A role for hyaluronan in macrophage accumulation and collagen deposition after bleomycin-induced lung injury

Elevated concentrations of hyaluronan (HA) are associated with the accumulation of macrophages in the lung after injury. We have investigated the role of HA in the inflammatory and fibrotic responses to lung injury using the intratracheal instillation of bleomycin in rats as a model. After bleomycin-induced lung injury, both HA content in bronchoalveolar lavage (BAL) and staining for HA in macrophages accumulating in injured areas of the lung were maximal at 4 d. Increased HA in BAL correlated with increased locomotion of isolated alveolar macrophages. HA-binding peptide was able to specifically block macrophage motility in vitro. Importantly, systemic administration of HA-binding peptide to rats before injury not only decreased alveolar macrophage motility and accumulation in the lung, but also reduced lung collagen alpha (I) messenger RNA and hydroxyproline contents. We propose a model in which HA plays a critical role in the inflammatory response and fibrotic consequences of acute lung injury.     

Comparison of the direct radiolabeled antiglobulin assay and the direct immunobead binding test for detection of sperm-associated antibodies

Thirty-seven semen samples were assayed for sperm-associated IgG and IgA using the immunobead test. Portions of these sperm samples were sent for testing with a direct radiolabeled antiglobulin assay and the testing results were compared. If the results of the immunobead test when only tail-tip bead binding was noted are regarded as negative, there was close correlation between the two assay methodologies.     

Complete genomic screen in Parkinson disease: evidence for multiple genes.

CONTEXT: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. OBJECTIVE: To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. MAIN OUTCOME MEASURES: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. RESULTS: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.     

Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease.

CONTEXT: The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. OBJECTIVE: To investigate whether the tau gene is involved in idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. MAIN OUTCOME MEASURE: Family-based tests of association, calculated using asymptotic distributions. RESULTS: Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P =.03; SNP 9i, P =.04; and SNP 11, P =.04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P =.11, and SNP 9iii, P =.87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P =.009) and a negative association with another haplotype (P =.007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3, 9i, 9ii, and 11). CONCLUSIONS: This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.     

A methodology model for quality management in a general hospital

A reappraisal is made of the relevance of industrial modes of quality management to the issues of medical care. Analysis of the nature of medical care, which differentiates it from the supplier-client relationships of industry, presents the main intrinsic characteristics, which create problems in application of the industrial quality management approaches to medical care. Several examples are the complexity of the relationship between the medical action and the result obtained, the client's nonacceptance of economic profitability as a value in his medical care, and customer satisfaction biased by variable standards of knowledge. The real problems unique to hospitals are addressed, and a methodology model for their quality management is offered. Included is a sample of indicator vectors, measurements of quality care, cost of medical care, quality of service, and human resources. These are based on the trilogy of planning quality, quality control, and improving quality. The conclusions confirm the inadequacy of industrial quality management approaches for medical institutions and recommend investment in formulation of appropriate concepts.     

Use of glycated hemoglobin to assess Glycemic control in Wistar diabetic fatty rats and Zucker fatty rats

The Wistar Diabetic Fatty rat (WDF fafa) is a congenic strain of the Wistar Kyoto rat. Studies using blood glucose reveal that only fatty male (not female) WDF rats spontaneously develop hyperglycemia when fed a stock diet. Blood glucose values have not provided consistent results for evaluation of glycemic status in fatty male WDF rats. Zucker fatty (fafa) rats, while sharing the fa gene and the development of hyperinsulinemia and hyperlipemia, do not spontaneously become hyperglycemic. In order to examine strain differences and the effects of age on long-term average glycemic status in WDF and Zucker rats, glycated hemoglobin (GHb) was analyzed. Glycated hemoglobin was measured in male lean and obese WDF and Zucker rats at 2, 3, 6, and 12 months of age. Nonfasted plasma glucose was measured in male lean and obese WDF rats at 2, 3, 6, and 12 months of age and in lean and obese Zucker rats at 3, 6, and 12 months of age. Plasma insulin was measured in lean and obese WDF and Zucker rats at 3, 6, and 12 months of age. Obese WDF rats had significantly elevated GHb compared to lean controls at 3, 6, and 12 months of age. Glycated hemoglobin was substantially above the normal range (3.8-6.5%) at 3 months of age (14.1%). Glycated hemoglobin significantly declined in the obese WDF rats between 6 and 12 months of age. Nonfasted plasma glucose was significantly elevated in the obese WDF rats at 3 months (14.1 +/- 2.1 mM/L) and 6 months of age (16.2 +/- 2.3 mM/L) compared to lean controls. At 12 months of age there was no difference in plasma glucose between obese and lean WDF rats. Obese and lean Zucker rats had similar levels of GHb and plasma glucose at all ages. In conclusion, GHb provides more integrated data for classifying disease status of WDF rats and evaluation of potential long-term complications associated with hyperglycemia.     

