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Biomedical subjects

M Weaver

Publications and source records attributed to M Weaver.

At least 19 recordsLinked to original sources
PubMed2000

NF1 microdeletion breakpoints are clustered at flanking repetitive sequences.

Neurofibromatosis type 1 patients with a submicroscopic deletion spanning the NF1 tumor suppressor gene are remarkable for an early age at onset of cutaneous neurofibromas, suggesting the deletion of an additional locus that potentiates neurofibromagenesis. Construction of a 3.5 Mb BAC/PAC/YAC contig at chromosome 17q11.2 and analysis of somatic cell hybrids from microdeletion patients showed that 14 of 17 cases had deletions of 1.5 Mb in length. The deletions encompassed the entire 350 kb NF1 gene, three additional genes, one pseudogene and 16 expressed sequence tags (ESTs). In these cases, both proximal and distal breakpoints mapped at chromosomal regions of high identity, termed NF1REPs. These REPs, or clusters of paralogous loci, are 15-100 kb and harbor at least four ESTs and an expressed SH3GL pseudogene. The remaining three patients had at least one breakpoint outside an NF1REP element; one had a smaller deletion thereby narrowing the critical region harboring the putative locus that exacerbates neurofibroma development to 1 Mb. These data show that the likely mechanism of NF1 microdeletion is homologous recombination between NF1REPs on sister chromatids. NF1 microdeletion is the first REP-mediated rearrangement identified that results in loss of a tumor suppressor gene. Therefore, in addition to the germline rearrangements reported here, NF1REP-mediated somatic recombination could be an important mechanism for the loss of heterozygosity at NF1 in tumors of NF1 patients.

Female↗
PubMed1999

Isolated pyogenic osteomyelitis of the odontoid process.

A case of isolated pyogenic osteomyelitis of the odontoid process is reported. Diagnosis was made using magnetic resonance imaging. Aggressive treatment, including transoral drainage of the abscess, antibiotics and cervical immobilization, resulted in a successful outcome. A review of the world's literature revealed only 15 previous reports of this rare entity.

Adolescent↗
PubMed1999

Cyclic ichthyosis with epidermolytic hyperkeratosis: A phenotype conferred by mutations in the 2B domain of keratin K1.

Bullous congenital ichthyosiform erythroderma (BCIE) is characterized by blistering and erythroderma in infancy and by erythroderma and ichthyosis thereafter. Epidermolytic hyperkeratosis is a hallmark feature of light and electron microscopy. Here we report on four individuals from two families with a unique clinical disorder with histological findings of epidermolytic hyperkeratosis. Manifesting erythema and superficial erosions at birth, which improved during the first few months of life, affected individuals later developed palmoplantar hyperkeratosis with patchy erythema and scale elsewhere on the body. Three affected individuals exhibit dramatic episodic flares of annular, polycyclic erythematous plaques with scale, which coalesce to involve most of the body surface. The flares last weeks to months. In the interim periods the skin may be normal, except for palmoplantar hyperkeratosis. Abnormal keratin-filament aggregates were observed in suprabasal keratinocytes from both probands, suggesting that the causative mutation might reside in keratin K1 or keratin K10. In one proband, sequencing of K1 revealed a heterozygous mutation, 1436T-->C, predicting a change of isoleucine to threonine in the highly conserved helix-termination motif. In the second family, a heterozygous mutation, 1435A-->T, was found in K1, predicting an isoleucine-to-phenylalanine substitution in the same codon. Both mutations were excluded in both a control population and all unaffected family members tested. These findings reveal that a clinical phenotype distinct from classic BCIE but with similar histology can result from K1 mutations and that mutations at this codon give rise to a clinically unique condition.

DNA Mutational Analysis↗
PubMed1999

Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse.

The CAG repeats in the human Huntington's disease (HD) gene exhibit striking length-dependent intergenerational instability, typically small size increases or decreases of one to a few CAGs, but little variation in somatic tissues. In a subset of male transmissions, larger size increases occur to produce extreme HD alleles that display somatic instability and cause juvenile onset of the disorder. Initial efforts to reproduce these features in a mouse model transgenic for HD exon 1 with 48 CAG repeats revealed only mild intergenerational instability ( approximately 2% of meioses). A similar pattern was obtained when this repeat was inserted into exon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90 and 109 units produced a graded increase in the mutation frequency to >70%, with instability being more evident in female transmissions. No large jumps in CAG length were detected in either male or female transmissions. Instead, size changes were modest increases and decreases, with expansions typically emanating from males and contractions from females. Limited CAG variation in the somatic tissues gave way to marked mosaicism in liver and striatum for the longest repeats in older mice. These results indicate that gametogenesis is the primary source of inherited instability in the Hdh knock-in mouse, as it is in man, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers. Moreover, the large CAG repeat increases seen in a subset of male HD transmissions are not reproduced in the mouse, suggesting that these arise by a different fundamental mechanism than the small size fluctuations that are frequent during gametogenesis in both species.

