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Biomedical subjects

K Newell

Publications and source records attributed to K Newell.

At least 19 recordsLinked to original sources
PubMed2006

CMV-IVIG for prevention of Epstein Barr virus disease and posttransplant lymphoproliferative disease in pediatric liver transplant recipients.

A randomized controlled trial of CMV-IVIG (cytomegalovirus-intravenous immunoglobulin) for prevention of Epstein Barr virus (EBV) posttransplant lymphoproliferative disease (PTLD) in pediatric liver transplantation (PLTx) recipients was begun in Pittsburgh and subsequently expanded to four additional sites. Protocol EB viral loads were obtained in a blinded fashion; additional loads could be obtained for clinical indications. Patients were followed for 2 years post-LTx. Eighty-two evaluable patients (39 CMV-IVIG, 43 placebo) developed 18 episodes of EBV disease (7 CMV-IVIG, 11 placebo) including nine cases of PTLD (three CMV-IVIG, six placebo). No significant differences were seen in the adjusted 2-year EBV disease-free rate (CMV-IVIG 79%, placebo 71%) and PTLD-free rate (CMV-IVIG 91%, placebo 84%) between treatment and placebo groups at 2 years (p > 0.20). The absence of significant effect of CMV-IVIG may be explained by a lack of efficacy of the drug or limitations of sample size.

Adolescent↗
PubMed2001

Self-injurious behavior: gene-brain-behavior relationships.

This paper summarizes a conference held at the National Institute of Child Health and Human Development on December 6-7, 1999, on self-injurious behavior [SIB] in developmental disabilities. Twenty-six of the top researchers in the U.S. from this field representing 13 different disciplines discussed environmental mechanisms, epidemiology, behavioral and pharmacological intervention strategies, neurochemical substrates, genetic syndromes in which SIB is a prominent behavioral phenotype, neurobiological and neurodevelopmental factors affecting SIB in humans as well as a variety of animal models of SIB. Findings over the last decade, especially new discoveries since 1995, were emphasized. SIB is a rapidly growing area of scientific interest to both basic and applied researchers. In many respects it is a model for the study of gene-brain-behavior relationships in developmental disabilities.

Animals↗
PubMed2001

Cortical neurons expressing calcium binding proteins are spared in dementia with Lewy bodies.

The consistent regional and laminar distribution of cortical Lewy bodies (LB) in brains of patients with dementia with Lewy bodies (DLB) suggests that only a certain subpopulation of neurons develops these alpha-synuclein-immunoreactive cytoplasmic inclusions. This study examined whether four non-overlapping neuronal subpopulations, defined by the expression of non-phosphorylated neurofilaments (SMI-32) and several calcium binding proteins (parvalbumin, calretinin and calbindin D28k), are vulnerable to LB formation. We performed peroxidase immunostaining to examine the distribution and to quantitate each neuronal subpopulation within the superior temporal sulcus (STS) area, and double-label immunohistochemistry to test for colocalization of alpha-synuclein and each neuronal marker in the STS and the entorhinal cortex. There were no significant differences between DLB brains and controls in the proportional quantity or laminar distribution of each neuronal subpopulation. Parvalbumin-immunoreactive neurons represented around 7%, calbindin D28k 8%, calretinin 10%, and SMI-32 about 20% of the total neuronal population in the STS cortex. Neurons expressing parvalbumin and SMI-32 showed a widespread distribution across layers II to VI. Neurons expressing calretinin were present in superficial layers (II to IV), and calbindin D28k-immunoreactive neurons were mostly distributed within granular layers II and IV. None of the LB observed in the STS or the entorhinal cortex were located in neurons expressing calcium binding proteins; 25% of the LB were contained in SMI-32 immunoreactive neurons. In conclusion, cortical neurons expressing calcium binding proteins are spared in DLB, while SMI-32-positive neurons are affected in proportion to their density in the cortex. However, the majority of cortical LB develop in neurons not identified by any of these markers.

