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Biomedical subjects

K Crawford

Publications and source records attributed to K Crawford.

At least 37 records · Page 2Linked to original sources
PubMed1999

Risk factors accelerating cerebral degenerative changes, cognitive decline and dementia.

OBJECTIVES: Factors accelerating cerebral degenerative changes represent potentially modifiable risks for cognitive decline. Putative risk factors accelerating subtle cognitive decline and dementia were correlated with repeated measures of cerebral atrophy, CT densitometry, perfusions and cognitive testing among neurologically and cognitively normative ageing volunteers. METHODS: Two hundred and twenty-four normative subjects at increased risk for cognitive decline were admitted to the study. Mean entry age was 59. 5+/-15.8 years. Mean follow-up is 4.3+/-3.1 years. At follow-up, 22 developed subtle cognitive decline (deltaCCSE>/=-3), 19 became demented, eight with vascular type (VAD) and 11 with Alzheimer's type (DAT) and 183 remain cognitively unchanged. Standardized questionnaires, medical, neuropsychological, neurological and blood work examinations were obtained. Cerebral atrophy, tissue densities and perfusions were measured by xenon-enhanced CT. RESULTS: After age 60, cerebral atrophy, ventricular enlargement, polio- and leuko-araiosis geometrically increased as perfusions declined. Risk factors accelerating perfusional decline, cerebral atrophy, polio-araiosis and leuko-araiosis (thinning of grey-white matter densities) were: transient ischaemic attacks (TIAs), hypertension, smoking, hyperlipidemia, male gender. At age 71.5+/-11.9, subtle cognitive decline began, accelerated by TIAs, hypertension and heart disease. Leuko-araiosis began before cognitive decline. TIAs, hypertension and hyperlipidemia correlated with VAD. Excessive cortical perfusional decreases and cerebral atrophy correlated with cognitive decline. Family history of neurodegenerative disease correlated with DAT. CONCLUSION: TIAs, hypertension, hyperlipidemia, smoking and male gender accelerate cerebral degenerative changes, cognitive decline and dementia.

Adult↗
PubMed1998

Retinoic acid and thyroid hormone may function through similar and competitive pathways in regenerating axolotls.

The objective of this study was to determine whether thyroid hormone (TH) would interfere with retinoic acid (RA), which proximalizes axolotl larvae regenerate limb pattern. RA and TH are ligands for members of the steroid hormone thyroid hormone nuclear binding protein superfamily which form functional homodimers, but may also form stable heterodimers with the RXR protein and may recognize identical DNA sequences. TH alone does not affect limb pattern but induces metamorphosis in regenerating animals. Coinjected animals do not metamorphose, and when compared to RA controls regenerate more proximal and in some cases anteroposterior (AP) and dorsoventral (DV) duplicate limb structures. In addition, the tissues that are normally lost or changed during metamorphosis appear to be sensitized resulting in the formation of (1) new dorsal gill lamellae accompanied by bifurcation and broadening of the original gill lamellae, (2) partial resorption of the tail fin, and (3) changes in eye position and snout morphology. Bifurcation of gill lamellae tips, but not the formation of supernumerary gills, is also observed in animals treated with RA alone. These results indicate that the molecular mechanism of RA and TH function through similar and perhaps competitive pathways.

Ambystoma↗
PubMed1998

In vitro strength comparison of hydroxyapatite cement and polymethylmethacrylate in subchondral defects in caprine femora.

