Lower Tolerance to Short-Term Dehydration?

Understanding the response of a crop to drought is the first step in the breeding of tolerant genotypes. In our study, two maize (Zea mays L.) genotypes with contrasting sensitivity to dehydration were subjected to moderate drought conditions. The subsequent analysis of their physiological parameters revealed a decreased stomatal conductance accompanied by a slighter decrease in the relative water content in the sensitive genotype. In contrast, the tolerant genotype maintained open stomata and active photosynthesis, even under dehydration conditions. Drought-induced changes in the leaf proteome were analyzed by two independent approaches, 2D gel electrophoresis and iTRAQ analysis, which provided compatible but only partially overlapping results. Drought caused the up-regulation of protective and stress-related proteins (mainly chaperones and dehydrins) in both genotypes. The differences in the levels of various detoxification proteins corresponded well with the observed changes in the activities of antioxidant enzymes. The number and levels of up-regulated protective proteins were generally lower in the sensitive genotype, implying a reduced level of proteosynthesis, which was also indicated by specific changes in the components of the translation machinery. Based on these results, we propose that the hypersensitive early stomatal closure in the sensitive genotype leads to the inhibition of photosynthesis and, subsequently, to a less efficient synthesis of the protective/detoxification proteins that are associated with drought tolerance