TGF-β1 improves cardiac performance via up-regulation of laminin receptor 37/67 in adult ventricular cardiomyocytes

TGF-β1 plays an important role in cardiac fibrosis, apoptosis, induction of hypertrophy and contractile dysfunction. This study investigates whether TGF-β1 plays a role in laminin receptor 37/67 (37/67 LR)-dependent regulation of cardiac performance. Therefore, isolated adult cardiomyocytes were stimulated with TGF-β1, the expression of the 37/67 LR was determined and cell shortening was investigated on cells attached to a non-specific, serum-based attachment substrate or to specific, laminin-coated dishes. The role of the MAP kinases in TGF-β1-dependent induction of the 37/67 LR was examined by addition of PD98059, SB202190 and SP600125. Finally, the expression of receptor mRNA was investigated in transgenic mice constitutively over-expressing TGF-β1 and the relationship to distress score and lung wet weight-to-body weight was analysed. TGF-β1 induced a significant increase of the 37/67 LR mRNA and protein expression. The cytokine induced p38 MAP kinase and JNK, but not ERK. Inhibition of either p38 MAP kinase or JNK attenuated the TGF-β1-dependent increase in 37/67 LR expression. TGF-β1 induced a loss of cell shortening in cells attached to a non-specific substrate, but not in cells on a pre-coated laminin matrix. Inhibition of JNK attenuated the protective effect of laminin receptor up-regulation on cardiac performance. Inhibition of p38 MAP kinase attenuated the depressive effect of TGF-β1 on basal cell shortening. In transgenic mice over-expressing TGF-β1 a strong induction of laminin receptor expression attenuated the severeness of the mice’ symptoms. This study shows a new and protective role of TGF-β1-dependent up-regulation of the 37/67 LR in cardiomyocytes in cardiac remodelling with increased laminin expression.     

Validation of the Augmentation Severity Rating Scale (ASRS): a multicentric, prospective study with levodopa on restless legs syndrome

BACKGROUND: Augmentation is the main complication during long-term dopaminergic treatment of restless legs syndrome (RLS) and reflects an overall increase in RLS severity. Its severity varies considerably from a minor problem to a devastating exacerbation of disease. Despite its clinical relevance, systematic evaluations have rarely been undertaken and there has been no development of methods to assess the severity of augmentation. To fill this gap, the European RLS Study Group (EURLSSG) has developed the Augmentation Severity Rating Scale (ASRS), using three items that assess the degree of change in three specific dimensions of augmentation. The changes in each dimension are summed to give an ASRS total score. METHODS: The ASRS was developed to cover the basic dimensions defining RLS augmentation. The items were developed by an interactive process involving professional and patient input. The ASRS that was evaluated included four major items and two alternative forms of one item. The validation was conducted using 63 (85%) mostly untreated RLS patients from six centers, who were treated for six months with levodopa (L-Dopa) (up to 500 mg/day, as clinically needed). Two consecutive assessments before and at baseline measured test-retest reliability. Consecutive ASRS ratings by two independent raters on a subsample of patients evaluated inter-rater reliability. Comparison with clinical severity ratings of two independent experts provided external validation of the ASRS. Comparison of patients with and without augmentation with regard to the items and the total score of the ASRS added discriminant validity. RESULTS: Sixty patients (63% females, mean age: 53 years, baseline International RLS Severity Rating (IRLS) score 24.7+/-5.2) were treated with a median daily dose of 300 mg L-Dopa (range: 50-500 mg). Thirty-six patients (60%) experienced augmentation. Item analyses indicated that one item could be removed as it did not contribute significantly to the test score and only one form of the duplicated item needed to be used. The final ASRS then included three items. Test-retest reliability for the total score was rho=0.72, and inter-rater reliability was rcc=0.94. Cronbach's alpha was 0.62. Validity as assessed by the correlation between the worst ASRS total score during the trial and the expert rating was rho=0.72. ASRS total score differed between patients without versus with augmentation (mean: 7.4 (standard deviation (SD)=4.0) vs. 2.0 (2.7) (P<0.0001). CONCLUSIONS: The ASRS is a reliable and valid scale to measure the severity of augmentation. Due to the need to systematically quantify augmentation for both long-term efficacy and tolerability, the ASRS may become a useful tool to monitor augmentation in future clinical trials.     

The New AASM Criteria for Scoring Hypopneas: Impact on the Apnea Hypopnea Index

Study Objectives:

To compare apnea-hypopnea indices (AHIs) derived using 3 standard hypopnea definitions published by the American Academy of Sleep Medicine (AASM); and to examine the impact of hypopnea definition differences on the measured prevalence of obstructive sleep apnea (OSA).

Design:

Retrospective review of previously scored in-laboratory polysomnography (PSG).

Setting:

Two tertiary-hospital clinical sleep laboratories.

Patients or Participants:

328 consecutive patients investigated for OSA during a 3-month period.

