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J Lewis

Publications and source records attributed to J Lewis.

At least 127 records · Page 7Linked to original sources
PubMed1999

Accelerated filament formation from tau protein with specific FTDP-17 missense mutations.

Tau is the major component of the neurofibrillar tangles that are a pathological hallmark of Alzheimers' disease. The identification of missense and splicing mutations in tau associated with the inherited frontotemporal dementia and Parkinsonism linked to chromosome 17 demonstrated that tau dysfunction can cause neurodegeneration. However, the mechanism by which tau dysfunction leads to neurodegeneration remains uncertain. Here, we present evidence that frontotemporal dementia and Parkinsonism linked to chromosome 17 missense mutations, P301L, V337M and R406W, cause an accelerated aggregation of tau into filaments. These results suggest one mechanism by which these mutations can cause neurodegeneration and frontotemporal dementia and Parkinsonism linked to chromosome 17.

Alzheimer Disease↗
PubMed1999

Alterations of INK4A and INK4B genes in adult soft tissue sarcomas: effect on survival.

BACKGROUND: The INK4A and INK4B genes map to chromosome 9p21, with the INK4A gene encoding two protein products, p16 and pl9ARF. Alterations of the INK4A and INK4B genes occur frequently in certain primary malignant neoplasms. This study was undertaken to evaluate the frequency of INK4A and INK4B gene alterations in a cohort of adult soft tissue sarcomas. METHODS: The status of the INK4A and INK4B genes was determined in 46 soft tissue sarcomas by use of the following methods: Southern blotting, polymerase chain reaction (PCR), single-strand conformation polymorphism analysis, comparative multiplex PCR, and a methylation assay focusing on the p16 promoter. Associations between alterations of the INK4A and INK4B genes and clinicopathologic variables, as well as with p53 and pRB (retinoblastoma protein) status, were evaluated by use of the two-tailed Fisher's exact test. Disease-specific survival was evaluated by use of the Kaplan-Meier method and the logrank test. Proportional hazards analysis was used to obtain estimates of relative risks. All P values are two-sided. RESULTS: Homozygous and hemizygous deletions, but no point mutations, were observed in these two genes. The overall frequency of gene alteration (deletion or rearrangement) was approximately 15% for the INK4A and INK4B genes, with changes restricted to high-grade sarcomas. Statistically significant associations were observed between INK4A/INK4B deletions (P = .036) or alterations (P = .005) and poor survival. Alteration of the INK4A and INK4B genes was the only statistically significant predictor for poor survival when controlling for tumor grade and size (P = .03). CONCLUSION/IMPLICATIONS: Coincident homozygous deletion of the INK4A and INK4B genes occurs frequently in adult soft tissue sarcomas. Loss of p16 and pl9ARF function in primary tumors, although not equivalent to alterations in p53 and pRB function, appears to be associated with cancers that have an aggressive biologic behavior.

Adult↗
PubMed1999

Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of multiple hamartomas involving many organs. About two-thirds of the cases are sporadic and appear to represent new mutations. With the cloning of two causative genes, TSC1 and TSC2 it is now possible to analyze both genes in TSC patients and identify germline mutations. Here we report the mutational analysis of the entire coding region of both TSC1 and TSC2 genes in 126 unrelated TSC patients, including 40 familial and 86 sporadic cases, by single-stranded conformational polymorphism (SSCP) analysis followed by direct sequencing. Mutations were identified in a total of 74 (59%) cases, including 16 TSC1 mutations (5 sporadic and 11 familial cases) and 58 TSC2 mutations (42 sporadic and 16 familial cases). Overall, significantly more TSC2 mutations were found in our population, with a relatively equal distribution of mutations between TSC1 and TSC2 among the familial cases, but a marked underrepresentation of TSC1 mutations among the sporadic cases (P = 0.0035, Fisher's exact test). All TSC1 mutations were predicted to be protein truncating. However, in TSC2 13 missense mutations were found, five clustering in the GAP-related domain and three others occurring in exon 16. Upon comparison of clinical manifestations, including the incidence of intellectual disability, we could not find any observable differences between TSC1 and TSC2 patients. Our data help define the distribution and spectrum of mutations associated with the TSC loci and will be useful for both understanding the function of these genes as well as genetic counseling in patients with the disease.

