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Biomedical subjects

S A Carter

Publications and source records attributed to S A Carter.

At least 19 recordsLinked to original sources
PubMed2001

The value of toe pulse waves in determination of risks for limb amputation and death in patients with peripheral arterial disease and skin ulcers or gangrene.

OBJECTIVES: The purpose of this study was to determine whether the presence of low amplitude of pulse waves recorded from the toes is related to the risk of subsequent amputation and death in patients with skin ulcers or gangrene and peripheral arterial disease, and how the risk of low wave amplitude relates to the risk associated with low peripheral pressures. METHODS: A total of 309 patients with 346 limbs with skin lesions and arterial disease referred to the vascular laboratory were followed up for an average of 5 years (range, 1-8 years). Measurements were carried out to obtain ankle and toe pressures, pressure indices, and toe pulse wave amplitude. These variables were related to the risks of major amputation and total and cardiovascular death by means of the Cox proportional hazards model. RESULTS: Low toe pulse wave amplitude (< or = 4 mm) was associated with increased risk of amputation (relative risks 4.20 in all limbs and 2.63 in those with toe pressure < or = 30 mm Hg; P <.01). Wave amplitude remained significantly associated with increased risk of amputation after controlling for each pressure variable (P <.01). Low pulse wave amplitude and toe/brachial index were associated with increased risks of both total and cardiovascular death in all patients (relative risks ranged from 1.43-1.73; P <.05) and in those with toe pressure of 30 mm Hg or less (relative risks 1.56-1.90; P <.05). CONCLUSIONS: Low toe pulse wave amplitude is related significantly to increased risks of amputation and death in patients with skin lesions and arterial disease. The presence of low wave amplitude provides significant information in addition to peripheral pressures with respect to the risk of amputation.

Aged↗
PubMed2000

Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean.

Uncoupling protein-3 (UCP-3) is a recently identified member of the mitochondrial transporter superfamily that is expressed predominantly in skeletal muscle. However, its close relative UCP-1 is expressed exclusively in brown adipose tissue, a tissue whose main function is fat combustion and thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy balance and lipid metabolism. However, direct evidence for these roles is lacking. Here we describe the creation of transgenic mice that overexpress human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a striking reduction in adipose tissue mass. The mice also exhibit lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. This provides evidence that skeletal muscle UCP-3 has the potential to influence metabolic rate and glucose homeostasis in the whole animal.

Adipose Tissue↗
PubMed2000

Vascular invasion routes and systemic accumulation patterns of tobacco mosaic virus in Nicotiana benthamiana.

Plant viruses must enter the host vascular system in order to invade the young growing parts of the plant rapidly. Functional entry sites into the leaf vascular system for rapid systemic infection have not been determined for any plant/virus system. Tobacco mosaic virus (TMV) entry into minor, major and transport veins from non-vascular cells of Nicotiana benthamiana in source tissue and its exit from veins in sink tissue was studied using a modified virus expressing green fluorescent protein (GFP). Using a surgical procedure that isolated specific leaf and stem tissues from complicating vascular tissues, we determined that TMV could enter minor, major or transport veins directly from non-vascular cells to produce a systemic infection. TMV first accumulated in abaxial or external phloem-associated cells in major veins and petioles of the inoculated leaf and stems below the inoculated leaf. It also initially accumulated exclusively in internal or adaxial phloem-associated cells in stems above the inoculated leaf and petioles or major veins of sink leaves. This work shows the functional equivalence of vein classes in source leaves for entry of TMV, and the lack of equivalence of vein classes in sink leaves for exit of TMV. Thus, the specialization of major veins for transport rather than loading of photoassimilates in source tissue does not preclude virus entry. During transport, the virus initially accumulates in specific vascular-associated cells, indicating that virus accumulation in this tissue is highly regulated. These findings have important implications for studies on the identification of symplasmic domains and host macromolecule vascular transport.