Aged↗
PubMed2000

alpha-Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining.

alpha-Synuclein is a presynaptic protein recently identified as a specific component of Lewy bodies (LB) and Lewy neurites. The aim of this study was to assess the morphology and distribution of alpha-synuclein immunoreactivity in cases of dementia with LB (DLB), and to compare alpha-synuclein with ubiquitin immunostaining. We examined substantia nigra, paralimbic regions (entorhinal cortex, cingulate gyrus, insula and hippocampus), and neocortex (frontal and occipital association cortices) with double alpha-synuclein and ubiquitin immunostaining in 25 cases meeting neuropathological criteria for DLB. alpha-Synuclein immunostaining was more specific than ubiquitin immunostaining in that it differentiated LB from globose tangles. It was also slightly more sensitive, staining 4-5% more intracytoplasmic structures, especially diffuse alpha-synuclein deposits that were ubiquitin negative. In addition to LB, alpha-synuclein staining showed filiform and globose neurites in the substantia nigra, CA2-3 regions of the hippocampus, and entorhinal cortex. A spectrum of alpha-synuclein staining was seen in substantia nigra: from diffuse "cloud-like" inclusions to aggregated intracytoplasmic inclusions with variable ubiquitin staining to classic LB. We hypothesize that these represent different stages in LB formation.

Aged↗
PubMed2000

Immunization levels and risk factors for low immunization coverage among private practices.

OBJECTIVES: Previous studies have indicated that provider characteristics are an important determinant of immunization coverage. The objectives of this study were to: 1) assess immunization coverage levels among 2-year-old children receiving care in private practices in 3 California counties; and 2) evaluate practice and patient risk factors for low immunization coverage. STUDY DESIGN: Cross-sectional chart review of immunization histories and provider survey of immunization policies. SETTING: Forty-five randomly selected, private medical practices in 3 counties in California. PATIENTS: Children 12 to 35 months old, followed by the participating practices. METHODS: Providers underwent a detailed assessment of their immunization coverage and completed a questionnaire describing their immunization policies and procedures. Immunization data were abstracted from randomly selected medical charts of children 12 to 35 months old. Only patients who met the criteria for active status (>/=2 visits and >/=1 visit during the preceding 18 months) were included in analyses. Immunization coverage levels were calculated and logistic regression was used to estimate the risk of underimmunization associated with different practice and child characteristics. RESULTS: Of the 72 eligible practices that were contacted, 45 participated in the study, yielding a participation rate of 62%. The median immunization coverage of participating offices was 54% (range: 0%-91%). Multivariate analysis revealed 5 independent risk factors for underimmunization. The strongest predictors were having fewer than 50% active children in the practice and children having fewer than 8 visits to the provider. Other significant predictors were the percentage of patients in the practice on Medicaid, administering diphtheria-tetanus-pertussis 4 at a separate visit from the Haemophilus influenzae type b booster, and practice location. CONCLUSIONS: These data provide new insights into immunization practices in an important clinical setting that has been poorly characterized previously. Immunization coverage levels were found to be low and significant risk factors for underimmunization were identified. Recommendations are made for immunization policy changes and targeting of immunization improvement interventions at practices that may be at risk for low immunization coverage. immunization, vaccination, immunization programs, primary prevention, private practice, child, preschool, pediatrics, family practice.

California↗
PubMed1999

Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies.

OBJECTIVE: To address the relationship between dementia and neuropathologic findings in dementia with Lewy bodies (DLB) in comparison with AD. METHODS: We evaluated the clinical presentation of autopsy-confirmed DLB in comparison with AD according to new Consortium on DLB criteria and compared the two conditions using quantitative neuropathologic techniques. This clinicopathologic series included 81 individuals with AD, 20 with DLB (7 "pure" DLB and 13 "DLB/AD"), and 33 controls. We counted number of LB, neurons, senile plaques (SP), and neurofibrillary tangles (NFT) in a high order association cortex, the superior temporal sulcus (STS), using stereologic counting techniques. RESULTS: The sensitivity and specificity of Consortium on DLB clinical criteria in this series for dementia, hallucinations, and parkinsonism are 53% and 83%, respectively, at the patient's initial visit and 90% and 68%, respectively, if data from all clinic visits are considered. In pathologically confirmed DLB brains, LB formation in an association cortical area does not significantly correlate with duration of illness, neuronal loss, or concomitant AD-type pathology. Unlike AD, there is no significant neuronal loss in the STS of DLB brains unless there is concomitant AD pathology (neuritic SP and NFT). CONCLUSIONS: The evaluation of new Consortium on DLB criteria in this series highlights their utility and applicability in clinicopathologic studies but suggests that sensitivity and specificity, especially at the time of the first clinical evaluation, are modest. The lack of a relationship of LB formation to the amount of Alzheimer-type changes in this series suggests that DLB is a distinct pathology rather than a variant of AD.

