Clinical, biochemical, and molecular studies in pyridoxine-dependent epilepsy. Antisense therapy as possible new therapeutic option.

Purpose: Pyridoxine-dependent epilepsy seizure (PDE; OMIM 266100) is a disorder associated with severe seizures that can be controlled pharmacologically with pyridoxine. In the majority of patients with PDE, the disorder is caused by the deficient activity of the enzyme α-aminoadipic semialdehyde dehydrogenase (antiquitin protein), which is encoded by the ALDH7A1 gene. The aim of this work was the clinical, biochemical, and genetic analysis of 12 unrelated patients, mostly from Spain, in an attempt to provide further valuable data regarding the wide clinical, biochemical, and genetic spectrum of the disease.

Fluorescence diagnosis and photodynamic therapy for Bowen's disease treatment.

Introduction: It has already been demonstrated the high efficacy of photodynamic therapy (PDT) for Bowen's disease (BD) treatment. Fluorescence diagnosis consists on registration of the fluorescence emitted by tissue after application of a photosensitizer, indicating presence of tumoral cells. It has been described as a useful tool for actinic keratosis.

Readthrough strategies for therapeutic suppression of nonsense mutations in inherited metabolic disease.

Inherited metabolic diseases (IMDs) belong to the group of rare diseases due to their low individual prevalence. Most of them are inherited in autosomal recessive fashion and represent good candidates for novel therapeutical strategies aimed at recovering partial enzyme function as they lack an effective treatment, and small levels of enzymatic activity have been shown to be associated with improved outcome and milder phenotypes. Recently, a novel therapeutic approach for genetic diseases has emerged, based on the ability of aminoglycosides and other compounds in allowing translation to proceed through a premature termination codon introduced by a nonsense mutation, which frequently constitute a significant fraction of the mutant alleles in a population.

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites.

Novel 9-aminoacridine derivatives were synthesized by linking the heteroaromatic core to different cinnamic acids through an aminobutyl chain. The test compounds demonstrated mid-nanomolar in vitro activity against erythrocytic stages of the chloroquine-resistant W2 strain of the human malaria parasite Plasmodium falciparum. Two of the most active derivatives also showed in vitro activity against liver-stage Plasmodium berghei, with activity greater than that of the reference liver-stage antimalarial primaquine.

N-cinnamoylated chloroquine analogues as dual-stage antimalarial leads.

The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity.

Erythrocytosis in a child due to Hb Andrew-Minneapolis [β144(HC1)Lys→Asn (AAG>AAT or AAC)] associated with a Spanish (δβ)(0)-thalassemia.

We report a rare association of δβ-thalassemia (δβ-thal) and a hemoglobin (Hb) variant with high oxygen affinity in a Spanish newborn. The proband had no Hb A and showed microcytosis and hypochromia; the peripheral blood smear was compatible with a thalassemia trait. Molecular studies revealed that the proband had a Spanish (δβ)(0)-thal (inherited from his father) and also carried a de novo variant (Hb Andrew-Minneapolis) because from the point of hematology, his mother was quite normal.

Functional characterization of novel genotypes and cellular oxidative stress studies in propionic acidemia.

Propionic acidemia (PA), caused by a deficiency of the mitochondrial biotin dependent enzyme propionyl-CoA carboxylase (PCC) is one of the most frequent organic acidurias in humans. PA is caused by mutations in either the PCCA or PCCB genes encoding the α- and β-subunits of the PCC enzyme which are assembled as an α6β6 dodecamer. In this study we have investigated the molecular basis of the defect in ten fibroblast samples from PA patients.

18S rRNA is a reliable normalisation gene for real time PCR based on influenza virus infected cells.

Background: One requisite of quantitative reverse transcription PCR (qRT-PCR) is to normalise the data with an internal reference gene that is invariant regardless of treatment, such as virus infection. Several studies have found variability in the expression of commonly used housekeeping genes, such as beta-actin (ACTB) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), under different experimental settings. However, ACTB and GAPDH remain widely used in the studies of host gene response to virus infections, including influenza viruses.