Age Factors↗
PubMed1999

Evaluation of the Washington State Workers' Compensation Managed Care Pilot Project I: medical outcomes and patient satisfaction.

OBJECTIVES: This study examined the effect of managed care on medical outcomes and patient satisfaction as part of an evaluation of the Washington State Workers' Compensation Managed Care Pilot. METHODS: One hundred twenty firms (7,041 employees) agreed to have their injured workers treated in managed-care plans. Managed care introduced two changes from the fee-for-service (FFS) delivery system currently used by injured workers in Washington State: (1) experience-rated capitation, and (2) a primary occupational-medicine delivery model. The FFS control group included injured workers employed at 392 firms (12,000 employees). A total of 1,313 workers who experienced occupationally related injuries or illnesses between April 1995 and June 1996 were interviewed by telephone at 6 weeks after injury regarding their medical outcomes and satisfaction with care. Workers whose injuries resulted in four or more lost workdays (n = 372) were also interviewed at 6 months after injury on the same topics. The areas surveyed included functional outcomes and satisfaction with care, providers, and access to providers. RESULTS: The measures of functional outcome reflected no consistent differences between the managed care and the FFS conditions. The workers who attended the managed-care system reported lower levels of satisfaction with care, particularly with access to providers. For example, 58% of managed-care patients reported satisfaction with their attending physician as compared with 69% of FFS patients (P<0.01). CONCLUSIONS: Workers treated through managed-care arrangements were less satisfied with their care, but their medical outcomes were similar to those of workers who received traditional FFS care. The current workers' compensation system in Washington State affords injured workers great latitude in choosing providers. If provider choice is substantially restricted by managed care, worker satisfaction is likely to diminish.

Adult↗
PubMed1999

Evaluation of the Washington State Workers' Compensation Managed Care Pilot Project II: medical and disability costs.

OBJECTIVES: This study examined the effect of managed care on medical and disability costs as part of an evaluation of the Washington State Workers' Compensation Managed Care Pilot (MCP). METHODS: One hundred twenty firms (7,041 employees) agreed to have their injured workers treated in managed care plans. Managed care introduced two changes from the fee-for-service (FFS) delivery system currently used by injured workers in Washington State: experience- rated capitation and a primary occupational medicine delivery network. The FFS control group included injured workers employed at 392 firms (12,000 employees). Medical and disability costs were compared for 1,058 injuries in the managed care group and 1,159 injuries in the FFS group occurring between April 1995 and June 1996. Univariate and multivariate statistical methods were used to analyze the effects of managed care on medical and disability costs. RESULTS: The mean unadjusted medical cost per injury ($587) for the managed care group was 21.5% lower (P = 0.06) than for the FFS group ($748). Adjustment for differences in worker and firm-level characteristics through multivariate analysis had little effect on the unadjusted results, except that the difference in costs between managed care and FFS groups became statistically significant (P<0.01). The major cost differences were for outpatient surgery (cost per surgery) and ancillary services (pharmacy, x-ray, physical therapy, and all other costs). In addition, disability costs, particularly percent on time loss and time-loss cost per injury, were significantly lower (P<0.01) in the managed care group. CONCLUSIONS: The results from the MCP suggest that substantial savings in workers' compensation medical and disability costs may be realized using the type of managed care intervention designed for this study. Delivering occupational health services through managed care arrangements whose design is based on an integrated, occupational health-centered delivery model may offer a viable approach for improving delivery systems, reducing costs and encouraging greater attention to disability prevention.

Adult↗
PubMed1999

Surgical outcome in patients with coexisting multiple sclerosis and spondylosis.