Aged↗
PubMed1999

Clinical and quantitative pathologic correlates of dementia with Lewy bodies.

OBJECTIVES: To examine the distribution of cortical Lewy bodies (LB) and their contribution to the clinical syndrome in dementia with LB (DLB) and to address their relationship to the pathologic markers of AD and PD. METHODS: We studied 25 cases meeting neuropathologic criteria for DLB: 13 cases without AD (Braak stage I or II) and 12 cases with concomitant AD changes (Braak stages III to V). Age at onset, disease duration, and clinical symptoms were reviewed for each case. We quantified the regional distribution of LB in substantia nigra, paralimbic areas (cingulate gyrus, insula, entorhinal cortex, and hippocampus), and neocortex (frontal and occipital association areas) using anti-alpha-synuclein immunostaining. We compared the LB pathology between groups of patients with different symptoms at onset or with specific clinical phenotypes. RESULTS: There were no significant differences in clinical symptoms or LB density between cases with or without concomitant AD. LB density showed a consistent gradient as follows: substantia nigra > entorhinal cortex > cingulate gyrus > insula > frontal cortex > hippocampus > occipital cortex. LB density in substantia nigra and neocortex was not significantly different in cases that started with parkinsonism compared with those that started with dementia. There were no significant differences in LB density in any region among patients with or without cognitive fluctuations, visual hallucinations, delusions, recurrent falls, or parkinsonism. Duration of the disease correlated with a global LB burden for each case (p = 0.02) but did not correlate with LB density in any individual area. Paralimbic and neocortical LB density were highly correlated with each other (p<0.0001), but neither of these correlated well with the number of LB in substantia nigra. LB density did not correlate with Braak stage or frequency of neuritic plaques. CONCLUSIONS: There is a consistent pattern of vulnerability to LB formation across subcortical, paralimbic, and neocortical structures that is similar for DLB cases with or without concomitant AD. Paralimbic and neocortical LB do not correlate with LB in substantia nigra, suggesting that DLB should not be considered just a severe form of PD. LB density correlates weakly with clinical symptoms and disease duration.

Age of Onset↗
PubMed1999

Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease.

OBJECTIVE: To evaluate the sensitivity of transcranial magnetic stimulation (TMS) to identify upper motor neuron involvement in patients with motor neuron disease. BACKGROUND: Diagnosis of ALS depends on upper and lower motor neuron involvement. Lower motor neuron involvement may be documented with electromyography, whereas definite evidence of upper motor neuron involvement may be elusive. A sensitive, noninvasive test of upper motor neuron function would be useful. METHODS: TMS and clinical assessment in 121 patients with motor neuron disease. RESULTS: TMS revealed evidence of upper motor neuron dysfunction in 84 of 121 (69%) patients, including 30 of 40 (75%) patients with only probable upper motor neuron signs and unsuspected upper motor neuron involvement in 6 of 22 (27%) patients who had purely lower motor neuron syndromes clinically. In selected cases, upper motor neuron involvement identified with TMS was verified in postmortem examination. Increased motor evoked potential threshold was the abnormality observed most frequently and was only weakly related to peripheral compound muscle action potential amplitude. In a subset of 12 patients reexamined after 11+/-6 months, TMS showed progression of abnormalities, including progressive inexcitability of central motor pathways and loss of the normal inhibitory cortical stimulation silent period. CONCLUSIONS: TMS provides a sensitive means for the assessment and monitoring of excitatory and inhibitory upper motor neuron function in motor neuron disease.