Hydroxyapatite cement was investigated in situ for the reconstruction of juxta-articular defects. Polymethylmethacrylate is currently the most commonly used material for the reconstruction of bone defects following the exteriorization and curettage of aggressive benign tumors. In vitro, we compared the effects of hydroxyapatite cement and polymethylmethacrylate in restoring the stiffness of the subchondral plate in a caprine femoral defect model. Ten matched pairs of caprine femora underwent nondestructive compression testing normal to the load-bearing surface. A standardized subchondral defect 12 mm in diameter was created in the medial femoral condyle. Compression testing was repeated to determine the reduction in stiffness caused by the defect. Each femur from each pair was randomly assigned to one of two groups (n=9), and the defects were augmented with either polymethylmethacrylate or hydroxyapatite cement. After 12 hours, compression testing was repeated to determine the subchondral stiffness after augmentation. Compared with intact femora, the defect specimens that were later treated with either polymethylmethacrylate or hydroxyapatite cement exhibited stiffness values of 70 (386+/-107 N/mm) and 59% (343+/-94 N/mm) respectively, which represented a significant reduction in stiffness (p=0.05). Augmentation with polymethylmethacrylate or hydroxyapatite cement restored stiffness by 81 (450+/-111 N/mm) and 71% (413+/-115 N/mm), respectively, of the values of intact specimens. Hydroxyapatite cement restored stiffness significantly (p=0.05) over the stiffness of the nonaugmented defect compared with the stiffness after augmentation with polymethylmethacrylate (p=0.12). Neither polymethylmethacrylate nor hydroxyapatite cement restored stiffness to that of intact femora (p=0.05). In the current detect model, hydroxyapatite cement was comparable with polymethylmethacrylate in restoring subchondral stiffness. Unlike polymethylmethacrylate, however, hydroxyapatite cement has the following advantages: it is osteoconductive, is replaced by host bone, and avoids the potential for thermal necrosis. Hydroxyapatite cement may therefore provide a viable alternative to polymethylmethacrylate for augmentation of juxta-articular and other bone defects.

Animals↗
PubMed1998

Racial/ethnic disparities in admissions to public and private psychiatric inpatient settings: the effect of managed care.

This study investigates the effect of managed care on access patterns among people of color who are severely and persistently mentally ill. The distribution of admissions to public and private psychiatric hospitals was compared for African-American, Asian, Latino, and white case managed clients of the Massachusetts Department of Mental Health before and after implementation of Medicaid managed mental health care in October 1997. Managed care appears to have increased access to private services across all racial and ethnic groups, although admissions of non-white patients were still more likely to take place in publicly operated settings. These data suggest that equalizing access to putatively better inpatient treatment settings may be an externality of managed care.

Adult↗
PubMed1997

Rescue of cardiac alpha-actin-deficient mice by enteric smooth muscle gamma-actin.

The muscle actins in higher vertebrates display highly conserved amino acid sequences, yet they show distinct expression patterns. Thus, cardiac alpha-actin, skeletal alpha-actin, vascular smooth muscle alpha-actin, and enteric smooth muscle gamma-actin comprise the major actins in their respective tissues. To assess the functional and developmental significance of cardiac alpha-actin, the murine (129/SvJ) cardiac alpha-actin gene was disrupted by homologous recombination. The majority ( approximately 56%) of the mice lacking cardiac alpha-actin do not survive to term, and the remainder generally die within 2 weeks of birth. Increased expression of vascular smooth muscle and skeletal alpha-actins is observed in the hearts of newborn homozygous mutants and also heterozygotes but apparently is insufficient to maintain myofibrillar integrity in the homozygous mutants. Mice lacking cardiac alpha-actin can be rescued to adulthood by the ectopic expression of enteric smooth muscle gamma-actin using the cardiac alpha-myosin heavy chain promoter. However, the hearts of such rescued cardiac alpha-actin-deficient mice are extremely hypodynamic, considerably enlarged, and hypertrophied. Furthermore, the transgenically expressed enteric smooth muscle gamma-actin reduces cardiac contractility in wild-type and heterozygous mice. These results demonstrate that alterations in actin composition in the fetal and adult heart are associated with severe structural and functional perturbations.

Actins↗
PubMed1996

Reproducibility in the measurement of atlanto-occipital instability in children with Down syndrome.

STUDY DESIGN: This study compared the reproducibility of three techniques used to measure translation between the occiput and C1 in children with Down syndrome. OBJECTIVES: Intraobserver and interobserver variability were computed to determine if there is a reliable way to measure occiput-C1 instability. SUMMARY OF BACKGROUND DATA: No studies have been performed comparing measurement techniques in children with Dow syndrome. METHODS: Powers ratios, basion-axial intervals, and translational anteroposterior motion as described by Wiesel and Rothman were calculated for 50 pairs of flexion-extension lateral cervical radiographs from children with Down syndrome. Calculations were made on two occasions by four reviewers. RESULTS: Mean differences between measurements for two observers were 0.14 for the Powers ratio, 1.3 mm for the Wiesel technique, and 1.8 mm for the basion-axial interval. The 95th percentiles of the differences between measurements for two observers were 0.38 for Powers ratios, 3.5 mm for the Wiesel technique, and 5.3 mm for the basion-axial interval. CONCLUSIONS: Measurement of atlanto-occipital translation by any of these methods is not reproducible. Although the technique by Wiesel and Rothman is the easiest to apply, confirmation of instability with magnetic resonance imaging should guide management.