OBJECTIVES: Multiple sclerosis (MS) is a neuro-degenerative disease of unknown etiology which results in destruction of myelin. A variety of neurologic signs and symptoms are associated with MS and include myelopathy, extremity weakness, low back pain, sciatica and paresthesias. Many of these signs and symptoms are identical to those experienced by patients with spondylosis (e.g. spinal stenosis, disc herniations). The coexistence of MS with spondylosis can be problematic both for diagnosis and treatment. MATERIALS AND METHODS: During the period 1992 to 1996 we identified 7 patients with previously diagnosed MS who developed new syndromes which were thought to be related to a variety of degenerative spine conditions. The diagnosis of MS was based on standard clinical, immunological and neuroradiological criteria. RESULTS: Five of 7 patients demonstrated significant improvement after surgery. One patient experienced a transient MS exacerbation after surgery. CONCLUSIONS: From our series we concluded that surgery for degenerative spine conditions can be performed in a safe and effective manner in patients with coexisting multiple sclerosis.

Adult↗
PubMed1999

Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development.

In the mature mouse lung, the proximal-distal (P-D) axis is delineated by two distinct epithelial subpopulations: the proximal bronchiolar epithelium and the distal respiratory epithelium. Little is known about the signaling molecules that pattern the lung along the P-D axis. One candidate is Bone Morphogenetic Protein 4 (Bmp4), which is expressed in a dynamic pattern in the epithelial cells in the tips of growing lung buds. Previous studies in which Bmp4 was overexpressed in the lung endoderm (Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. and Hogan, B. L. M. (1996) Development 122, 1693-1702) suggested that this factor plays an important role in lung morphogenesis. To further investigate this question, two complementary approaches were utilized to inhibit Bmp signaling in vivo. The Bmp antagonist Xnoggin and, independently, a dominant negative Bmp receptor (dnAlk6), were overexpressed using the surfactant protein C (Sp-C) promoter/enhancer. Inhibiting Bmp signaling results in a severe reduction in distal epithelial cell types and a concurrent increase in proximal cell types, as indicated by morphology and expression of marker genes, including the proximally expressed hepatocyte nuclear factor/forkhead homologue 4 (Hfh4) and Clara cell marker CC10, and the distal marker Sp-C. In addition, electron microscopy demonstrates the presence of ciliated cells, a proximal cell type, in the most peripheral regions of the transgenic lungs. We propose a model in which Bmp4 is a component of an apical signaling center controlling P-D patterning. Endodermal cells at the periphery of the lung, which are exposed to high levels of Bmp4, maintain or adopt a distal character, while cells receiving little or no Bmp4 signal initiate a proximal differentiation program.

Animals↗
PubMed1999

Application of mixed models to assess exposures monitored by construction workers during hot processes.

Particulate exposures were assessed among construction workers engaged in hot processes in four jobs (boilermakers, ironworkers, pipefitters and welder-fitters) at nine sites in the U.S. After being trained by occupational hygienists, the workers obtained shift-long personal samples at each site for total particulates (TP). Selected samples were also assayed for manganese (Mn), nickel (Ni), and chromium (Cr). Workers provided information about process- and task-related covariates that were present on the days of monitoring. Data were investigated with mixed-model regression analyses that designated the jobs and covariates as fixed effects and the worker and error terms as random effects. Results indicated that the within-worker variance components, but not the between-worker variance components, could be pooled among jobs. Mean air levels for a given agent varied by roughly six to 100 fold among the jobs, with boilermakers and ironworkers experiencing much higher levels of TP and Mn than pipefitters and welder-fitters. Limited data also suggested that welder-fitters were exposed to greater levels of Ni and Cr than pipefitters. Sufficient sample sizes were available to evaluate the effects of covariates upon exposures to TP and Mn. As expected, processes involving more than 50% hot work led to substantially higher levels of TP and Mn than those involving shorter durations of hot work. Local-exhaust or mechanical ventilation reduced exposure to TP (but not Mn) by as much as 44%, and shielded or manual arc welding increased exposure to Mn (but not TP) by about 80%. Parameters estimated with these mixed models were used to calculate probabilities that workers were exposed at levels above U.S. occupational exposure limits (OELs). Regarding TP and Mn, these calculations suggested that 26-95% of exposures to boilermakers and pipefitters and 2-13% of exposures to pipefitters and welder-fitters exceeded the current Threshold Limit Values. Among welder-fitters, limited data also pointed to probabilities of 2-50% for exceeding particular OELs for Ni and Cr. Using the significance of the estimated random-worker effects as a gauge for the uniformity of exposure within a job, administrative or engineering changes appear appropriate for reducing exposures to boilermakers and ironworkers, while individual personal environments should be investigated for pipefitters and welder-fitters.

Hot Temperature↗
PubMed1998

Functional interactions of genes mediating convergent extension, knypek and trilobite, during the partitioning of the eye primordium in zebrafish.