Codon, Nonsense↗
PubMed1999

Pediatric telephone triage protocols: standardized decisionmaking or a false sense of security?

STUDY OBJECTIVE: To determine whether implementation of a set of standardized pediatric telephone triage protocols results in consistent triage dispositions when applied by different operators. METHODS: A descriptive study with interrater comparisons was performed. Telephone interviews simulated the setting of a triage station in a university hospital-based pediatric emergency department. A mock parent presented 15 standardized respiratory cases in random order to 12 pediatric ED nurses. Nurses assigned patients' complaints to severity categories using 9 respiratory complaint protocols extracted from a commercially available pediatric telephone triage tool. Protocol selection and severity endpoints were recorded. Interobserver agreement among nurses was analyzed by the kappa statistic. Comparisons of operator characteristics and triage results were carried out by ANOVA. RESULTS: Interrater agreement in triage disposition among nurses was poor (kappa,.11; 95% confidence interval,.02 to.20). Protocol selection varied; the group used a mean of 3 different disposition-generating protocols per case. Disposition also varied, with up to 4 different severity endpoints per protocol in a given case. A post-hoc comparison of the mean disposition severity between nurses did not reach significance at an adjusted level (P =.04). Fifty-eight percent of the nurses felt confined by the protocols, and 42% admitted to at least 1 intentional deviation from them. CONCLUSION: It may not simply be assumed that the use of protocols will standardize care. This is particularly important in the case of triage, with current trends toward medical decisionmaking by less skilled providers with diminishing patient contact. Although triage protocols may be useful to guide clinical thinking, their consistency must be validated before they may be safely disseminated for general use.

Adolescent↗
PubMed1999

Ultrasonic plaque character and outcome after lower limb angioplasty.

PURPOSE: The value of ultrasonic plaque characteristics in identifying patients at "high-risk" of restenosis after percutaneous transluminal angioplasty (PTA) was studied. METHODS: Thirty-one arterial stenoses (6 common iliac, 2 external iliac, 1 profunda femoris, 21 superficial femoral, and 1 popliteal) in 17 patients who underwent angioplasty were studied by means of duplex scanning. With a computer-based program, B-mode images were digitized and normalized using 2 reference points, blood and adventitia. A grey level of 0 to 5 was allocated for the lumen (blood) and 180 to 190 for the adventitia on a linear gray scale of 0 to 255 (0 = absolutely black; 255 = absolutely white), and the overall plaque gray-scale median (GSM) of the pixels of the plaque was used as a measure of plaque echodensity. After PTA, follow-up of stenoses was done on day 1, weekly for 8 weeks, at 3 months, 6 months, and 1 year. The total plaque thickness (sum of anterior and posterior components), minimal luminal diameter (MLD), and peak systolic velocity ratio (PSVR) were measured for all stenoses. An increase of more than 2 in the PSVR was the duplex criterion used to signify restenosis. RESULTS: The GSM of the stenoses before angioplasty ranged from 6 to 71 (mean, 31.3 +/- 17.9); 17 stenoses had a GSM less than 25 (mean, 18.7 +/- 5.3), and 14 had a GSM more than 25 (mean, 46.4 +/- 15.8). When the GSM was less than 25, the absolute reduction in plaque thickness on day 1 post-PTA was 3.3 +/- 1.8 mm, in contrast to 1.8 +/- 1.6 mm when GSM was more than 25 (P <.03). The restenosis rate (PSVR more than 2) was 41% at 6 months and remained unchanged at 1 year. When the GSM was less than 25, restenosis occurred in 11% of lesions, in comparison with 78% when the GSM was more than 25 (P <.001). CONCLUSION: Plaque echodensity can be used to evaluate stenoses before PTA, to predict initial success and identify a subgroup that has a high prevalence of restenosis. The identification of a group at "high-risk" of restenosis can improve the selection of patients for the procedure and also be used in prospective studies on the prevention of restenosis.