Plants, Toxic↗
PubMed2000

Skin perfusion pressure of the foot is a good substitute for toe pressure in the assessment of limb ischemia.

PURPOSE: Noninvasive measurements of limb systolic pressures are used routinely in the assessment of the severity of peripheral arterial disease, including the evaluation for critical limb ischemia. However, ankle pressures cannot be measured reliably in patients with medial calcification, which is especially common among patients with diabetes. Skin lesions on the toes or previous digital amputations may preclude the measurement of toe pressures. Measurements of skin perfusion pressure (SPP) are not subject to such limitations and were shown to be useful in the assessment of the severity of peripheral arterial disease. Because toe pressure is often used in the evaluation of severity of arterial disease and in the assessment for critical ischemia, we undertook to study whether there is a sufficient correlation between toe pressure and foot SPP that would allow the use of SPP measurements when toe pressures cannot be measured. METHODS: Measurements were carried out in 85 limbs of 71 patients referred to the vascular laboratory for evaluation for peripheral arterial disease. Diabetes mellitus was present in 43 patients. Each patient had foot SPP and toe pressure measurements. Toe pressures measured with photoplethysmography were correlated with foot SPP measured with laser Doppler scanning. RESULTS: There was a strong linear correlation between SPP and toe pressure (r = 0.87; P <.01). Also, significant correlation was found in both the patients with diabetes and the patients without diabetes (r = 0.85 and 0.93, respectively; P <.01 in both cases). CONCLUSIONS: We concluded that SPP measured in the foot correlates well with toe pressure and can be substituted for toe pressure measurement in patients in whom toe pressures cannot be measured.

Adult↗
PubMed1999

Monitoring the assembly of Ig light-chain amyloid fibrils by atomic force microscopy.

Aggregation of Ig light chains to form amyloid fibrils is a characteristic feature of light-chain amyloidosis, a light-chain deposition disease. A recombinant variable domain of the light chain SMA was used to form amyloid fibrils in vitro. Fibril formation was monitored by atomic force microscopy imaging. Single filaments 2.4 nm in diameter were predominant at early times; protofibrils 4.0 nm in diameter were predominant at intermediate times; type I and type II fibrils 8.0 nm and 6.0 nm in diameter, respectively, were predominant at the endpoints. The increase in number of fibrils correlated with increased binding of the fluorescent dye thioflavin T. The fibrils and protofibrils showed a braided structure, suggesting that their formation involves the winding of protofibrils and filaments, respectively. These observations support a model in which two filaments combine to form a protofibril, two protofibrils intertwine to form a type I fibril, and three filaments form a type II fibril.

Amyloid↗
PubMed1999

ATP2A2 mutations in Darier's disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class.

Darier's disease (DD) is an autosomal dominant skin disorder characterized clinically by multiple keratotic papules, and histologically by focal loss of adhesion between epidermal cells (acantholysis) and by abnormal keratinization. Variant forms of cutaneous phenotype, sometimes familial, have been described. Associated neuropsychiatric features, including mental handicap, schizophrenia, bipolar disorder and epilepsy, have also been reported. The cause of DD was shown recently to be mutation in the ATP2A2 gene at 12q24.1, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2 (SERCA2). Here, we show that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epidermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identified 40 different patient-specific mutations in 47 families. The majority (23/40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associated significantly with atypical clinical features. The clearest association was with the familial haemorrhagic variant where all four families tested had a missense mutation. Three of the families (one Scottish family and two unrelated Italian families) exhibited the same N767S substitution in the M5 transmembrane domain, and a fourth family, from Sweden, had a C268F substitution in the M3 transmembrane domain. Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic, but inconsistent, effect of defective ATP2A2 expression.

Calcium-Transporting ATPases↗
PubMed1998

Refined genetic mapping of the darier locus to a <1-cM region of chromosome 12q24.1, and construction of a complete, high-resolution P1 artificial chromosome/bacterial artificial chromosome contig of the critical region.