Adolescent↗
PubMed1995

Dominant mutants identify new roles for p34cdc2 in mitosis.

A large number of dominant mutants have been generated in the fission yeast cdc2 gene, causing lethality when expressed in wild-type cells. The mutants interfere with distinct aspects of p34cdc2 function, producing one of four different phenotypes: mitotic arrest, multiple rounds of S phase in the absence of mitosis, premature mitosis or G2 arrest. The mitotic mutants DL41, DL45 and DL50 are characterized in this paper. Over-expression of DL41 or DL45 causes mitotic arrest, specifically interfering with sister chromatid separation, without preventing spindle elongation. This suggests a role for p34cdc2 in triggering sister chromatid separation at anaphase. DL41 and DL45 also cause abnormal septum formation, suggesting that p34cdc2 may also be involved in regulating this process in fission yeast. These mitotic aspects of p34cdc2 function may involve interaction with p13suc1, since increased expression of suc1 partially suppresses DL41 and DL45. Over-expression of DL50 causes premature mitotic entry in cells that have not completed S phase, resulting in lethality. DL41, DL45 and DL50 correspond to mutation of p34cdc2 residues predicted to be on the surface of the protein, identifying potential sites of interaction with mitotic regulators of p3cdc2, and these residues are conserved amongst cdc2 proteins found in other eukaryotes.

CDC2 Protein Kinase↗
PubMed1995

Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant.

Hepatitis C virus (HCV) establishes a persistent infection in humans and chimpanzees despite the presence of virus-specific, class I major histocompatibility complex-restricted CD8+ cytotoxic T lymphocytes (CTLs) in the liver. The data presented here demonstrate that CTLs directed against a conserved epitope in the HCV nonstructural 3 protein persist in the liver of a chronically infected chimpanzee for at least 2 years after infection. However, these CTLs did not recognize the HCV quasi-species present in the plasma of this animal at week 16 postinfection or at later time points. Escape from the CTL response was facilitated by an aspartic acid to glutamic acid (D-->E) substitution at amino acid position 1449 in all HCV genomes that were sequenced. The results of this study strongly support the concept that CTL responses can select for variant viruses with an enhanced ability to persist in a host and have important implications for the design of vaccines against HCV.

Amino Acid Sequence↗
PubMed1995

Tissue-nonspecific alkaline phosphatase participates in the establishment and growth of feather germs in embryonic chick skin cultures.

Alkaline phosphatase activity is present in the mesoderm of embryonic chick skin and becomes spatially restricted to the dermal condensation of the developing feather germs. Inhibitors to tissue-nonspecific (liver/bone/kidney), but not intestinal alkaline phosphatase inhibit the establishment and growth of feather germs in cultured skins. A window of maximum sensitivity to the inhibitor was observed to be the first day of culture when early development and establishment of pattern takes place. The cDNA for the avian tissue-nonspecific alkaline phosphatase was cloned and sequenced, and Southern analysis revealed a single copy of this gene in the avian genome. Northern analysis revealed that a 2.8 kb transcript for this form of alkaline phosphatase is present in developing skin.

Alkaline Phosphatase↗
PubMed1995

Evaluation of fluid absorption during laser prostatectomy by breath ethanol techniques.

PURPOSE: Laser prostatectomy has evolved as a less invasive method of relieving bladder outlet obstruction due to prostatic enlargement. The elimination of adenomatous tissue by laser induced coagulation necrosis theoretically avoids the sequelae of fluid absorption noted during traditional transurethral resection of the prostate. However, to our knowledge no accurate determination of fluid absorption during laser prostatectomy has been performed to date. MATERIALS AND METHODS: A technique previously described to determine the amount of irrigant absorbed during transurethral resection of the prostate measures breath ethanol levels using a standard alcohol breath analyzer during the procedure after a predetermined amount of ethanol is added to the irrigant fluid. This method was used in 4 men undergoing laser prostatectomy. RESULTS: All 4 subjects had ethanol levels of 0 throughout the operation, indicating that little or no irrigant fluid was absorbed. CONCLUSIONS: We demonstrated in a quantitative manner that fluid absorption during laser prostatectomy is almost nil and patients are, indeed, at no risk for the transurethral resection syndrome.