Adult↗
PubMed1998

Unraveling the mystery of cognitive changes in old age: correlation of neuropsychological evaluation with neuropathological findings in the extreme old.

In order to understand what cognitive changes can be expected with aging versus those caused by disease, the New England Centenarian Study examined correlations between neuropsychological evaluation and neuropathological studies of centenarian subjects. Sixty-nine subjects were administered an extensive neuropsychological test battery designed for centenarians. Six brain donors from this group have subsequently died, and neuropathological studies of their brains have been performed to determine the presence of Alzheimer's disease (AD) and other pathological states. Of these six centenarians, three subjects had Clinical Dementia Rating scores of 0 and no dementia on neuropsychological testing, and subsequent neuropathology showed very limited AD changes. In fact, despite a range of neuropsychological findings, none of the subjects in this series met neuropathological criteria for a diagnosis of definite AD. Findings suggest that dementia is not inevitable with aging and that dementia in this age group is surprisingly often not attributable to AD.

Aged↗
PubMed1998

Morphologic bone marrow changes in patients with posttransplantation lymphoproliferative disorders.

The clinical workup of patients with posttransplantation lymphoproliferative disorders (PTLPDs) frequently involves bone marrow biopsies. However, little is known about the morphologic bone marrow changes in patients with PTLPD. To define the spectrum of morphologic bone marrow changes in such patients, we evaluated the bone marrow biopsy samples of 26 transplant patients with proven extramedullary PTLPD and of 20 transplant patients without PTLPD. Morphologic changes were present in 14 of 26 patients with PTLPD (54%) and consisted of aggregates of lymphoid and plasma cells with variable histologic and cytologic features. Cells expressing Epstein-Barr virus-encoded small transcripts (EBER) were seen in 9 of 13 bone marrow biopsy samples with morphologic changes and in none of the biopsy samples without morphologic changes. Bone marrow changes were significantly more frequent in patients with PTLPD who were younger than 18 years of age (76%) compared with those who were older than 18 years of age (11%). The difference in mortality rates between the patient groups with and without bone marrow changes was statistically not significant, possibly because of the small sample size. The finding that children with PTLPD have an increased incidence of bone marrow changes supports the notion that Epstein-Barr virus-associated PTLPD involves different pathogenetic mechanisms in pediatric patients than in adults.

Adolescent↗
PubMed1998

Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity.

A mutation in the alpha-synuclein gene has recently been linked to some cases of familial Parkinson's disease (PD). We characterized the expression of this presynaptic protein in the midbrain, striatum, and temporal cortex of control, PD, and dementia with Lewy bodies (DLB) brain. Control brain showed punctate pericellular immunostaining. PD brain demonstrated alpha-synuclein immunoreactivity in nigral Lewy bodies, pale bodies and abnormal neurites. Rare neuronal soma in PD brain were immunoreactive for alpha-synuclein. DLB cases demonstrated these findings as well as alpha-synuclein immunoreactivity in cortical Lewy bodies and CA2-3 neurites. These results suggest that, even in sporadic cases, there is an early and direct role for alpha-synuclein in the pathogenesis of PD and the neuropathologically related disorder DLB.

Aged↗
PubMed1996

Differential effects of staphylococcal toxic shock syndrome toxin-1 on B cell apoptosis.

Superantigens, such as toxic shock syndrome toxin 1 (TSST-1), have been implicated in the pathogenesis of several autoimmune and allergic diseases associated with polyclonal B cell activation. In this report, we studied the in vitro effects of TSST-1 on B cell activation. We show herein that TSST-1 produced antagonistic effects on Ig synthesis by peripheral blood mononuclear cells (PBMC) from normal subjects, depending on the concentration used; Ig production was inhibited at 1000 pg/ml (P < 0.01) and enhanced at 1 and 0.01 pg/ml (P < 0.01) of toxin. Cultures of PBMC were then examined for morphologic features and DNA fragmentation characteristic for apoptosis. B cells exhibited a significantly higher (P < 0.01) incidence of apoptosis after stimulation with 1000 pg/ml of TSST-1 compared with 1 or 0.01 pg/ml of toxin or medium alone. Abundant expression of Fas, a cell surface protein that mediates apoptosis, was detected on B cells after stimulation with 1000 pg/ml of TSST-1 and was significantly higher on B cells undergoing apoptosis than on live cells (P = 0.01). Additionally, increased Fas expression and B cell death occurred at concentrations of TSST-1 inducing the production of high amounts of gamma interferon (IFN-gamma), and both events could be blocked by neutralizing anti-IFN-gamma antibody. These findings suggest that high concentrations of TSST-1 can induce IFN-gamma-dependent B cell apoptosis, whereas at low concentrations it stimulates Ig synthesis by PBMC from normal subjects. These findings support the concept that staphylococcal toxins have a role in B cell hyperactivity in autoimmunity and allergy.

