Role of p38 map kinase in glycine-induced hepatocyte resistance to hypoxic injury

BACKGROUND/AIMS: Glycine hepatoprotection is well known. However, the mechanisms involved are still poorly characterized. METHODS: Glycine protection was investigated in isolated rat hepatocytes pretreated with 2 mmol/L glycine 15 min before incubation under hypoxic conditions. RESULTS: Glycine significantly reduced Na+ overload and hepatocyte death caused by hypoxia. Glycine protection required the activation of a signal pathway involving Src, Pyk2 and p38 MAP kinases. Glycine treatment also induced a 11% increase of hepatocyte volume and transient ATP release. The prevention of cell swelling by hepatocyte incubation in a hypertonic medium as well as the degradation of extracellular ATP with apyrase or the block P2 purinergic receptors with suramin reverted glycine-induced cytoprotection and inhibited Src, Pyk2 and p38 MAPK activation. Glycine down-modulated Na+/H+ exchanger (NHE) activity, without affecting the development of intracellular acidosis during hypoxia. Such an effect was reverted by inhibiting p38 MAPK that also abolished glycine protection against Na+ overload caused by hypoxia. CONCLUSIONS: Glycine-induced ATP release in response to a moderate hepatocyte swelling led to the autocrine stimulation of P2 receptors and to the activation of Src, Pyk2 and p38 MAPK that increased hepatocyte resistance to hypoxia by preventing Na+ influx through NHE.     

The quality of electronic patient records in Finnish primary healthcare needs to be improved

Objective

To analyse the technical quality of electronic patient records in relation to legislation and to evaluate their quality associated with the quality of consultations as rated by patients and GPs.

Design

Cross-sectional study of electronic patient records.

Setting

Four primary healthcare (PHC) centres in Finland using three different electronic patient record systems.

Subjects

Patient records of 175 PHC consultations by 50 GPs, rated as the best (n=86) and the worst (n=89) of a total of 2191 consultations.

Main outcome measures

Documentation of records compared with legislation, the general informative value of records, and its relation to the experienced quality of consultations and to the electronic system employed.

Results

Reason for encounter was mentioned in 79% of cases and patient history in 32%. An acute problem was described moderately well or well in 84%, examination findings in 62%, medical problem or diagnosis in 90%, and treatment in 95% of cases. Medication was documented adequately in 38% of the cases where medication was documented. Concerning general informative value, 18% were assessed as poor, 62% as moderate, and 20% as good. No correspondence was found between experienced quality of consultation and general informative value in the patient records. The quality of patient records was found to change according to the electronic system employed.

Conclusions

Finnish patient records are inadequate documents of consultations and below the standard of that country''s legislation. Developing better models of recording would guarantee a higher quality of work.     

Spoligotypes of Mycobacterium tuberculosis complex isolates from patients residents of 11 states of Brazil

One of the high tuberculosis (TB) incidence countries in the world, Brazil is characterized by considerable differences in TB incidence on regional and state level. In the present study, we describe Brazilian spoligotypes of 1991 Mycobacterium tuberculosis complex (MTC) clinical isolates from patients residents of 11 states from different regions of the country, diagnosed between 1996 and 2005. By performing spoligotyping on a large number of M. tuberculosis clinical isolates, one of the main objectives of this study was to determine the major genotype families causing TB in Brazil and to verify the region-associated genotype distribution. We observed a total of 577 distinct spoligopatterns, 12.6% of these corresponded to orphan patterns while 87.4% belonged to 326 shared-types (SITs). Among the latter, 86 SITs (isolated from 178 patients) had been observed for the first time in this study, the most frequent being SIT2517 which belonged to the T3-ETH lineage and was exclusively found among patients residents of Belém, the capital of the state of Pará (n=8 isolates). Irrespective of shared-type labeling, a total of 19.5% strains were unique (unclustered) in our study as opposed to 80.5% clustered isolates (189 clusters, size range from 2 to 205 isolates). The three largest clusters were SIT42 of the Latin-America & Mediterranean (LAM) 9 clade (10.3%), SIT53 of the T clade (7.6%), and SIT50 of the Haarlem clade (5.4%). The predominant MTC lineages in Brazil in decreasing order belonged to the LAM (46%); the ill-defined T (18.6%); the Haarlem (12.2%), the X (4.7%), the S (1.9%), and the East African Indian (EAI) (0.85%) families. The rest of clades grouped together as Mycobacterium africanum, Mycobacterium bovis, Beijing, Central Asian (CAS), and the Manu types, represented less than 1% of the strains. Finally, about 15% of the isolates showed spoligotype signatures that were not yet classified among well-defined lineages. In conclusion, we provide hereby a first insight into the population structure of MTC isolates in Brazil, showing the predominance of both LAM and T family and the existence of region-associated genotypes.     