Absorption↗
PubMed1995

Association of cytotoxic T lymphocyte (CTL) escape mutations with persistent hepatitis C virus (HCV) infection.

Mechanisms by which HCV evades the cellular immune response in persistently infected humans and chimpanzees are poorly defined, but could involve mutations in epitopes recognized by class I MHC restricted CTLs. To investigate this possibility, we identified an epitope in the NS3 protein of HCV that was recognized by intrahepatic CTLs from a chimpanzee that developed persistent HCV infection after experimental challenge with the virus. Fine mapping studies with truncated synthetic peptides revealed that the epitope was 9 amino acids in length, encompassing residues 1445 to 1454 (GDFDSVIDC) of NS3. This sequence was completely conserved in all full-length NS3 genomes described to date. In view of the fact that the major genotypes of HCV may differ by up to -30% in overall amino acid homology, it appears in contrast that this epitope is highly conserved. The role of CTL escape mutations in HCV persistence was assessed in the virus inoculum used to infect this chimpanzee and in post-inoculation plasma samples. Sequencing of 6-10 M13 clones containing a 232-nucleotide fragment amplified with NS3-specific primers revealed that the epitope in the challenge inoculum and a post-inoculum plasma sample obtained at week 4 were identical to the published sequence of HCV-I. In contrast, all molecular clones sequenced from week 16, 25 and 28 plasma samples contained a single Asp--> Glu (D-->E) amino acid substitution at residue 1449. Significantly, four independently derived CTL clones established from the liver of this chimpanzee at various times up to two years after infection recognized target cells pulsed with a nonameric peptide representing the wild-type HCV-I sequence, but not those pulsed with a peptide containing the D-->E mutation. These data suggest that CTL escape mutations may play a role in viral persistence.

Amino Acid Sequence↗
PubMed1994

Essential role of vif in establishing productive HIV-1 infection in peripheral blood T lymphocytes and monocyte/macrophages.

The role of vif during the establishment of human immunodeficiency virus type 1 (HIV-1) infection of peripheral blood T lymphocytes and monocyte/macrophages was investigated using vif mutants of three HIV-1 proviral DNAs. Vif was found to be essential for the establishment of productive HIV-1 infection in peripheral blood T lymphocytes after cell-free infection with HXB2 and DFCI-HD, a vpr-positive, vpu-positive, nef-positive derivative of HXB2. A chimeric HIV-1 provirus in which the T-cell line-tropic env sequences in DFCI-HD were replaced with the macrophagetropic env of the ADA strain was constructed for studies on the role of vif during the establishment of HIV-1 infection in primary monocyte/macrophages. These studies showed that vif is also essential for the initiation of productive HIV-1 infection in primary monocyte/macrophage cultures after cell-free virus transmission. The DFCI-HD-ADA virus was shown to replicate in the CD4+ T-cell line Molt 4 clone 8 but not in other T-cell or monocytic cell lines, as previously shown for another macrophagetropic strain YU-2 (1), suggesting that this cell line may be useful for future studies on at least some macrophagetropic strains of HIV-1. The finding that vif is essential for the establishment of productive HIV-1 infection in primary T lymphocytes and monocyte/macrophages suggests that vif may be required for HIV-1 transmission and disease pathogenesis during natural infections and thus may be a good target for prophylactic or therapeutic intervention.

Cell Line↗
PubMed1993

The hepatitis C virus encodes a serine protease involved in processing of the putative nonstructural proteins from the viral polyprotein precursor.

The hepatitis C virus (HCV) nonstructural protein 3 (NS3) domain has been predicted from sequence comparisons to represent a trypsin-like serine protease. By expressing wild-type and mutant HCV-1 cDNAs in transfected mammalian cells, we have identified putative nonstructural proteins 3 (72 kDa), 4 (10 kDa and 27 kDa) and 5 (58 kDa) and have shown that their processing from the viral polyprotein precursor is dependent on Ser1165 located in the proposed protease catalytic site. Data obtained from in vitro RNA translations indicate that unlike the processing of the NS2/NS3 junction, NS3/NS4 processing is dependent on Ser1165. In contrast to the situation for the related flaviviral NS3 proteases, the HCV NS3-mediated cleavage of the NS3/NS4 junction does not require the upstream NS2 domain and may not occur at dibasic sites.

