Clinical features of chromosome 22q11.2 microdeletion syndrome in 208 Chilean patients

Patients with chromosome 22q11 deletion syndrome exhibit significant phenotypic variability. Epidemiologic data suggest a higher incidence in Hispanics, but limited clinical information is available from Latin-American patients. We describe the clinical features of Chilean patients with 22q11 deletion syndrome and compare their findings with those reported in large European, Japanese and US series. Data were obtained from 208 patients from five medical centers. Mean age at diagnosis was 5.2 years, with a median of 2.3 years. Congenital heart defects were present in 59.6%, lower than other large series that averaged 75.8%. Palate abnormalities were present in 79%, higher than previous reports averaging 56%. Patients with congenital heart disease were diagnosed earlier (median 0.3 years of age) than those without heart defects (median 5.6 years) and had greater mortality attributable to the syndrome (9.8% vs 2.4%, respectively). The differences in frequencies of major anomalies may be due to growing awareness of more subtle manifestations of the syndrome, differences in clinical ascertainment or the presence of modifier factors. These observations provide additional data useful for patient counseling and for the proposal of health care guidelines.     

The second wind phenomenon in very young McArdle’s patients

We investigated the phenomenon of second wind in four patients with McArdle’s disease: a brother and sister (aged 4 and 12 years respectively) and two unrelated patients, a boy of 14 and a 17-year-old girl. We also studied the siblings’ healthy 6-year-old sister. Each patient performed a 15-min exercise test at a constant workload and a subsequent graded exercise test until exhaustion. Overall the healthy girl and the youngest McArdle’s patient, the 4-year-old boy, did not show a second wind phenomenon. Further, the peak cardio-respiratory capacity of the young McArdle’s boy was normal for his age (32.3mL02/kg/min) and he did not report any function limitations during physical education classes.     

A supratentorial,hemorrhagic, intraparenchymal epidermoid cyst

Epidermoid cysts are slow growing benign tumors that represent < 1–2% of all intracranial tumors and rarely present as supratentorial, intraparenchymal masses. We present the first report of a supratentorial, hemorrhagic, intraparenchymal epidermoid cyst with its presentation, our operative approach, post-operative course, radiographic features, and a literature review.     

Proteomic analysis by two‐dimensional electrophoresis to identify the normal human chondrocyte proteome stimulated by tumor necrosis factor α and interleukin‐1β

Objective

To determine the intracellular proteome of normal human chondrocytes stimulated with interleukin‐1β (IL‐1β) and tumor necrosis factor α (TNFα) and to ascertain differences in the protein expression patterns of these 2 cytokines.

Methods

Normal human knee cartilage chondrocytes were incubated for 48 hours without stimulation or stimulated with IL‐1β (5 ng/ml) or with TNFα (10 ng/ml). For each culture condition, protein extracts from 4 normal subjects were pooled and resolved using 2‐dimensional electrophoresis. Protein spots were visualized with Sypro stain, and qualitative and quantitative analyses were performed using PDQuest software. Protein spots were then identified by mass spectrometry, using matrix‐assisted laser desorption ionization−time‐of‐flight/time‐of‐flight technology.

Results

We identified 37 spots by mass spectrometry (MS) or by MS/MS, corresponding to 35 different proteins. In IL‐1β–stimulated chondrocytes, IL‐1β was found to modulate 22 proteins, as compared with unstimulated chondrocytes. All of these proteins except connective tissue growth factor (CCND2) were up‐regulated. Proteins involved in cellular metabolism and energy (23%) that were up‐regulated or induced by IL‐1β included nicotinamide phosphoribosyltransferase, long‐chain fatty acid–coenzyme A ligase 4, δ‐aminolevulinic acid dehydratase, triosephosphate isomerase, and an isoform of glyceraldehyde‐3‐phosphate dehydrogenase. In TNFα‐stimulated chondrocytes, TNFα was found to modulate 20 proteins, as compared with unstimulated chondrocytes. All of these except chitinase 3–like 1 (cartilage glycoprotein 39), proteasome activator complex subunit 2, and G3PDH, were up‐regulated. Eighteen proteins were differently modulated by IL‐1β and TNFα. Of these, 45% were related to metabolism.