PTEN genomic deletion is an early event associated with ERG gene rearrangements in prostate cancer

What’s known on the subject? and What does the study add? So far we know that ERG rearrangements and PTEN deletions interact to induce prostate cancer in transgenic mice. The study confirms that an association also exists between the two genetic aberrations in human prostate cancer, as there is increased incidence of PTEN deletions in cases with ERG rearrangements.

OBJECTIVE

To investigate the interaction between, and significance of, ERG gene rearrangements and PTEN genomic deletions in relation to the development and progression of prostate cancer (PCA).

PATIENTS AND METHODS

We interrogated an initial cohort of 220 men with localized PCA using fluorescence in situ hybridization for ERG rearrangements and PTEN genomic deletions.

RESULTS

The incidences of ERG rearrangements and PTEN deletions in PCA were significantly higher than in high‐grade prostatic intra‐epithelial neoplasia (HGPIN) and benign prostate tissue (P < 0.001). ERG rearrangements and PTEN deletions were detected in 41.9 and 42.6% of patients’ tumours, respectively. ERG rearrangements were never detected in benign prostate tissue, while PTEN aberrations were present at a basal level of 4.6%. PTEN hemizygous deletions showed higher frequency than homozygous deletions within each diagnostic category from benign prostate tissue to HGPIN and PCA (P ≤ 0.001). Furthermore, in 29 patients where all three tissues were available, PTEN genomic aberrations in PCA were significantly different from those in benign tissue (P = 0.005) and HGPIN (P = 0.02), reflecting the accumulation of genomic aberrations in the early stages of disease progression. Within this cohort, 71.4% of homozygous and 44.2% of hemizygous PTEN deletions occurred simultaneously with ERG rearrangements (P ≈ 0). Stratified according to Gleason score (GS), hemizygous PTEN deletions across various GS groups were observed at a higher frequency than homozygous deletions. However, PTEN homozygous deletions showed positive trends with higher GS, increasing in poorly differentiated PCA (GS 8–10) in comparison to moderately and well differentiated tumours (GS 6 and 7).

CONCLUSION

We show significant association between ERG gene rearrangements and PTEN genomic aberrations in subset of PCA. Our analysis also provides further support for the observation that homozygous PTEN deletions can occur within the subset of HGPIN lesions, and shows accumulating genetic aberrations with disease progression, evidenced by higher detection in PCA than in HGPIN and more PTEN homozygous deletions in GS 8–10 than in 6–7.     

Metaphase and array comparative genomic hybridization: unique copy number changes and gene amplification of medulloblastomas in South America

Tumors of the central nervous system are the second most frequent malignancy of childhood, accounting for the majority of cancer-related deaths in this age group. Among these tumors, medulloblastomas (MB) remain in need of further genomic characterization toward understanding of pathogenesis and outcome predictors. Eight pediatric embryonal brain tumors were analyzed: five MB (one being desmoplastic), one PNET, one medulloepithelioma, and one ependymoblastoma. Analyses identified genomic imbalances, including the gain of 16p and the nonsyntenic coamplification of MYCN and TERT loci. More detailed FISH analysis showed that coamplification of MYCN and TERT in one of the MBs manifested as dispersed nuclear speckling, consistent with the presence of double minute chromosomes. There was considerable cell-to-cell copy number heterogeneity present, but it was clear that both genes were amplified concordantly. The amplification of oncogenes seems to play an important role in the pathogenesis of MB, and the association between MYCN and TERT amplifications and poor prognosis has not been well recognized. The uncharacteristic pattern of genomic imbalances detected in MB tumors may be a reflection of the characteristics of these tumors occurring in South America.     