A novel congenital disorder of glycosylation type without central nervous system involvement caused by mutations in the phosphoglucomutase 1 gene.

Recent years have seen great advances in our knowledge of congenital disorders of glycosylation (CDG), a clinically and biochemically heterogeneous group of genetic diseases caused by defects in the synthesis (CDG-I) or processing (CDG-II) of glycans that form glycoconjugates. This paper reports a new subtype of non-neurological CDG involving the impaired cytoplasmic biosynthesis of nucleotide sugars needed for glycan biosynthesis. A patient presented with muscle fatigue, elevated creatine kinase, growth hormone deficiency, and first branchial arch syndrome.

[Myocardial viability assessment].

The prognosis for patients with chronic coronary artery disease and severe left ventricular dysfunction is poor, despite advances in different therapies. The assessment of myocardial viability has become an important aspect of the diagnosis, prognosis and management of patients with ischemic cardiomyopathy. Patients with left ventricular dysfunction, with a substantial amount of severely ischemic myocardium are at highest risk, and are likely to benefit from coronary revascularization.

Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects.

Oxidative stress has been described as a putative disease mechanism in pathologies associated with an elevation of homocysteine. An increased reactive oxygen species (ROS) production and apoptosis rate have been associated with several disorders of cobalamin metabolism, particularly with methylmalonic aciduria (MMA) combined with homocystinuria cblC type. In this work, we have evaluated several parameters related to oxidative stress and apoptosis in fibroblasts from patients with homocystinuria due to defects in the MTR, MTRR, and MTHFR genes involved in the remethylation pathway of homocysteine.

Incidence of hand-foot syndrome with capecitabine in combination with chemotherapy as first-line treatment in patients with advanced and/or metastatic gastric cancer suitable for treatment with a fluoropyrimidine-based regimen.

Introduction: Hand-foot syndrome (HFS) is a limiting toxicity of capecitabine, which is not life-threatening but could compromise capecitabine efficacy.

Materials And Methods: This phase II, multicenter, non-controlled study assessed the safety, particularly grade three HFS incidence, and efficacy of four capecitabine-based chemotherapy regimens [cisplatin/capecitabine (CX), epirubicin/cisplatin/capecitabine (ECX), epirubicin/oxaliplatin/capecitabine (EOX) and docetaxel/cisplatin/capecitabine (DCX)] as first-line treatment for advanced and/or metastatic gastric cancer.

Results: One hundred and eight patients were assigned to one of the four treatment groups, according to investigator's criteria, and grouped together for both safety and efficacy primary analyses.

The effects of national health care reform on local businesses--Part III: secondary research questions--discoveries and implications.

This is the third part of a 3-part examination of what may potentially be expected from the 2010 national health care reform legislation. Political researchers and pundits have speculated endlessly on the many changes mandated by the 2010 national health care reform legislation, styled the Patient Protection and Affordable Care Act. A review and assessment of this legislation at several levels (federal, state, state agency, local region, and individual business leaders) were undertaken.

DPAGT1-CDG: report of a patient with fetal hypokinesia phenotype.

Congenital disorders of glycosylation (CDG) are due to either defects in the synthesis of the glycan moiety of glycoproteins or glycolipids and in the attachment of the glycans to proteins and lipids. Some 50 CDG have been identified. They represent a challenge for clinicians because most are multisystem diseases with a heterogeneous spectrum of clinical manifestations with involvement of any organ and system.

Cinnamic acid/chloroquinoline conjugates as potent agents against chloroquine-resistant Plasmodium falciparum.

Cinnamic acid derivatives containing a 4-amino-7-chloroquinoline scaffold (blue) and substituted cinnamoyl building blocks (green) linked through an alkylamine chain (red) were found to have potent (11-59 nM) in vitro activities against erythrocytic chloroquine- resistant Plasmodium falciparum.

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: towards the development of potential dual action antimalarials.

A series of cinnamic acid/4-aminoquinoline conjugates conceived to link, through a proper retro-enantio dipeptide, a heterocyclic core known to prevent hemozoin formation, to a trans-cinnamic acid motif capable of inhibiting enzyme catalytic Cys residues, were synthesized as potential dual-action antimalarials. The effect of amino acid configuration and the absence of the dipeptide spacer were also assessed. The replacement of the D-amino acids by their natural L counterparts led to a decrease in both anti-plasmodial and falcipain-inhibitory activity, suggesting that the former are preferable.