Angioplasty, Balloon↗
PubMed1999

Expression of Delta1 and Serrate1 (Jagged1) in the mouse inner ear.

The Notch signalling pathway is thought to play a key part in controlling the production of sensory hair cells in the vertebrate inner ear via lateral inhibition; but there is disagreement as to which Notch ligands are expressed in hair cells as they develop. We show, using a mouse Delta1:LacZ knock-in as a reporter, that nascent hair cells, but not their neighbours, express Delta1. Expression of Serrate1 (Jagged1), meanwhile becomes restricted to the supporting cells of each sensory patch. Delta1 is also expressed: (a) at early stages, at the site of otic neurogenesis; and (b) in scattered cells of the endolymphatic sac, as is Serrate1.

Animals↗
PubMed1999

Inhibition of virus-induced neuronal apoptosis by Bax.

The Bax protein is widely known as a pro-apoptotic Bcl-2 family member that when overexpressed can trigger apoptosis in multiple cell types and is important for the developmental cell death of neurons. However, Bax was found here to be a potent inhibitor of neuronal cell death in mice infected with Sindbis virus. Newborn mice, which are highly susceptible to a fatal infection with neurotropic Sindbis virus, were significantly protected from neuronal apoptosis and fatal disease when infected with a recombinant Sindbis virus encoding Bax. Deletion of the N terminus of Bax, which mimics cleaved Bax, converted Bax into a pro-apoptotic factor in vivo. As mice mature during the first week after birth, they acquire resistance to a fatal Sindbis virus infection. However, Bax-deficient mice remained very sensitive to fatal disease compared with their control littermates, indicating that endogenous Bax functions as a survival factor and contributes to age-dependent resistance to Sindbis virus-induced mortality. The protective effects of Bax were reproduced in cultured hippocampal neurons but not in cultured dorsal root ganglia neurons. These findings indicate that cell-specific factors determine the anti-apoptotic versus pro-apoptotic function of Bax.

Alphavirus Infections↗
PubMed1999

Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage.

To define predictors of survival time in late human immunodeficiency virus type 1 (HIV-1) disease, long- and short-duration survivors were studied after their CD4+ T cells fell to </=50/mm3. Immune activation of CD4+ and CD8+ T cells, as measured by elevated cell surface expression of CD38 antigen, was strongly associated with shorter subsequent survival (P</=.002). The naive CD45RA+CD62L+ T cell reserve was low in all subjects and did not predict survival (P=.34 for CD4+ and.08 for CD8+ cells). Higher virus burden correlated with CD8+ but not CD4+ cell activation and, after correcting for multiple comparisons, was not associated with shorter survival (P=.02). All of the patients' viruses used CCR5, CXCR4, or both, and coreceptor usage did not predict survival (P=. 27). Through mechanisms apparently unrelated to higher virus burden, immune activation is a major determinant of survival in advanced HIV-1 disease.

ADP-ribosyl Cyclase↗
PubMed1999

Relationship of human papillomavirus to Schneiderian papillomas.

OBJECTIVES/HYPOTHESIS: To classify a large group of Schneiderian papillomas (SPs) into their histologic subtypes and to determine the incidence of human papillomavirus (HPV) in each subtype. STUDY DESIGN: Pathologic review and polymerase chain reaction-based (PCR-based) examination of archived tissue. METHODS: Slides of 114 tumors diagnosed as Schneiderian, inverting, fungiform, or cylindric cell papillomas, or any associated carcinomas, were examined by a head and neck pathologist. Using PCR, consensus primers for the L1 region of HPV were used to determine the presence of HPV in the tumors. This was also performed on normal turbinate control specimens. RESULTS: Eighty-two (78%) were the inverting subtype, 21 (20%) the fungiform subtype, and 2 (2%) the cylindric cell type. Nine tumors were diagnosed as either verrucous or squamous cell carcinoma. Eighty-eight percent of the tumors had DNA of sufficient quality to be amplified using PCR. Of these, 5 of 69 (6.8%) inverting, 17 of 17 (100%) fungiform, and 0 of 2 cylindric cell papillomas were positive for HPV. One of nine (11.1%) cancers was positive for HPV. No normal turbinate tissue contained HPV. HPV types 6b and 11 accounted for all cases of fungiform papillomas. Of the five HPV-positive inverting papillomas, three had HPV type 11 and two had HPV type 16. The single carcinoma containing HPV contained HPV type 18. CONCLUSIONS: The histologic subtype of SPs is important, as their etiologies appear to be different. HPV 6b and 11 appear to be involved in all cases of fungiform papillomas but are only rarely involved in cases of inverting or cylindric cell papillomas. HPV 16 may rarely play a role in cases of inverting papillomas, and HPV 16 and 18 may be involved in a subset of cases of carcinomas originating in an inverting papilloma.