Parent Involvement in Maternal,Infant, and Early Childhood Home Visiting Programs: an Integrative Review

Prevention Science - Despite the evidence and investment in evidence-based federally funded maternal, infant, and early childhood home visiting, substantial challenges persist with parent...     

Berberine attenuates inflammation and oxidative stress and modulates lymphocyte E-NTPDase in acute hyperlipidemia

Hyperlipidemia is a common clinically encountered health condition worldwide that promotes the development and progression of cardiovascular diseases, including atherosclerosis. Berberine (BBR) is a natural product with acknowledged anti-inflammatory, antioxidant, and metabolic effects. This study evaluated the effect of BBR on lipid alterations, oxidative stress, and inflammatory response in rats with acute hyperlipidemia induced by poloxamer-407 (P-407). Rats were pretreated with BBR (25 and 50 mg/kg) for 14 days and acute hyperlipidemia was induced by a single dose of P-407 (500 mg/kg). BBR ameliorated hypercholesterolemia, hypertriglyceridemia, and plasma lipoproteins in P-407-adminsitered rats. Plasma lipoprotein lipase (LPL) activity was decreased, and hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was enhanced in hyperlipidemic rats. The expression of low-density lipoprotein receptor (LDL-R) and ATP-binding cassette transporter 1 (ABCA1) was downregulated in hyperlipidemic rats. BBR enhanced LPL activity, upregulated LDL-R, and ABCA1, and suppressed HMG-CoA reductase in P-407-administered rats. Pretreatment with BBR ameliorated lipid peroxidation, nitric oxide (NO), pro-inflammatory mediators (interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α, interferon-γ, IL-4 and IL-18) and enhanced antioxidants. In addition, BBR suppressed lymphocyte ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase (E-ADA) as well as NO and TNF-α release by macrophages isolated from normal and hyperlipidemic rats. In silico investigations revealed the binding affinity of BBR toward LPL, HMG-CoA reductase, LDL-R, PSK9, ABCA1, and E-NTPDase. In conclusion, BBR effectively prevented acute hyperlipidemia and its associated inflammatory responses by modulating LPL, cholesterolgenesis, cytokine release, and lymphocyte E-NTPDase and E-ADA. Therefore, BBR is an effective and safe natural compound that might be employed as an adjuvant against hyperlipidemia and its associated inflammation.     

T-cell lymphoblastic leukemia in early childhood presents NOTCH1 mutations and MLL rearrangements

T-cell acute lymphoblastic leukemia (T-ALL) may affect children in very early age. However, the critical events leading to this brief latency is still unclear. We used standard methods to explore NOTCH1 mutations and other specific molecular markers in 15 early childhood T-ALL cases. Most of them consisted of immature differentiation subtype. Despite being found in a lower frequency than that described for overall pediatric T-ALL, NOTCH1 alterations were the most frequent ones. Other alterations included MLL⁺ (n = 4), SIL-TAL1⁺ (n = 3), FLT3 mutation (n = 1) and HOX11L2⁺ (n = 1). Our results suggest that NOTCH1 and MLL abnormalities are primary leukemogenic hits in early T-ALL.     

Cytogenetic molecular delineation of a terminal 18q deletion suggesting neo-telomere formation

Deletion of the long arm of chromosome 18 is one of the most common segmental aneusomies compatible with life and usually involves a deletion of the terminal chromosomal region. However, the mechanisms implicated in the stabilization of terminal deletions are not well understood. In this study, we analyzed a girl with moderate mental retardation who had a cytogenetically visible terminal 18q deletion. In order to characterize the breakpoint in the terminal 18q region, we used fluorescence In situ hybridization (FISH) with bacterial artificial chromosomes (BACs) and pan-telomeric probes and also the array technique based on comparative genomic hybridization (array-CGH). FISH with pan-telomeric probes revealed no signal in the terminal region of the deleted chromosome, indicating the absence of normal telomere repeat (TTAGGG)n sequences in 18q. We suggest that neo-telomere formation by chromosome healing was involved in the repair and stabilization of this terminal deletion.