[Voluntary abortion and domestic violence among women attended at a public maternity hospital of Salvador-BA].

Quantitative study in order to study domestic violence in women with induced abortion. Interviews were conducted with 147 women hospitalized for induced abortion in a public maternity hospital in Salvador, Bahia. The subjects are characterized by mostly women, black, poorly educated, economically dependent on spouses, experienced psychological abuse, physical and sexual abuse committed by their spouses.

Huprine X and huperzine A improve cognition and regulate some neurochemical processes related with Alzheimer's disease in triple transgenic mice (3xTg-AD).

Background: Different studies have established that cholinergic neurodegeneration could be a major pathological feature of Alzheimer's disease (AD). Thus, enhancement of the central cholinergic neurotransmission has been regarded as one of the most promising strategies for the symptomatic treatment of AD, mainly by means of reversible acetylcholinesterase inhibitors (AChEIs). The cognitive-enhancing properties of both huprine X, a new AChEI, and the structurally related huperzine A, as well as their effects on the regulation of several neurochemical processes related to AD have been studied in triple transgenic mice (3xTg-AD).

Glomerella Leaf Spot Caused by a Nonhomothallic Strain of Glomerella cingulata on Highbush Blueberry Nursery Plants in Buenos Aires, Argentina.

In February 2009, irregular-shaped leaf spots affected blueberry (Vaccinium corymbosum L. 'Blue Crisp', 'Misty', and 'Sharp Blue') nursery plants in Buenos Aires. Single-spore cultures on potato dextrose agar and oat agar showed aerial white mycelium that turned light and dark gray, dark brown acervuli with setae, and a salmon-to-orange conidial mass.

The effects of national health care reform on local businesses--part II: study methodology and primary research questions.

This is the second part of a 3-part examination of what may be potentially expected from the 2010 national health care reform legislation. Political researchers and pundits have speculated endlessly on the many changes mandated by the 2010 national health care reform legislation, styled the Patient Protection and Affordable Care Act. A review and assessment of this legislation at several levels (federal, state, state agency, local region, and individual business leaders) were undertaken.

Minigenes to confirm exon skipping mutations.

Although several bioinformatic tools exist to predict the effect on splicing of a nucleotide change, experimental verification with minigenes is essential for diagnostic purposes, as well as for revealing disease mechanisms and monitoring therapeutic interventions. Minigenes are splice reporter vectors (also known as exon-trapping vectors) that allow confirmation of the effect of mutations on the splicing process, indicated when patients' samples for RNA studies are not available. The minigene vector codes for exonic portions of a gene defined by functional 5' splice donor and 3' splice acceptor sites separated by intronic sequences where a polylinker is located.

Apoptotic cells can deliver chemotherapeutics to engulfing macrophages and suppress inflammatory cytokine production.

Immunosuppression via cell-cell contact with apoptotic cells is a well studied immunological phenomenon. Although the original studies of immune repression used primary cells, which undergo spontaneous cell death or apoptosis in response to irradiation, more recent studies have relied on chemotherapeutic agents to induce apoptosis in cell lines. In this work, we demonstrate that Jurkat cells induced to die with actinomycin D suppressed inflammatory cytokine production by macrophages, whereas cells treated with etoposide did not.

Feasibility of nonsense mutation readthrough as a novel therapeutical approach in propionic acidemia.

Aminoglycosides and other compounds can promote premature termination codon (PTC) readthrough constituting a potential therapy for patients with nonsense mutations. In a cohort of 190 propionic acidemia (PA) patients, we have identified 12 different nonsense mutations, six of them novel, accounting for 10% of the mutant alleles. Using an in vitro system, we establish the proof-of-principle that nonsense mutations in the PCCA and PCCB genes encoding both subunits of the propionyl-CoA carboxylase (PCC) enzyme can be partially suppressed by aminoglycosides, with different efficiencies depending on the sequence context.