Interventions:

N/A

Measurements and Results:

AHIs were originally calculated using previous AASM hypopnea scoring criteria (AHI_Chicago), requiring either > 50% airflow reduction or a lesser airflow reduction with associated > 3% oxygen desaturation or arousal. AHIs using the “recommended” (AHI_Rec) and the “alternative” (AHI_Alt) hypopnea definitions of the AASM Manual for Scoring of Sleep and Associated Events were then derived in separate passes of the previously scored data. In this process, hypopneas that did not satisfy the stricter hypopnea definition criteria were removed. For AHI_Rec, hypopneas were required to have ≥ 30% airflow reduction and ≥ 4% desaturation; and for AHI_Alt, hypopneas were required to have ≥ 50% airflow reduction and ≥ 3% desaturation or arousal. The median AHI_Rec was approximately 30% of the median AHI_Chicago, whereas the median AHI_Alt was approximately 60% of the AHI_Chicago, with large, AHI-dependent, patient-specific differences observed. Equivalent cut-points for AHI_Rec and AHI_Alt compared to AHI_Chicago cut-points of 5, 15, and 30/h were established with receiver operator curves (ROC). These cut-points were also approximately 30% of AHI_Chicago using AHI_Rec and 60% of AHI_Chicago using AHI_Alt. Failure to adjust cut-points for the new criteria would result in approximately 40% of patients previously classified as positive for OSA using AHI_Chicago being negative using AHI_Rec and 25% being negative using AHI_Alt.

Conclusions:

This study demonstrates that using different published standard hypopnea definitions leads to marked differences in AHI. These results provide insight to clinicians and researchers in interpreting results obtained using different published standard hypopnea definitions, and they suggest that consideration should be given to revising the current scoring recommendations to include a single standardized hypopnea definition.

Citation:

Ruehland WR; Rochford PD; O''Donoghue FJ; Pierce RJ; Singh P; Thornton AT. The new AASM criteria for scoring hypopneas: Impact on the apnea hypopnea index. SLEEP 2009;32(2):150–157.     

Antisaccade performance is related to genetic loading for schizophrenia

Disturbances of the oculomotor system are promising endophenotypes for schizophrenia. Increased error rates in the antisaccade task and prolonged antisaccade latencies have been found in patients with schizophrenia and their first degree relatives. We investigated oculomotor performance in 41 parents of schizophrenia patients and 22 controls with a prosaccade task and an antisaccade task. Parents were grouped into parents with a positive family history for schizophrenia (N = 9) and parents with a negative family history for schizophrenia (N = 32). An overlap-paradigm was applied; eye movements were recorded using infrared oculography. The combined group of parents made more antisaccade direction errors than controls (p = 0.005) and there was a linear increase in direction errors from controls via negative family history parents to positive family history parents (p = 0.008). Antisaccade latencies were prolonged in the combined parent group (p = 0.057) compared to controls and there was a linear increase in latency with genetic loading (p = 0.018). No group differences were found for prosaccade parameters. These results support the hypothesis that antisaccade impairment is associated with genetic loading for schizophrenia.     

Simplifying paediatric immunization with a fully liquid DTP–HepB–Hib combination vaccine: Evidence from a comparative time-motion study in India

An observational time-motion study investigated logistic, programmatic and safety-related advantages and limits in the delivery of a fully liquid DTP–HepB–Hib combination vaccine versus a lyophilized combination vaccine requiring reconstitution. The study was conducted in 2006, observing 312 child vaccinations in a tertiary hospital setting in Kolkata, India. The time for vaccination was on average 46 s (35.12%) lower with the fully liquid vaccine (p < 0.05). In addition, the fully liquid combination was easier and potentially safer to handle and as well tolerated as the lyophilized formulation. Fully liquid combination vaccines have the potential to simplify immunization schedules, contribute to better resource management and improve efficiency of immunization programs.     

The role of the octarepeat region in neuroprotective function of the cellular prion protein

Structural alterations of the cellular prion protein (PrP(C)) seem to be the core of the pathogenesis of prion diseases. However, the physiological function of PrP(C )remains an enigma. Cell culture experiments have indicated that PrP(C) and in particular its N-terminal octarepeat region together with the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways have a fundamental involvement in neuroprotection and oxidative stress reactions. We used wild-type mice, PrP knockout (Prnp(-/-)) animals and transgenic mice that lack the octarepeat region (C4/-) and subjected them to controlled ischemia. We identified an increased cleavage and synthesis of PrP(C) in ischemic brain areas of wild-type mice compared with sham controls. The infarct size in Prnp(-/-) animals was increased threefold when compared with wild-type mice. The infarct size in C4/- animals was identical to Prnp(-/-) mice, that is, around three times larger than in wild-type mice. We showed that the PrP in C4/- mice does not functionally rescue the Prnp(-/-) phenotype; furthermore it is unable to undergo beta cleavage, although an increased amount of C1 fragments was found in ischemic brain areas compared with sham controls. We demonstrated that the N-terminal octarepeat region has a lead function in PrP(C) physiology and neuroprotection against oxidative stress in vivo.     

Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine

Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the development of clinically efficient cancer immunotherapy. Inhibition of antitumor immune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased frequencies of CD4+CD25hi regulatory T cells (Treg cells) have been described as an additional mechanism reducing immunity. We assessed 73 patients with B-cell chronic lymphocytic leukemia (CLL) and 42 healthy controls and demonstrated significantly increased frequencies of cytotoxic T lymphocyte-associated protein 4 (CTLA4+)-, Forkhead box P3 (FOXP3+)-, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR+)-, CD62L+-, transforming growth factor beta1 (TGF-beta1+)-, interleukin 10 (IL-10+)-Treg cells in patients with CLL, with highest frequencies in untreated or progressing patients presenting with extended disease. Most surprisingly, in the majority of patients with CLL treated with fludarabine-containing therapy regimens the inhibitory function of Treg cells was decreased or even abrogated. In addition, frequencies of Treg cells were significantly decreased after therapy with fludarabine. In light of similar findings for cyclophosphamide the combination of fludarabine and cyclophosphamide might be further exploited in strategies reducing immunosuppression prior to cancer immunotherapy.