Animals↗
PubMed1995

Reduction of tumour intracellular pH and enhancement of melphalan cytotoxicity by the ionophore Nigericin.

Nigericin is an ionophore which permits the influx of H+ ions into cells down a concentration gradient, thus reducing intracellular pH (pHi) when extracellular pH is low. The effects of nigericin on the pHi of solid murine tumours in vivo were examined using 31P magnetic resonance spectroscopy. Nigericin at 2.5 mg/kg i.p. reduced pHi by 0.2-0.3 pH unit in the KHT and RIF-I tumours but had no effect on pHi in the SCCVII/Ha tumour. In vitro studies have shown that reduced pH can increase the toxicity of melphalan. Therefore, the anti-tumour effect of combining nigericin with melphalan was also examined. Nigericin at 2.5 mg/kg i.p. given before various doses of melphalan resulted in substantial delay in growth of the RIF-I tumour over that induced by melphalan alone. This observation was confirmed by an in vivo/in vitro excision assay, where nigericin given before melphalan produced a 30-fold increase in cell killing. By contrast, no enhancement of melphalan-induced cell killing by nigericin was observed in the KHT and SCCVII/Ha tumours, using growth delay and in vivo/in vitro excision assays, respectively.

Animals↗
PubMed1994

Matrix-degrading metalloproteinases in tumor progression.

The matrix-degrading metalloproteinases (MMPs) have been implicated in tumor invasion and metastasis. Recently it has become clear that the expression of MMPs in tumors is frequently localized to stromal cells surrounding malignant tumor cells. In the mouse skin model of multi-stage carcinogenesis, the MMP stromelysin is expressed in stromal fibroblast-like cells surrounding benign and malignant squamous cell carcinomas. Conversion of these tumors to highly invasive and metastatic spindle-cell tumors is however, associated with the expression of stromelysin-1 mRNA in the tumor cells themselves. The analysis of MMPs in human colon adenocarcinomas at different stages of tumor progression revealed that matrilysin was the only MMP expressed in the tumor cells, while stromelysin-1 and stromelysin-3 mRNA was detected in stromal cells surrounding malignant tumor cells. Matrilysin mRNA is detected in benign tumors as well as malignant tumor cells, and the relative level and percent of tumors expressing matrilysin correlates with the stage of tumor progression. These results suggest that both stromal and tumor cell metalloproteinases may contribute to tumor invasion and metastasis, and also suggests that MMPs may play a role in earlier events in the tumor progression pathway. A potential role for MMPs in tumor growth is illustrated by results which suggest that the expression of matrilysin in human colon cancer-derived cells increases tumorigenicity following injection into the cecum, and that transgenic mice expressing matrilysin mRNA show a marked proliferative response. MMPs may therefore play multiple roles in tumor progression.

Adenocarcinoma↗
PubMed1993

Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity.

