Quality improvement in acute stroke: the New York State Stroke Center Designation Project.

BACKGROUND: Many hospitals lack the infrastructure required to treat patients with acute stroke. The Brain Attack Coalition (BAC) published guidelines for the establishment of primary stroke centers. OBJECTIVE: To determine if stroke center designation and selective triage of acute stroke patients improve quality of care. METHODS: Baseline chart abstraction was performed on all stroke patients admitted to 32 hospitals serving Brooklyn and Queens, NY, from March to May 2002. Hospitals were invited to meet BAC guideline-based criteria. Adherence was verified by on-site visits. After designation, acute stroke patients were selectively triaged. Remeasurement data were collected from August to October 2003. RESULTS: The authors abstracted 1,598 charts at baseline and 1,442 charts at remeasurement. From baseline to remeasurement, median times decreased for door to physician contact (25 vs 15 minutes, p = 0.001), CT performance for potential tissue plasminogen activator (t-PA) candidates (68 vs 32 minutes, p < 0.001), and t-PA administration (109 vs 98 minutes (p = NS). IV t-PA utilization increased from 2.4 to 5.2% (p < 0.005), select t-PA protocol violations decreased from 11.1 to 7.9% (p = NS), and the stroke unit admission rate increased from 16 to 39% (p < 0.001). In stroke centers (n = 14) vs nondesignated hospitals (n = 18), there were shorter median times from door to physician contact (10 vs 25 minutes, p < 0.001), CT performance for potential t-PA candidates (31 vs 40 minutes, p = NS), and t-PA administration (95 vs 115 minutes, p < 0.05). Stroke centers, compared with nondesignated centers, admitted acute stroke patients to stroke units more often (55.9 vs 10.9%, p < 0.001). CONCLUSIONS: Stroke center designation and selective triage of acute stroke patients improved the quality of care, including access to timely thrombolytic therapy and stroke units.

Ultrastructural analysis of a murine model of congenital hydrocephalus produced by overexpression of transforming growth factor-beta1 in the central nervous system.

The purpose of this study was to elucidate using transmission electron microscopy (TEM) the ultrastructural changes that occur within the cortical gray matter of a novel reproducible model of congenital hydrocephalus in mice created to overexpress the cytokine transforming growth factor-beta1 (TGF-beta1) in the central nervous system. Brain tissue was obtained from mice from a colony engineered to overexpress TGF-beta1 at two days postpartum and compared to a wild-type aged-matched control. This tissue was fixed using a solution containing 1.25% paraformaldehyde and 1.25% glutaraldehyde in phosphate buffer at least 3-4 h and then cut into 40-50 microm sections. Randomly selected thin sections were stained with uranyl acetate and lead citrate, and then analyzed using a JEOL-100CX or 1200EX transmission electron microscope at accelerating voltage 80 kV. Dramatic neuronal and glial pathology was observed throughout the cortical neuropil in TGF-beta1 mice. The most striking change in the hydrocephalic mice was severe edema with extracellular fluid, possibly due to cerebrospinal fluid (CSF) penetration into the cortex. In addition, severe disruption of the cytoplasmic matrix was seen throughout the cortex, with damage to cellular organelles and particularly severe damage to mitochondria. Our results suggest that congenital hydrocephalus may be associated with significant damage to cortical tissue.

Functional regulatory regions of human transcription factor MEF2C.

Myocyte enhancer-binding factor 2C (MEF2C), a transcription factor expressed at high levels in muscle and brain, is implicated in the terminal differentiation and post-mitotic survival of neurons. In this study MEF2C deletion mutants and naturally-occurring isoforms were transfected into COS and P19 cells with two different reporter genes, to test the relative transcriptional activities of the MEF2C constructs. Deletion of parts of the carboxy terminus, in particular amino acids 387-473, enhanced transcriptional activation. A region rich in serine, threonine, proline, and tyrosine from amino acids 312-367 was sufficient to activate transcription at low levels when coupled to amino acids 1-86, which contain the DNA-binding (MADS/MEF) domain of MEF2C, but also depended on amino acids 87-311 for full effect. A construct with amino acids 312-350 missing showed significantly less transcriptional activation than proteins containing this sequence. MEF2C constructs were uniformly localized to the cell nucleus by immunostaining with an antibody to the constant N-terminal region of MEF2C. Western blot and gel shift studies of extracts from transfected cells and from in vitro transcription/translation suggest that variation in the amount of protein expressed or in DNA-binding properties does not account for observed differences in transcriptional activation. This structural information may be useful for elucidating the mechanisms of MEF2C in interacting with other factors to regulate target genes.

Chronologic changes of cerebral ventricular size in a transgenic model of hydrocephalus.