Conclusion

IL‐1β and TNFα induce different profiles of intracellular protein expression in healthy human chondrocytes. Most of the proteins that are differently regulated are proteins that are implicated in the generation of cellular energy and in glycolysis.

     

Association of a KCNA5 gene polymorphism with systemic sclerosis–associated pulmonary arterial hypertension in the European Caucasian population

Objective

Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor β receptors; however, some other candidate genes have also been advocated, including potassium voltage‐gated channel, shaker‐related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH.

Methods

Four KCNA5 single‐nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes.

Results

The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48–0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13–0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21–0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc.

Conclusion

Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

     

Receptor screening technologies in the evaluation of Amazonian ethnomedicines with potential applications to cognitive deficits

Ethnopharmacological relevance

Amazonian peoples utilize a variety of psychoactive plants that may contain novel biologically active compounds. Efforts to investigate such remedies in terms of neuropharmacology have been limited.

Aim of this study

This study identified Amazonian ethnomedicines with potential for the treatment of cognitive deficits in schizophrenia and dementias, and characterized their interactions with CNS neurotransmitter receptors in vitro.

Materials and methods

Approximately 300 Amazonian species with folk uses or constituents indicative of central nervous system activity were incorporated into a database constructed from literature searches, herbarium surveys, and interviews with traditional practitioners. Approximately 130 of these targeted species were collected in Loreto province, Peru, and 228 fractions derived from them were screened in 31 radioreceptor assays via the resources of the NIMH Psychoactive Drug Screening Program. A subset was also screened in functional assays at selected serotonin, muscarinic, and adrenergic receptors.

Results

Ninety-one samples displayed ≥60% inhibition of radioligand binding activity in receptor assays; 135 samples displayed agonist or antagonist activity (or both) in functional assays.

Conclusions

Potential CNS activity was detected in about 40% of the samples screened, with some correlations to both folk uses and phytochemical constituents. These results may point to novel and potentially therapeutic CNS active compounds.     

Lipid-based drug delivery systems for cancer treatment

It is a fact that chemotherapy agents have little specificity for cancer cells, this leading to low concentrations into the tumor interstititum and severe side effects on healthy tissues. The formulation of lipid-based nanomedicines against cancer has been hypothesized to improve drug localization into the tumor tissue and to increase the anticancer efficacy of concentional drugs, while minimizing their systemic adverse effects. In this review, special attention is devoted to the analysis of the state-of-the-art in the development of lipid-based drug carriers against cancer. Specifically, the most significant in vitro and in vivo results on the use of niosomes, liposomes, and solid lipid nanoparticles are revised. It is concluded that biodistribution profiles of chemotherapy agents can be controlled by their loading to such nanoplatforms. Lipid-based nanomedicines offer an interesting approach to the delivery of anticancer drugs to brain tumors, and to reverse multi-drug resistance of cancer cells. Finally, a deep evaluation of the applicability of drug delivery strategies in the formulation of lipid-based nanoplatforms is carried out. They involve active drug targeting (including ligand-mediated delivery, and stimuli-sensitive carriers), and passive drug targeting (through the enhanced permeability and retention effect) to tumors.     

Antiproliferative activity of three methoxylated flavonoids isolated from Zeyheria montana Mart. (Bignoniaceae) leaves

The present study isolated three major active flavonoids, two flavones named 4',5,7-trimethoxy-luteolin (1) and 6-hydroxy-5,7-dimethoxyflavone (2) and the flavanone 5-hydroxy-6,7-dimethoxyflavanone (3) from Zeyheria montana dichloromethane leaf extract. Isolation and purification were conducted with the application of column chromatography and structures were assigned by spectral analysis. All compounds were evaluated for cytotoxic activities against human tumor cell lines UACC-62 (melanoma), MCF-7 (breast), NCI-ADR/RES (breast expressing phenotype multiple drug resistance), 786-0 (renal), NCI-H460 (lung, non-small cells), PC-3 (prostate), OVCAR-3 (ovarian), HT-29 (colon) and K562 (leukemia) in vitro. All compounds were active in different degrees on several tumor cell lines and flavanone 3 showed cytotoxicity against almost all cell lines, particularly against human NCI-ADR/RES and K562 cell lines. In conclusion, three antiproliferative compounds were isolated for the first time from Zeyheria montana and its leaves were characterized as an important source of methoxylated flavones and flavanone as potential antitumor compounds.