Vertebrate eye development in the anterior region of the neural plate involves a series of inductive interactions dependent on the underlying prechordal plate and signals from the midline of the neural plate, including Hedgehog. The mechanisms controlling the spatiotemporal expression pattern of hedgehog genes are currently not understood. Cyclopia is observed in trilobite (tri) and knypek (kny) mutants with affected convergent extension of the embryonic axis during gastrulation. Here, we demonstrate that tri mutants show a high frequency of partial or complete cyclopia, kny mutants exhibit cyclopia infrequently, while knym119 trim209 double-mutant embryos have dramatically reduced convergent extension and are completely cyclopic. We analyzed the relationships between the convergent extension defect, the expression of hedgehog and prechordal plate genes, and the formation of cyclopia in knym119 and trim209 mutants. Our results correlate the cyclopia phenotype with the abnormal location of hh-expressing cells with respect to the optic primordium. We show that cyclopia in these mutants is not due to an incompetence of tri and kny cells to respond to Hedgehog signaling. Rather, it is a consequence of exceeding a critical distance (>40-50 micrometer) between hedgehog-expressing cells and the prospective eye field. We hypothesize that at this distance, midline cells are not in an appropriate position to physically separate the eye field and that HH and other signals do not reach the appropriate target cells. Furthermore, tri and kny have overlapping functions in establishing proper alignment of the anterior neural plate and midline cells expressing shh and twhh genes when the partitioning of the eye primordium takes place.

Animals↗
PubMed1998

Treatment of malnutrition with 1.1% amino acid peritoneal dialysis solution: results of a multicenter outpatient study.

A peritoneal dialysis (PD) solution containing 1.1% amino acids as the osmotic agent was evaluated in a 3-month randomized, prospective, open-label study in malnourished PD patients. Patients in the treatment group (DAA) received one or two exchanges daily with the amino acid solution, depending on tolerance, in place of glucose solutions. Controls (DD) received their usual therapy with glucose dialysate. Fifty-four DAA and 51 DD patients completed the study. In DAA, but not in DD patients, there was a significant increase at month 3 in serum insulin-like growth factor-1 (IGF-1) levels and significant decreases in serum potassium (all 3 months) and inorganic phosphorus levels (months 1 and 3), indicating a general anabolic response. Prealbumin and transferrin levels were significantly increased in DAA but not in DD patients at month 1, but the groups did not differ at months 2 and 3. In patients with baseline albumin levels less than 3.5 g/dL (bromcresol green [BCG] method), DAA patients showed increases in albumin, transferrin (months 1 and 2), and prealbumin levels (all 3 months) relative to baseline values, whereas these serum protein levels were unchanged in DD patients, although the changes from baseline did not differ between groups. In this subgroup, midarm muscle circumference (MAMC) did not change in DD or DAA patients. In patients with baseline albumin levels of 3.5 g/dL or greater, DD patients had decreases in albumin and total protein levels at all 3 months and in prealbumin levels at months 1 and 2, relative to baseline. In DAA patients, there were fewer changes in serum proteins. MAMC increased significantly from baseline in DAA but not in DD patients, although changes from baseline did not differ between DAA and DD groups. DAA patients showed no changes in peritoneal membrane transport characteristics. The results indicate that treatment with one or two exchanges daily of this amino acid-based PD solution is safe and provides nutritional benefit for malnourished PD patients.

Amino Acids↗
PubMed1998

Identifying achievable benchmarks of care: concepts and methodology.

Webster's Dictionary defines a benchmark as 'something that serves as a standard by which others can be measured'. Benchmarking pervades the health care quality improvement literature, and benchmarks are usually based on subjective assessment rather than on measurements derived from data. As such, benchmarks may fail to yield an achievable level of excellence that can be replicated under specific conditions. In this paper, we provide an overview of benchmarking in health care. We then describe the evolution of our data-driven method for identifying an Achievable Benchmark of Care (ABC) on the basis of process-of-care indicators. Here, our experience leads us to postulate the following premises for sound benchmarks: (i) benchmarks should represent a level of excellence; (ii) benchmarks should be demonstrably attainable; (iii) providers with high performance should be selected from among all providers in a predefined way using reliable data; (iv) all providers with high performance levels should contribute to the benchmark level; and (v) providers with high performance levels but small numbers of cases should not unduly influence the level of the benchmark. An example of an ABC applied to the cooperative cardiovascular project leads the reader through the computation of an ABC. Finally, we consider several refinements of the original ABC concept that are in progress, e.g. how to approach the special problems posed by very small denominators. The ABC methodology has been well accepted in multiple quality improvement projects. This approach lends objectivity and reliability to benchmarks that have been a widely used, but until now, arbitrarily defined tool.