Animals↗
PubMed1993

Dietary restriction of adult male rhesus monkeys: design, methodology, and preliminary findings from the first year of study.

Dietary restriction (DR) retards aging processes and extends maximum life span in rodents and in simpler animals. We initiated a study in 30 adults (8-14 years old) male rhesus monkeys to determine whether or not aging processes are retarded by adult-onset DR in a primate species and herein report results from the experiment's first year. Following a 3-6 month period when baseline data were obtained, 15 animals were assigned to a control group and given free access to a semipurified diet for 6-8 hours per day. The other 15 monkeys were fed the same diet but at 70% of their baseline intake levels predetermined individually. The animals are being evaluated semi-annually for body size and composition, physical activity, metabolic rate, glucose tolerance and insulin sensitivity, hematologic indices, immunologic function, and fingernail growth. Ocular function is assessed annually. The preliminary observations after one year are: (a) all monkeys appear to be in excellent health; (b) average body weights for controls increased by 9% while monkeys on DR did not gain weight; (c) monkeys on DR have less body fat than do control monkeys, whereas the amount of lean body mass has not been significantly influenced by DR; (d) there was a small but statistically significant reduction in physical activity for monkeys on DR relative to controls; and (e) DR has not overtly influenced the other measures. Control monkeys gradually reduced their voluntary levels of food intake during the first year of study, and food allotments to DR monkeys are being adjusted accordingly in order to reinstate the intended 30% difference between groups. These early data indicate that DR can be safely instituted in adult monkeys, but that longer term and/or more severe DR is required to determine if it is capable of influencing age-sensitive indices in long-lived primates.

Accommodation, Ocular↗
PubMed1993

A unique, predominant hepatitis C virus variant found in an infant born to a mother with multiple variants.

To demonstrate vertical transmission of hepatitis C virus (HCV) from an HCV-infected, non-human immunodeficiency virus type 1-infected mother to her infant and to assess the distribution of viral species in the mother and infant, the hypervariable region of the gene encoding the putative envelope glycoprotein E2 (E2HV) was sequenced in three mothers and one mother-infant pair. The data indicate that (i) quasi-species distributions of HCV E2HV variants were found in all four mothers, (ii) a single predominant HCV E2HV variant was found in the infant of a mother shown to have nine predominant E2HV variants, and (iii) the infant's E2HV variant was highly related to, but not identical with, the nine variants identified in the mother at the time of birth. These findings indicate that HCV is transmitted from mother to infant and raise the possibility that the transmission occurs in utero.

Amino Acid Sequence↗
PubMed1992

Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: potential role in chronic HCV infections.

E2/nonstructural protein 1, the putative envelope glycoprotein (gp72) of HCV, possesses an N-terminal hypervariable (E2 HV) domain from amino acids 384 to 414 of unknown significance. The high degree of amino acid sequence variation in the E2 HV domain appears to be comparable to that observed in the human immunodeficiency virus type 1 gp120 V3 domain. This observation and the observation that the HCV E2 HV domain lacks conserved secondary structure imply that, like the V3 loop of human immunodeficiency virus 1 gp120, the N-terminal E2 region may encode protective epitopes that are subject to immune selection. Antibody-epitope binding studies revealed five isolate-specific linear epitopes located in the E2 HV region. These results suggest that the E2 HV domain is a target for the human immune response and that, in addition to the three major groups of HCV, defined by nucleotide and amino acid sequence identity among HCV isolates, E2 HV-specific subgroups also exist. Analysis of the partial or complete E2 sequences of two individuals indicated that E2 HV variants can either coexist simultaneously in a single individual or that a particular variant may predominate during different episodes of disease. In the latter situation, we found one individual who developed antibodies to a subregion of the E2 HV domain (amino acids 396-407) specific to a variant that was predominant during one major episode of hepatitis but who lacked detectable antibodies to the corresponding region of a second variant that was predominant during a later episode of disease. The data suggest that the variability in the E2 HV domain may result from immune selection. The findings of this report could impact vaccine strategies and drug therapy programs designed to control and eliminate HCV.

Amino Acid Sequence↗