Substitution of aspartic acid at beta57 with alanine alters MHC class II peptide binding activity but not protein stability: HLA-DQ (alpha1*0201, beta1*0302) and (alpha1*0201, beta1*0303)

In class II major histocompatibility complex (MHC) proteins, residue beta57 is usually aspartic acid. Alleles carrying serine, valine, or alanine at this position are strongly correlated with the development of insulin-dependent diabetes mellitus (IDDM). Asp(beta)57 participates in a conserved salt bridge that bridges the alpha and beta subunits in the peptide-binding site. It has been proposed that the correlation between IDDM and MHC alleles lacking Asp(beta)57 may be due to an instability of the protein caused by loss of this salt bridge. Using a pair of HLA-DQ proteins (alpha1*0201, beta1*0302) and (alpha1*0201, beta1*0303) differing only in having aspartic acid or alanine at position beta57, we show that the polymorphism does not have a significant effect on protein stability for either the empty or peptide-loaded forms. However, the circular dichroism spectra indicate that empty and peptide-loaded Alabeta57 proteins display slightly different secondary structures relative to their Aspbeta57 counterparts. A set of three peptides shows different binding affinities for DQ(alpha1*0201, beta1*0302) relative to DQ(alpha1*0201, beta1*0303). We propose that substitution of Asp(beta)57 residue causes a local rearrangement within the DQ peptide-binding site that alters the peptide-binding specificity. This rearrangement may help to explain the previously observed differences in SDS stability between Asp and non-Asp(beta)57 DQ proteins.     

Rey-Osterrieth Complex Figure performance in adults with attention deficit hyperactivity disorder: a validation study of the Boston Qualitative Scoring System

Rey-Osterrieth Complex Figure (ROCF) productions from 18 adults with Attention Deficit Hyperactivity Disorder (ADHD) were compared to 18 matched controls using the Boston Qualitative Scoring System (BQSS). ADHD adults showed impairment in measures of configural accuracy, planning, and neatness. A logistic regression model resulted in 75% sensitivity and 81% specificity in discriminating ADHD from control subjects. In contrast, there was no significant difference on the traditional ROCF 36-point score, and the sensitivity and specificity for the 36-point score were lower (68% and 71%, respectively). These findings suggest persisting executive dysfunction in adults with ADHD that can be detected in ROCF productions. Thus, the BQSS may be a useful tool contributing to the neuropsychological evaluation of adults with ADHD.     

Vascular depression: a new view of late-onset depression

We have suggested that cerebrovascular disease may predispose, precipitate, or perpetuate some late-life depressive syndromes. The mechanisms of "vascular depression" include disruption of cortico-striato-pallido-thalamo-cortical (CSPTC) pathways or their modulating systems. This view is supported by the presentation of vascular depression, which consists of depressive symptoms, cognitive abnormalities, as well as neuroimaging findings that may result from CSPTC impairment. Moreover, clinical and electrophysiological evidence of CSPTC impairment, an abnormality frequently found in patients with vascular depression, appears to be associated with poor response to antidepressant treatment and early relapse and recurrence. The vascular depression hypothesis provides the conceptual background for studies that may have clinical and theoretical impact. Agents influencing dopamine, acetylcholine, and opioid neurotransmitters may be studied in vascular depression, since these are essential neurotransmitters of the frontostriatal circuitry. Drugs used for prevention and treatment of cerebrovascular disease may be shown to reduce the risk for vascular depression or improve its outcomes. The choice of antidepressants in vascular depression may depend on their effect on neurological recovery from ischemic lesions. Finally, identification of specific relationships between specific symptoms, cognitive deficits, and disability may lead to interventions that target the patients' deficits as well as their interactions with psychosocial factors known to contribute to depression. Research can clarify the pathways to vascular depression by focusing on the site of lesion, the resultant brain dysfunction, the presentation of depression and time of onset, and the contribution of nonbiological factors.     

Optimal histopathologic examination of the sentinel lymph node for breast carcinoma staging

Sentinel lymph node dissection is a minimally invasive surgical technique for staging of breast carcinoma. The optimal pathologic examination of the sentinel node (SN) has not yet been determined. Our standard protocol for evaluation of the SN in patients with breast cancer included frozen section at one level, plus paraffin sections at two levels, separated by 40 microm, and stained with hematoxylin and eosin and cytokeratin immunohistochemistry (IHC) at each paraffin section level. In the current study, we evaluated the use of step sections and cytokeratin IHC in 60 SNs (42 consecutive patients) that were tumor-negative on frozen section and hematoxylin and eosin staining at permanent section levels 1 and 2. The SN were reexamined with cytokeratin IHC at eight additional levels (levels 3-10) of the paraffin block, each separated by 40 microm. Previous IHC sections from levels 1 and 2 had shown micrometastases in nine SNs (eight patients) and no tumor cells in the remaining 51 SNs (34 patients). Of the 51 previously negative SNs, only two (4%) SNs from one (3%) patient had metastatic carcinoma cells in levels 3-10. Thus, the additional step sections with cytokeratin IHC did not significantly increase the number of patients with tumor-positive SNs. We currently recommend that the SN be examined with cytokeratin IHC at two levels of the paraffin block. This should optimize sentinel lymph node dissection as a staging technique and minimize the labor and financial burden associated with multiple step sections and IHC stains.