Alabama↗
PubMed1998

Long-term transcutaneous electrical nerve stimulation (TENS) use: impact on medication utilization and physical therapy costs.

OBJECTIVE: A study was conducted to assess a variety of treatment outcomes in long-term users of transcutaneous electrical nerve stimulation (TENS) who suffer from chronic pain. Key components of the study examined the effects of long-term TENS therapy on pain-related medications and physical/occupational therapy (PT/OT) use. DESIGN: From a population of 2,(X)3 chronic pain patients (CPPs) who acquired a TENS device (Epix XL, Empi, Inc., St. Paul, MN, U.S.A.) for pain management, a randomly selected sample of 376 patients who used TENS were interviewed by telephone by an independent research firm. The survey assessed a variety of outcome variables including changes in medication use, number of pain-related medications, and use of PT/OT prior to TENS and after a minimum 6 months of TENS treatment. The data were subjected to a paired t test analysis. A cost simulation model was then applied to the medication and PT/OT data. RESULTS: The mean duration of pain, for which TENS was prescribed, was 40 +/- 60 months. As compared with the period prior to TENS use, this long-term TENS user group reported a statistically significant reduction in the following types of pain medications: opiate analgesics, tranquilizers, muscle relaxants, nonsteroidal anti-inflammatory drugs (NSAIDs), and steroids. PT/OT use was also significantly reduced. Cost simulations of pain medications and PT/OT are presented. CONCLUSIONS: Long-term use of TENS is associated with a significant reduction in the utilization of pain medication and PT/OT. In this study population, cost simulations of medication and PT/OT indicate that with long-term TENS use, costs can be reduced up to 55% for medications and up to 69% for PT/OT. The potential for TENS associated improvement, combined with reduced medication-related complications and costs, are important points that clinicians should consider when constructing a treatment plan for chronic pain patients. Finally, cost simulation techniques provide a useful tool for assessing outcomes in pain treatment and research.

Adult↗
PubMed1997

Familial neurofibromatosis 1 microdeletions: cosegregation with distinct facial phenotype and early onset of cutaneous neurofibromata.

A notable subset of the recent literature on the disorder neurofibromatosis type 1 (NF1) describes patients with NF1, facial anomalies, and other unusual findings. We describe a molecular re-evaluation of two such families reported previously by Kaplan and Rosenblatt [1985], who suggested that their NF1 manifestations, facial phenotype, and other findings could result from a disorder distinct from NF1. Submicroscopic deletions involving the NF1 gene were identified in both families by fluorescent in situ hybridization and analysis of somatic cell hybrids. Affected subjects of the first family were heterozygous for a microdeletion of approximately 2 Mb, which included the entire NF1 gene and flanking contiguous sequences. The family was remarkable for cosegregation of the NF1 microdeletion with facial abnormalities and a pattern of early onset of cutaneous neurofibromata upon transmission from an affected mother to her three affected children. The propositus of the second family carried a deletion that at the least involved NF1 exon 2 through intron 27, which is > 200 kilobases in length. Because all persons in the family were deceased, the size of the deletion could not be determined precisely. Facial anomalies were observed in the propositus and his NF1-affected mother and sister. The data from these families support our hypothesis, which was initially based solely on sporadic deletion cases, that deletion of the entire NF1 gene, or in conjunction with deletion of unknown contiguous genes, causes the facial anomalies and early onset of neurofibromata observed in this subset of NF1 patients. In addition, other features observed in the persons in these families suggest that some NF1 microdeletion patients may be at increased risk for connective tissue abnormalities and/or neoplasms.

Adolescent↗
PubMed1997

Assessing public health performance in Iowa's counties.

Local health agencies in Iowa were surveyed to assess the performance of public health practices in their communities. Responses were received from 97 percent of counties. Less than 50 percent of counties were performing half of the indicators of the Assessment function. Policy Development functions also were frequently not performed. Performance was best in the Assurance function, with 86 percent of counties reporting that they inform and educate the public. However, the other three types of Assurance practices (Manage, Implement, and Evaluate) were performed less frequently. Comparison of the performance of Iowa's rural counties reveals a profile nearly identical to that reported elsewhere for a group of six other states.

Benchmarking↗