We have maintained a transgenic mouse model of hydrocephalus created to overproduce the cytokine, transforming growth factor-beta1 (TGF-beta1) in the central nervous system (CNS). The aim of the present study was to estimate the embryonic period when the transgenic mice would develop hydrocephalus, by investigating the chronological developmental changes of the cerebral ventricles. Qualitative analysis of ventricular size was performed on sections cut in the coronal plane of embryos at the 15th (E15) and 18th (E18) embryonic days, and postnatal mice aged 4 days (P4). The presence of the TGF-beta1 transgene was determined by performing polymerase chain reaction (PCR) analysis. We have examined 24 embryos and 14 postnatal mice. By performing PCR analysis, the TGF-beta1 transgene was determined to be present in 16 (42.1%). Five of 16 embryos at E15 carried the transgene, and showed a slight enlargement of the lateral ventricles. Three of 8 embryos at E18 carried the transgene, and had remarkable enlargement of the lateral ventricles. Eight of 14 pups at P4 carried the transgene, and 7 of 8 pups with the transgene developed hydrocephalus. In pups that were positive for the transgene, massive enlargement of the lateral ventricles was observed and there was an associated thinning of the overlying cerebral cortex. These results suggest that congenital hydrocephalus may develop at an important embryonic time period, which coincides with the stage of neural stem cell proliferation and differentiation in the CNS.

Follow-up of patients at low risk for hepatic malignancy with a characteristic hemangioma at US.

PURPOSE: To determine the need for follow-up imaging in patients with a low risk of malignancy and with ultrasonographic (US) findings typical of hepatic hemangioma. MATERIALS AND METHODS: A computer search of US reports completed between 1991 and 1994 helped identify 383 patients whose reports contained the word "hemangioma." One hundred eleven patients were excluded because the lesion's appearance was atypical (n = 16) or because the patients had a high risk of malignancy (prior history or current evidence of extrahepatic malignancy or chronic hepatic disease [n = 95]). Fifty-nine patients were excluded because they were lost to follow-up (n = 41) or had clinical follow-up of less than 2 years (n = 18). The conditions of the remaining 213 patients with typical-appearing hemangiomas and a low risk of malignancy were analyzed. One hundred twenty-one patients underwent imaging follow-up or histopathologic confirmation. Ninety-two had clinical follow-up of more than 2 years (mean, 46 months). RESULTS: Of the 213 patients, four had benign lesions other than hemangiomas. One patient who subsequently developed a malignancy (neuroendocrine metastases from primary colonic carcinoma diagnosed 22 months after initial US) potentially had an early metastasis that was misdiagnosed as a hemangioma. CONCLUSION: On the basis of these results, the authors no longer recommend follow-up studies in their patients with a low risk of malignancy and a typical-appearing hemangioma at US.

Characterization of a model of hydrocephalus in transgenic mice.

OBJECT: The purpose of this study was to elucidate the pathophysiological characteristics of hydrocephalus in a new transgenic model of mice created to overproduce the cytokine transforming growth factor-beta1 (TGFbeta1) in the central nervous system (CNS). METHODS: Galbreath and colleagues generated transgenic mice that overexpressed TGFbeta1 in the CNS in an effort to examine the role of this cytokine in the response of astrocytes to injury. Unexpectedly, the animals developed severe hydrocephalus and died. The authors have perpetuated this transgenic colony to serve as a model of congenital hydrocephalus, breeding asymptomatic carrier males that are heterozygous for the transgene with wild-type females. One hundred twelve (49.6%) of 226 mice developed clinical manifestations of hydrocephalus, characterized by dorsal doming of the calvaria, spasticity, limb tremors, ataxia, and, ultimately, death. The presence of the TGFbeta1 transgene was determined by performing polymerase chain reaction (PCR) analysis of sample tail slices. Animals with the hydrocephalic phenotype consistently carried the transgene, although some animals with the transgene did not develop hydrocephalus. Animals without the transgene did not develop hydrocephalus. Alterations in brain structure were characterized using magnetic resonance (MR) imaging, gross and light microscopic analysis, and immunocytochemical studies. Magnetic resonance imaging readily distinguished hydrocephalic animals from nonhydrocephalic controls and demonstrated an obstruction at the outlets of the fourth ventricle. Gross and light microscopic examination confirmed the MR findings. The results of immunofluorescent staining of brain tissue slices revealed the presence of the TGFbeta1 cytokine and its receptor preferentially in the meninges and subarachnoid space in both hydrocephalic and control mice. Reverse transcriptase-PCR analysis demonstrated tissue-specific expression of the TGFbeta1, gene in the brains of transgenic mice, and enzyme-linked immunosorbent assay confirmed overexpression of the TGFbeta1 cytokine in brain, cerebrospinal fluid, and plasma. CONCLUSIONS: The transgenic murine model provides a reproducible representation of congenital hydrocephalus. The authors hypothesize that overexpression of TGFbeta1 in the CNS causes hydrocephalus by altering the environment of the extracellular matrix and interfering with the circulation of cerebrospinal fluid. A model of hydrocephalus in which the genetic basis is known should be useful for evaluating hypotheses regarding the pathogenesis of this disorder and should also help in the search for new treatment strategies.