DNA, Neoplasm↗
PubMed1999

Dosing and delivery of a recombinant surfactant in lung-injured adult sheep.

The purpose of this study was to evaluate a surfactant based on a recombinant surfactant protein-C (rSP-C) at three different doses (25, 100, and 200 mg lipid/kg) in the saline lavage adult sheep model of acute lung injury. All three doses resulted in significant improvements in gas exchange, although the 100 and 200 mg/kg doses were superior to the 25 mg/kg dose. There were no significant differences in effect of the 100 and 200 mg/kg doses. In addition, the physiologic efficacy and lobar surfactant distribution patterns were similar when two different surfactant delivery methods were compared. This comparison involved administering the surfactant directly into each lobe under bronchoscopic guidance, versus instilling the surfactant through an endotracheal tube into the lungs. However, the former technique took significantly longer to perform (24.5 +/- 3.3 min versus 11.6 +/- 2.5 min, p < 0.05) and required a skilled bronchoscopist. In conclusion, rSP-C surfactant was effective in improving gas exchange in this model of lung injury, although higher doses were required for optimal responses. The bronchoscopic administration technique produced results similar to those of the tracheal instillation method, but had some disadvantages that may limit the widespread clinical use of this technique in patients with lung injury.

Animals↗
PubMed1999

Status passages: the experience of HIV-positive gay men.

Data obtained in in-depth interviews with 25 HIV-positive gay men are used to expand upon the literature on status passages, specifically the processes involved in accommodating to HIV and the associated socially stigmatized identity. Experiences reported by respondents suggested that Persons living with HIV and AIDS (PHAs) may experience several status transitions as part of their HIV career, each with its own corresponding turning points and benchmarks. For the men interviewed, the processes involved in accommodating to HIV in many ways parallelled that of adapting to other stigmatized statuses, especially those related to chronic illness. Receiving an HIV-positive diagnosis can force an individual into an involuntary, irreversible and undesirable status passage. It can also lead to numerous role exits, besides that of HIV negative. Part of the status transitions experienced by the PHAs in this study involved accommodating to illness and alterations in identity. In an effort to reconstruct identity, most of the men interviewed tended to seek out similar others for information, support and affirmation. Efforts to become part of the PHA community were explained as an attempt to end personal isolation and fight the stigma associated with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Experience of menopausal symptoms by Chinese and Canadian women.

OBJECTIVE: This study examines the differences in frequency and distress caused by menopausal symptoms experienced by Canadian and Chinese women. DESIGN: Cross-sectional surveys were conducted in Canada and China. SETTING: The Canadian studies were conducted in Toronto. The Chinese data were collected in Guangzhou City. PARTICIPANTS: Women, 47-62 years old, 2-7 years after a natural menopause, were recruited. METHODS: Two hundred and eighty-two Canadians were recruited for two menopause studies. Data from 297 Chinese were obtained through a household survey. From a 105-item symptom questionnaire, women indicated the frequency and distress caused by symptoms in the previous month. MAIN OUTCOME MEASURES: Frequency and mean distress score of problems were ranked and compared. Using the importance score method, a Chinese questionnaire was constructed and compared with the Menopause-Specific Quality of Life questionnaire. RESULTS: The frequency of symptoms and distress experienced by Canadian and Chinese women differed markedly. Fourteen of the 29 items differed between the Chinese questionnaire and the Menopause-Specific Quality of Life questionnaire. CONCLUSIONS: There are striking differences between Chinese and Canadian women in the frequency and distress caused by menopausal symptoms. The Canadian questionnaire may not be relevant for Chinese women.