Darier disease (DD) (MIM 124200) is an autosomal dominant skin disorder characterized by loss of adhesion between epidermal cells and by abnormal keratinization. We present linkage analysis showing, in four families, key recombination events that refine the location of the DD locus on chromosome 12q23-24.1 to a region of <1 cM. We have constructed a YAC/P1 artificial chromosome (PAC)/bacterial artificial chromosome (BAC)-based physical map that encompasses this refined DD region. The map consists of 35 YAC, 69 PAC, 16 BAC, and 2 cosmid clones that were ordered by mapping 54 anonymous sequence-tagged sites. The critical region is estimated to be 2.4 Mb in size, with an average marker resolution of 37.5 kb. The refinement of the critical interval excludes the ALDH2, RPL6, PTPN11, and OAS genes, as well as seven expressed sequence tags (ESTs) previously mapped in the DD region. The three known genes (ATP2A2, PPP1CC, and SCA2) and the 10 ESTs mapped within the critical region are not obvious candidates for the DD gene. Therefore, this detailed integrated physical, genetic, and partial transcript map provides an important resource for the isolation of the DD gene and, possibly, other disease genes.

Chromosome Mapping↗
PubMed1997

The challenge and importance of defining critical limb ischemia.

Patients with critical limb ischemia are at risk of limb loss and have very high cardiovascular and total mortality rates, which are greater than can be accounted for by the usual risk factors for atherosclerosis. A definition of critical ischemia is necessary to determine the natural history of the disease and to assess and compare the efficacy of various forms of therapy. The definition needs to be based on hemodynamic criteria because clinical manifestations and outcomes are not reliable. The reasons for the difficulties in arriving at a generally acceptable definition are explored. Building on the previous work of others, modified hemodynamic definitions for critical and subcritical ischemia, which include measurements of pressures and of indices of microcirculation, are proposed.

Blood Pressure↗
PubMed1996

Invasion of minor veins of tobacco leaves inoculated with tobacco mosaic virus mutants defective in phloem-dependent movement.

To fully understand vascular transport of plant viruses, the viral and host proteins, their structures and functions, and the specific vascular cells in which these factors function must be determined. We report here on the ability of various cDNA-derived coat protein (CP) mutants of tobacco mosaic virus (TMV) to invade vascular cells in minor veins of Nicotiana tabacum L. cv. Xanthi nn. The mutant viruses we studied, TMV CP-O, U1mCP15-17, and SNC015, respectively, encode a CP from a different tobamovirus (i.e., from odontoglossum ringspot virus) resulting in the formation of non-native capsids, a mutant CP that accumulates in aggregates but does not encapsidate the viral RNA, or no CP. TMV CP-O is impaired in phloem-dependent movement, whereas U1mCP15-17 and SNC015 do not accumulate by phloem-dependent movement. In developmentally-defined studies using immunocytochemical analyses we determined that all of these mutants invaded vascular parenchyma cells within minor veins in inoculated leaves. In addition, we determined that the CPs of TMV CP-O and U1mCP15-17 were present in companion (C) cells of minor veins in inoculated leaves, although more rarely than CP of wild-type virus. These results indicate that the movement of TMV into minor veins does not require the CP, and an encapsidation-competent CP is not required for, but may increase the efficiency of, movement into the conducting complex of the phloem (i.e., the C cell/sieve element complex). Also, a host factor(s) functions at or beyond the C cell/sieve element interface with other cells to allow efficient phloem-dependent accumulation of TMV CP-O.

Capsid↗
PubMed1996

Mapping nucleotides in the 126-kDa protein gene that control the differential symptoms induced by two strains of tobacco mosaic virus.

