Biomedical subjects

Michael Haber

Publications and source records attributed to Michael Haber.

11 recordsLinked to original sources

PubMed2006

Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses.

Accumulating evidence is redefining the importance of neuron-glial interactions at synapses in the CNS. Astrocytes form "tripartite" complexes with presynaptic and postsynaptic structures and regulate synaptic transmission and plasticity. Despite our understanding of the importance of neuron-glial relationships in physiological contexts, little is known about the structural interplay between astrocytes and synapses. In the past, this has been difficult to explore because studies have been hampered by the lack of a system that preserves complex neuron-glial relationships observed in the brain. Here we present a system that can be used to characterize the intricate relationship between astrocytic processes and synaptic structures in situ using organotypic hippocampal slices, a preparation that retains the three-dimensional architecture of astrocyte-synapse interactions. Using time-lapse confocal imaging, we demonstrate that astrocytes can rapidly extend and retract fine processes to engage and disengage from motile postsynaptic dendritic spines. Surprisingly, astrocytic motility is, on average, higher than its dendritic spine counterparts and likely relies on actin-based cytoskeletal reorganization. Changes in astrocytic processes are typically coordinated with changes in spines, and astrocyte-spine interactions are stabilized at larger spines. Our results suggest that dynamic structural changes in astrocytes help control the degree of neuron-glial communication at hippocampal synapses.

Animals↗

PubMed2006

A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling.

Mutations in the parkin gene are responsible for a common familial form of Parkinson's disease. As parkin encodes an E3 ubiquitin ligase, defects in proteasome-mediated protein degradation are believed to have a central role in the pathogenesis of Parkinson's disease. Here, we report a novel role for parkin in a proteasome-independent ubiquitination pathway. We have identified a regulated interaction between parkin and Eps15, an adaptor protein that is involved in epidermal growth factor (EGF) receptor (EGFR) endocytosis and trafficking. Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15. Binding of the parkin ubiquitin-like (Ubl) domain to the Eps15 ubiquitin-interacting motifs (UIMs) is required for parkin-mediated Eps15 ubiquitination. Furthermore, EGFR endocytosis and degradation are accelerated in parkin-deficient cells, and EGFR signalling via the phosphoinositide 3-kinase (PI(3)K)-Akt pathway is reduced in parkin knockout mouse brain. We propose that by ubiquitinating Eps15, parkin interferes with the ability of the Eps15 UIMs to bind ubiquitinated EGFR, thereby delaying EGFR internalization and degradation, and promoting PI(3)K-Akt signalling. Considering the role of Akt in neuronal survival, our results have broad new implications for understanding the pathogenesis of Parkinson's disease.

Adaptor Proteins, Vesicular Transport↗

PubMed2006

Validity of the 30-item geriatric depression scale in patients with Parkinson's disease.

Depression in Parkinson's disease (dPD) is difficult to diagnose because depressive symptoms can overlap with symptoms of Parkinson's disease (PD). Subject-rated scales such as the 30-item Geriatric Depression Scale (GDS) may be useful in screening for dPD. There were 57 patients (33 men, 24 women; mean age, 58.6 years [SD +/- 8.4]) enrolled in a study of pallidotomy for intractable PD who were evaluated for depression before and after surgery. Subjects were evaluated using the 17-item Hamilton Depression Rating Scale (HDRS), Structured Clinical Interview for Diagnostic and Statistical Manual-III (SCID), and the GDS. SCID was used to diagnose major depression with confirmation by an expert geropsychiatrist. Receiver-operating curves (ROC) were used to identify cutoff points with maximal discriminant validity for diagnosing dPD. A total of 213 evaluation time points were included for the 52 patients with time points that included a valid SCID diagnosis, GDS, and HDRS. A ROC established points of maximum specificity/sensitivity for the GDS at a cutoff of 9/10 (sensitivity = 0.809, specificity = 0.837, positive predictive value [PPV] = 0.584, negative predictive value [NPV] = 0.939) and for the HDRS at a cutoff of 12/13 (sensitivity = 0.810, specificity = 0.821, PPV = 0.580, NPV = 0.934). The GDS was moderately correlated with the HDRS (Pearson's r = 0.54; P < 0.001). The GDS is useful in screening for dPD. A cutoff score of 9/10 has acceptable discriminant validity for dPD, and the GDS has a moderate correlation with the HDRS in PD patients.