Affect↗
PubMed1998

Vertebrate segmentation: the clock is linked to Notch signalling.

The periodic formation of somites during vertebrate segmentation has been suggested to involve a molecular 'segmentation clock'. Recent observations of cyclic Lunatic fringe expression in chick and mouse embryos link the segmentation clock to Delta-Notch signalling.

Animals↗
PubMed1998

Catalytic mechanism of Kdo8P synthase: transient kinetic studies and evaluation of a putative reaction intermediate.

The mechanistic pathway for the reaction catalyzed by Kdo8P synthase has been investigated, and the cyclic bisphosphate 2 has been examined as a putative reaction intermediate. Two parallel approaches were used: (1) chemical synthesis of 2 and evaluation as an alternate substrate for the enzyme and (2) transient kinetic studies using rapid chemical quench methodology to provide direct observation and characterization of putative intermediate(s) during enzyme catalysis. The putative cyclic bisphosphate intermediate 2, possessing the stereochemistry of the beta-pyranose form, was synthesized and evaluated as a substrate and as an inhibitor of Kdo8P synthase. The substrate activity was examined by monitoring the release of anomeric phosphate over time using proton-decoupled 31P NMR spectroscopy. A very similar time course for the formation of inorganic phosphate was found in each experiment and the corresponding control experiment; i.e., no enzyme-catalyzed acceleration in the anomeric phosphate hydrolysis was detected. It was found however that 2 binds to the enzyme and is a competitive inhibitor with respect to phosphoenolpyruvate binding, having a Ki value of 35 microM. In a parallel study, we have performed single-turnover rapid chemical quench experiments to examine both the forward and reverse directions to identify a putative enzyme intermediate(s). Our results clearly demonstrate that the cyclic bisphosphate intermediate 2 does not accumulate under single-enzyme turnover conditions. This observation, coupled with the results obtained through the evaluation of synthetic 2 as a substrate, strongly suggests that the Kdo8P synthase catalytic pathway does not involve the formation of 2 as a reaction intermediate. Taken together, these combined results support the original hypothesis [Hedstrom, L., and Abeles, R. H. (1988) Biochem. Biophys. Res. Commun. 157, 816-820], which suggests a reaction pathway involving an acyclic bisphosphate intermediate 1.

Aldehyde-Lyases↗
PubMed1998

Untangling the effects of hunger, anxiety, and nausea on energy intake during intravenous cholecystokinin octapeptide (CCK-8) infusion.

Infusions of cholecystokinin (CCK) may exert their effects on appetite by inducing feelings of nausea or anxiety. In this double blind, placebo controlled crossover study, the impact of these effects on appetite were examined. Fifteen male subjects received a 20 min i.v. infusion of cholecystokinin octapeptide (CCK-8) (4 ng/kg/min) or saline. The infusion commenced 20 min after a soup preload and 10 min before an ad libitum test meal. Visual analogue scales of appetite and mood were measured over 3 h, and subjects were instructed to report any other sensations they experienced over this time. CCK-8 significantly reduced premeal hunger, elevated premeal anxiety, and reduced energy intake at the ad libitum test meal. Meal duration and rate of eating (kcal/min) were also significantly reduced after CCK-8. After the smaller meal with CCK-8, hunger rose quickly to a higher level than with placebo. The return of hunger was commensurate with the smaller amount of energy consumed and indicated that CCK did not exert an enduring effect on hunger suppression. A significant correlation was found between the reduction in energy intake and hunger (r = 0.75 p < 0.01), but not with anxiety (r = 0.15 not significant). Analyses were performed separately on subjects who did (n = 8), or did not (n = 7) report gastrointestinal disturbance. Energy intake was reduced by 56.6% and 44.6%, respectively. These results indicate that, although feelings of anxiety and nausea may accompany CCK infusions, they are not necessary for the effects of CCK on appetite. These data provide support for a role of CCK in satiety.

Adolescent↗