Solid tumors have been observed to develop an acidic extracellular environment, which is believed to occur as a result of lactic acid accumulation produced during aerobic and anaerobic glycolysis. Experiments using glycolysis-deficient ras-transfected Chinese hamster lung fibroblasts have been performed to test the hypothesis that lactic acid production within solid tumors is responsible for the development of tumor acidity. The variant cells have defects in glucose transport and in the glycolytic enzyme phosphoglucose isomerase with 1% activity compared to parental cells. Consequently, the in vitro rate of lactic acid production by variant cells was < 4% compared to parental cells. An in vitro correlation between lactic acid production and acidification of exposure medium was observed for parental and variant cells. Implantation of both cell lines into nude mice led to tumors with minimal difference in growth rate. As expected, variant cells died when exposed to hypoxic conditions in culture, and parental tumors were observed to have a larger fraction of cells resistant to radiation due to hypoxia (27%) than variant tumors (2%). Using pH microelectrodes, parental (n = 12) and variant (n = 12) tumors were observed to have extracellular pH (pHe) values of 6.65 +/- 0.07 and 6.78 +/- 0.04 (mean +/- SE, P = 0.13), respectively, whereas normal muscle had a pHe of 7.29 +/- 0.06 (P < 0.0001 for both cell lines). The lactic acid content of variant tumors was found to be similar to that in serum, whereas parental tumors had lactic acid content that was higher than in serum (P < 0.0001). We conclude that there was no correlation between lactic acid content and acidosis for these tumors derived from ras-transfected fibroblasts. These results provide evidence that the production of lactic acid via glycolysis is not the only mechanism responsible for the development of an acidic environment within solid tumors.

Aerobiosis↗
PubMed1992

Effects of agents which inhibit the regulation of intracellular pH on murine solid tumours.

Cell killing can be achieved in an acidic environment in tissue culture (medium pH less than 7.0) by agents (nigericin, carbonylcyanide-3-chlorophenylhydrazone (CCCP)) which transport protons from the extracellular space into the cytoplasm. Cell killing is enhanced when these agents are used in combination with compounds (amiloride, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS)) which inhibit the membrane-based exchangers responsible for the regulation of intracellular pH (pHi). We describe experiments which assess the ability of these agents to kill tumour cells in spheroids and in vivo. Both nigericin and CCCP were observed to penetrate tissue based on their ability to kill tumour cells in spheroids. The mean extracellular pH (pHe) of the KHT fibrosarcoma and the EMT-6 sarcoma were observed to be 0.21 and 0.32 pH units more acidic than the mean pHe in muscle tissue. Intraperitoneal (i.p.) administration of the vasodilator hydralazine (10 mg kg-1) caused a reduction of the mean pHe of the KHT but not the EMT-6 tumour. Nigericin (2.5 mg kg-1, i.p.) plus amiloride (10 mg kg-1, i.p.) followed 30 min later by hydralazine (10 mg kg-1, i.p.) reduced the surviving fraction of cells in the KHT and EMT-6 tumours, but had minimal effects on growth delay. When KHT tumours were treated with 15 Gy X-rays followed immediately by nigericin plus amiloride and hydralazine a reduced surviving fraction as well as an increase in tumour growth delay was observed compared to radiation alone. The administration of nigericin (2.5 mg kg-1, i.p.) or the combination of nigericin (2.5 mg kg-1, i.p.) followed by hydralazine (10 mg kg-1, intravenous (i.v.)) resulted in reductions of tumour pHi of 0.27 and 0.29 pH units respectively as determined by 31P magnetic resonance spectroscopy (MRS). Our results show that the combination of nigericin and hydralazine (with or without amiloride) can kill cells in rodent solid tumours and that cell killing is associated with a reduction in the mean pHi of tumour cells.

Amiloride↗
PubMed1992

Practical screening priorities for hearing impairment among children in developing countries.

Routine screening for hearing impairment in childhood is now widespread in industrial countries, although there is considerable controversy over the most efficient techniques and procedures. In most developing countries, however, routine screening programmes for hearing impairment do not currently exist. The problems involved in implementing screening programmes in developing and industrial countries are very different, and in selecting screening procedures for a particular population the following factors have to be taken into consideration: the environmental test conditions; the availability of resources for equipment and the training of testers; the local attitudes towards disability; the level of hearing impairment that may cause handicaps; and the major types of pathology causing hearing impairment. We suggest that in developing countries children should be screened at school entry using a simple field audiometer and that the external ear be inspected for the presence of a discharge. There is an urgent need to develop reliable and simple screening procedures for infants and young children; where possible, all children should be screened for severe or significant hearing impairment before the age of 2 years. No screening should, however, be implemented until appropriate follow-up services are available.

Acoustic Impedance Tests↗