Aged↗

PubMed2006

Controlled pilot study of the effects of neuromuscular therapy in patients with Parkinson's disease.

The objectives of this study is to examine the effects of neuromuscular therapy (NMT) on motor and nonmotor symptoms in Parkinson's disease (PD). Thirty-six subjects with PD were randomly assigned to NMT or music relaxation (MR, or active control). Subjects received treatment twice a week for 4 weeks. Testing was conducted at baseline, after final treatment, and 8 days after final treatment. Primary outcome measures were the Motor subscale of the United Parkinson Disease Rating Scale (UPDRS) and the Clinical Global Impression scale (CGI-Change). Secondary outcome measures included a PD-specific quality of life scale (PDQ-39), quantitative measures of motor function, and severity scales for anxiety and depression symptoms. NMT resulted in a significant and sustained improvement in the Motor subscale of the UPDRS (P < or = 0.0001), most notable in the tremor scores. Also improved 1 week after the last treatment were the CGI scores (P = 0.007) and the finger-tapping speed (P = 0.001). The MR active control group had a slight improvement in tremor but evidenced no other change in motor function. Both groups exhibited a modest improvement in quality of life immediately after the last treatment. This effect was sustained for 8 days only in the MR group. In the nonmotor domains, the MR group evidenced improvements in mood (P = 0.001) and anxiety (P = 0.002), whereas NMT had no effect on mood (P = 0.09), and its initial effect on anxiety (P = 0.0009) dissipated after 8 days (P = 0.40). Group differences for UPDRS motor score and patient CGI-Change were superior in the NMT compared to the MR group. There was no group difference in PDQ-39 scores or in nonmotor measures. The findings suggest that NMT can improve motor and selected nonmotor symptoms in PD and that this effect is more durable for the motor symptoms. The results of this pilot study warrant larger controlled studies to examine dose range, durability, and mechanisms of NMT in PD function.

Affect↗

PubMed2006

Coefficients of agreement for fixed observers.

Agreement between fixed observers or methods that produce readings on a continuous scale is usually evaluated via one of several intraclass correlation coefficients (ICCs). This article presents and discusses a few related issues that have not been raised before. ICCs are usually presented in the context of a two-way analysis of variance (ANOVA) model. We argue that the ANOVA model makes inadequate assumptions, such as the homogeneity of the error variances and of the pairwise correlation coefficients between observers. We then present the concept of observer relational agreement which has been used in the social sciences to derive the common ICCs without making the restrictive ANOVA assumptions. This concept did not receive much attention in the biomedical literature. When observer agreement is defined in terms of the difference of the readings of different observers on the same subject (absolute agreement), the corresponding relational agreement coefficient coincides with the concordance correlation coefficient (CCC), which is also an ICC. The CCC, which has gained popularity over the past 15 years, compares the mean squared difference between readings of observers on the same subject with the expected value of this quantity under the assumption of 'chance agreement', which is defined as independence between observers. We argue that the assumption of independence is unrealistic in this context and present a new coefficient that is not based on the concept of chance agreement.

Analysis of Variance↗

PubMed2005

Household-based costs and benefits of vaccinating healthy children in daycare against influenza virus: results from a pilot study.