The differential symptom determinants of the Holmes' masked (M) and U1 strains of tobacco mosaic virus previously were mapped to the 5'-coterminal open reading frame (ORF) encoding the 126-kDa protein and the N-terminal two-thirds of the 183-kDa protein. Both proteins influence viral RNA accumulation, but the function of, and impact on, symptom formation by large domains within the 126-kDa gene, which are not conserved with sequences in analogous ORFs from other related viruses, are unknown. In the current study, cDNA clones representing each strain (i.e., MIC-TMV and U1-TMV) were mutated in these nonconserved domains to further define the nucleotides responsible for mosaic symptom induction on Nicotiana tabacum. Progeny virus of a mutant containing only eight nucleotide substitutions from the MIC-TMV sequence to the U1-TMV sequence within the 126-kDa protein ORF of MIC-TMV induced U1-TMV-like symptoms. Single or multiple substitutions among these eight nucleotides further defined residues critical for symptom modulation. Complementary substitutions in the MIC-TMV and U1-TMV sequences did not always yield progeny virus that induced complementary visual symptoms. Progeny of some mutants contained second-site spontaneous mutations at specific positions shown to influence symptom phenotype. For a subset of the stable site-directed mutants, there was no correlation between severity of systemic symptoms and chlorotic lesion size or virus accumulation in these chlorotic lesions on inoculated leaves.

Base Sequence↗
PubMed1996

Value of toe pulse waves in addition to systolic pressures in the assessment of the severity of peripheral arterial disease and critical limb ischemia.

PURPOSE: Although pressure measurements are useful in the assessment of the severity of the arterial obstruction, they do not completely identify limbs with and without critical limb ischemia. Our objective was to test whether addition of the measurements of toe pulse waves (PW), which depend on distal perfusion, to pressure measurements could improve the determination of the severity of arterial disease and the presence of critical limb ischemia. METHODS: We measured toe pressure (TSP) and ankle/brachial index (ABI) and recorded PW with photoplethysmography in 358 limbs of 182 patients. RESULTS: TSP, ABI, and PW amplitude were lower in 67 limbs with rest pain, skin lesions, or both, with mean differences of 29 mm Hg, 0.12, and 16 mm, respectively (p < 0.01). Similarly, in the subgroup of 107 limbs with TSP < or = 30 mm Hg, TSP, and PW amplitude, but not ABI, were lower in 53 limbs with rest pain, skin lesions, or both, with mean differences of 10 mm Hg and 7 mm (p < 0.01). Multiple logistic regression showed that after controlling was done for TSP and ABI, the odds ratio for the presence of rest pain, skin lesions, or both associated with PW amplitude < or = 4 mm was 4.3 (95% confidence interval 1.7, 11.0; p < 0.01). In the subgroup with TSP < or = 30 mm Hg, this odds ratio was 3.5 (95% confidence interval 1.0, 11.6; p < 0.05). CONCLUSIONS: The findings indicate that addition of PW recording to pressure measurements is likely to increase the accuracy of assessment for critical limb ischemia.

Aged↗
PubMed1996

Effects of ambulation on foot oxygen tension in limbs with peripheral atherosclerosis.

As walking a few steps increases the arteriovenous pressure difference for blood flow through the feet, we studied the effect of a brief period of walking on transcutaneous oxygen tension (tcPO2). Foot tcPO2 was measured using Clarke type electrodes before, during and after a brief period of repetitive walking on the treadmill in 15 patients with various degrees of arterial obstruction. TcPO2 was significantly higher during walking, than while standing on the treadmill, in limbs with severe disease manifested by toe systolic pressure <30 mmHg (mean change 0.7 kPa or 5 mmHg, P=0.001). Also, supine tcPO2 was significantly higher following periods of walking than before in limbs with toe pressure both below and above 30 mmHg (mean change 1.5 kPa or 11 mmHg, P<0.001). The results indicate that a brief period of walking increases skin oxygenation. Regimens of such exercise may promote healing in some limbs with arterial disease.

Aged↗
PubMed1996

The 126- and 183-kilodalton proteins of tobacco mosaic virus, and not their common nucleotide sequence, control mosaic symptom formation in tobacco.