BACKGROUND: Vaccinating children against influenza virus may reduce infections in immunised children and household contacts, thereby reducing the household-based cost associated with respiratory illnesses. OBJECTIVE: To evaluate the impact of influenza virus vaccination of daycare children on costs of respiratory illnesses of the children and their household contacts from the household and societal perspective. STUDY DESIGN: Cost analysis of data from a randomised controlled trial covering the period November to April of 1996-7 and 1998-9. Children (127 in 1996-7 and 133 in 1998-9) from daycare centres in Californian (USA) naval bases received influenza virus vaccine (inactivated) or hepatitis A virus vaccination. OUTCOME MEASURES: Direct and indirect costs (1997 and 1999 US dollars) of respiratory illnesses in households of vaccinated and not vaccinated daycare children, excluding the cost of vaccination. RESULTS: There were no statistically significant differences in household costs of respiratory illness between households with or without influenza virus-vaccinated children (USD 635 vs USD 492: p = 0.98 [1996-7]; USD 412.70 vs USD 499.50: p = 0.42 [1998-9]). In 1996-7, adult and 5- to 17-year-old contacts of vaccinated children had lower household costs than contacts of unvaccinated children (USD 58.50 vs USD 83.20, p = 0.01 and USD 32.80 vs USD 59.50, p = 0.04, respectively), while vaccinated children 0-4 years old had higher household costs than unvaccinated children in the same age group (USD 383 vs USD 236, p = 0.05). In 1998-9, there were no differences within individual age groups. Results from societal perspective were similar. CONCLUSIONS: Overall, from both the household and societal perspectives, there were no economic benefits to households from vaccinating daycare children against influenza virus. However, we found some over-time inconsistency in results; this should be considered if changing recommendations about routine influenza virus vaccination of healthy children. Our study size may limit the generalisability of the results.

Adolescent↗

PubMed2004

Estimating vaccine efficacy from household data observed over time.

Estimation of vaccine efficacy has traditionally focused on the reduction in susceptibility to infection, or the vaccine efficacy for susceptibility (VE(S)). However, a vaccine, such as a prophylactic HIV vaccine, may also lower the infectiousness of a vaccinated person who became infected. The relative reduction in infectiousness due to vaccination is the vaccine efficacy for infectiousness (VE(I)). Estimation of VE(I) is challenging because it requires information on exposure to infection, and gathering this type of information is often expensive and difficult, or even impossible. Household studies are expected to provide more information on who is exposed to whom. In a previous paper, we developed a method for estimating VE(S) and VE(I) from a household study where only the final outbreak data are available. However, the resulting estimates were quite unstable. In this work, we develop a survival model for the estimation of VE(S) and VE(I) from household data where the time of infection is known for every study participant. Using stochastic simulations, we show that the proposed method significantly reduces the bias and mean square error in the estimation of both VE(S) and VE(I) as compared to the method based on final outbreak data. We also show that when time-to-event data are available, a household study produces more robust estimators than a same-size study of unrelated individuals. In addition, we investigate the bias in estimating VE(S) and VE(I) due to misclassification of infection status when only illness data, rather than true infection data, are available.

Computer Simulation↗

PubMed2003

Randomized trial of pallidotomy versus medical therapy for Parkinson's disease.

Thirty-six patients with Parkinson's disease (PD) were randomized to either medical therapy (N = 18) or unilateral GPi pallidotomy (N = 18). The primary outcome variable was the change in total Unified Parkinson's Disease Rating Scale (UPDRS) score at 6 months. Secondary outcome variables included subscores and individual parkinsonian symptoms as determined from the UPDRS. At the six month follow-up, patients receiving pallidotomy had a statistically significant reduction (32% decrease) in the total UPDRS score compared to those randomized to medical therapy (5% increase). Following surgery, patients' showed improvement in all the cardinal motor signs of PD including tremor, rigidity, bradykinesia, gait and balance. Drug-induced dyskinesias were also markedly improved. Although the greatest improvement occurred on the side contralateral to the lesion, significant ipsilateral improvement was also observed for bradykinesia, rigidity and drug-induced dyskinesias. A total of twenty patients have been followed for 2 years to assess the effect of time on clinical outcome. These patients have shown sustained improvement in the total UPDRS (p < 0.0001), "off" motor (p < 0.0001) and complications of therapy subscores (p < 0.0001). Sustained improvement was also seen for tremor, rigidity, bradykinesia, percent on time and drug-induced dyskinesias.

Antiparkinson Agents↗

PubMed2003

CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice.

Systemic lupus erythematosus (SLE) is a CD4(+) T cell-dependent, immune complex-mediated, autoimmune disease that primarily affects women of childbearing age. Generation of high-titer affinity-matured IgG autoantibodies, specific for double-stranded DNA and other nuclear antigens, coincides with disease progression. Current forms of treatment of SLE including glucocorticosteroids are often inadequate and induce severe side effects. Immunological approaches for treating SLE in mice using anti-CD4 mAb's or CTLA4-Ig and anti-CD154 mAb's have proven to be effective. However, like steroid treatment, these regimens induce global immunosuppression, and their withdrawal allows for disease progression. In this report we show that lupus-prone NZB x NZW F(1) mice given three injections of anti-CD137 (4-1BB) mAb's between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the mice's lifespan from 10 months to more than 2 years. Autoantibody production in recipients was rapidly suppressed without inducing immunosuppression. Successful treatment could be traced to the fact that NZB x NZW F(1) mice, regardless of their age or disease status, could not maintain pathogenic IgG autoantibody production in the absence of continuous CD4(+) T cell help. Our data support the hypothesis that CD137-mediated signaling anergized CD4(+) T cells during priming at the DC interface.

Acute Disease↗

PubMed2003

Acute effects of exercise in patients with previous deep venous thrombosis: impact of the postthrombotic syndrome.

BACKGROUND: The postthrombotic syndrome (PTS) occurs frequently after deep venous thrombosis (DVT) and is believed to worsen with upright posture and physical activity. However, the effects of exercise in patients with previous DVT have not been studied. STUDY OBJECTIVES: To determine whether previous DVT and PTS limit the ability to exercise, and whether exercise increases the severity of venous symptoms and signs. DESIGN AND SETTING: A repeated-measures cohort study that was conducted at a university-affiliated teaching hospital, 1999-2000. PARTICIPANTS: Subjects with a first episode of unilateral DVT at least 1 year earlier were recruited from the Thrombosis Clinic (total, 41 subjects; with PTS, 19 subjects). INTERVENTION: Treadmill exercise session. MEASUREMENTS AND RESULTS: Venous symptoms, calf muscle fatigability, flexibility, and leg volume before and after treadmill exercise were measured and compared. Exercise did not worsen venous symptoms, despite a higher gain in affected leg volume in subjects with PTS vs subjects without PTS (mean difference: affected leg, 53 mL; unaffected leg, -15 mL; p = 0.018). Calf flexibility significantly improved after exercise in subjects with PTS (gastrocnemius: affected-unaffected, PTS vs no PTS + 4.5 degrees, p = 0.0029; soleus: affected-unaffected, PTS vs no PTS + 5.7 degrees, p = 0.0011). CONCLUSIONS: Exercise did not acutely exacerbate symptoms and, in subjects with PTS, resulted in improved flexibility in the affected leg. Our findings suggest that treadmill or similar exercise is unlikely to make symptoms of PTS worse, and may improve flexibility. Further study is indicated to determine whether a regular exercise-training program might have a role in the management of patients with PTS, since, to date, the treatment options for this condition are limited.

Adult↗

PubMed2002

Overall concordance correlation coefficient for evaluating agreement among multiple observers.

Accurate and precise measurement is an important component of any proper study design. As elaborated by Lin (1989, Biometrics 45, 255-268), the concordance correlation coefficient (CCC) is more appropriate than other indices for measuring agreement when the variable of interest is continuous. However, this agreement index is defined in the context of comparing two fixed observers. In order to use multiple observers in a study involving large numbers of subjects, there is a need to assess agreement among these multiple observers. In this article, we present an overall CCC (OCCC) in terms of the interobserver variability for assessing agreement among multiple fixed observers. The OCCC turns out to be equivalent to the generalized CCC (King and Chinchilli, 2001, Statistics in Medicine 20, 2131-2147; Lin, 1989; Lin, 2000, Biometrics 56, 324-325) when the squared distance function is used. We evaluated the OCCC through generalized estimating equations (Barnhart and Williamson, 2001, Biometrics 57, 931-940) and U-statistics (King and Chinchilli, 2001) for inference. This article offers the following important points. First, it addresses the precision and accuracy indices as components of the OCCC. Second, it clarifies that the OCCC is the weighted average of all pairwise CCCs. Third, it is intuitively defined in terms of interobserver variability. Fourth, the inference approaches of GEE and the U-statistics are compared via simulations for small samples. Fifth, we illustrate the use of the OCCC by two medical examples with the GEE, U-statistics, and bootstrap approaches.

Adult↗