Nucleotide substitutions at two positions within the open reading frame encoding the 126-kDa protein in the attenuated masked (M) strain of tobacco mosaic tobamovirus (TMV) to those found in the virulent U1-TMV genome led to the induction of near U1-TMV-like symptoms on leaves of Nicotiana tabacum L. cv. Xanthi nn by progeny virus (M. H. Shintaku, S. A. Carter, Y. Bao, and R. S. Nelson, Virology 221:218-225, 1996). In this study, further site-directed mutations were made at these positions within the M strain cDNA to determine whether the protein or nucleotide sequence directly controlled the symptom phenotype. The protein and not the nucleotide sequence directly controlled the symptom phenotype when amino acid 360 within the 126-kDa protein sequence was altered and likely controlled the symptom phenotype when amino acid 601 was altered. The effects of the substitutions at amino acid position 360 on viral protein accumulation were studied by pulse-labeling proteins in infected protoplasts. Accumulation of the 126- and 183-kDa proteins was less for an attenuated mutant than for two virulent mutants, but the viral movement protein and coat protein accumulated to levels reported to be sufficient for normal systemic symptom development. The size of necrotic local lesions on N. tabacum L. cv. Xanthi NN was negatively correlated with symptom development and accumulation of the 126-kDa protein for these mutants. With reference to this last finding, an explanation of the cause of the differing symptoms induced by these viruses is presented.

Amino Acid Sequence↗
PubMed1996

Enhanced cytochemical detection of viral proteins and RNAs using double-sided labeling and light microscopy.

We have developed a double-sided labeling technique for detecting viral proteins or RNAs in plastic-embedded leaf tissue by immunocytochemistry or in situ hybridization, respectively, and light microscopy. The signal from the target was enhanced by double-sided labeling when compared with single-sided labeling because sections were submerged in labeling solutions with both sides accessible to antibodies or complementary RNAs. The additional label was visible during microscopic analysis. Background signal was decreased since the tissue was probed and washed under conditions where folds and creases in the tissue were minimized. This technique uses the same equipment and chemicals as for single-sided labeling, and thus adjustments for reagent expenditures are not necessary. The procedure should be applicable to animal and plant tissue.

Animals↗
PubMed1994

Linkage analyses in British pedigrees suggest a single locus for Darier disease and narrow the location to the interval between D12S105 and D12S129.

Darier disease is a dominantly inherited skin disorder in which there appears to be abnormal adhesion between keratinocytes. We and others have shown that the disease in some British pedigrees is closely linked to markers mapping to 12q23-q24.1. In the present study we have defined crossovers that enable us to narrow the location of the disease gene to the interval between the D12S105 and the D12S129 markers. This interval may be expected to be on the order of about 4 cM on the basis of linkage data obtained using the primary CEPH reference families. Our data provide further evidence for locus homogeneity: each of four large British pedigrees, two of which have previously been subjected to preliminary characterization, shows statistically significant evidence for linkage to markers mapping to 12q23-q24.1.

Chromosome Mapping↗
PubMed1994

Germline mutations in the neurofibromatosis type 2 tumour suppressor gene.

The recent identification of the NF2 tumour suppressor gene has enabled large scale screening for pathological mutations in the gene. We have sought germline mutations in the NF2 gene by SSCP and heteroduplex analysis of cDNA and genomic DNA samples followed by cloning and sequencing of mutant alleles. In the present report we describe 11 putative pathological mutations, including five nonsense mutations, three short insertions or deletions causing frameshifts and three missense mutations. Most stop mutations and frameshift mutations were found in individuals expressing a severe phenotype while one of the three missense mutations was associated with a mild phenotype. Four unrelated NF2 patients of the 93 tested were found to have identical nonsense mutations caused by a C to T transition (C169) in a CpG dinucleotide, which is a potential mutational hotspot in the NF2 tumour suppressor gene.

Base Sequence↗