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Biomedical subjects

M D Holmes

Publications and source records attributed to M D Holmes.

At least 37 records · Page 2Linked to original sources
PubMed2000

Cytokines enhance airway smooth muscle contractility in response to acetylcholine and neurokinin A.

OBJECTIVE: In vivo airway hyperresponsiveness has been demonstrated following inhalation of specific cytokines in normal individuals. Whether this airway hyperresponsiveness results from a direct effect of cytokines on airway smooth muscle contractility, or via changes in airway wall structure is not known. The aim of the present study was to determine the effect of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) on airway smooth muscle contractility in vitro. METHODOLOGY: Ovine tracheal smooth muscle strips were incubated for 18 h at room temperature in Dulbecco's modified Eagle's medium, supplemented with antibiotics, with IL-1beta (10 ng/mL) and TNF-alpha (100 ng/mL), in an atmosphere of 5%CO2:95%O2. Following incubation cumulative concentration-response curves to acetylcholine (ACh) and neurokinin A (NKA) were obtained. Antagonist affinity studies were performed to determine whether the cytokine-induced enhanced contractility to ACh and NKA resulted from a functional alteration to specific M3 and NK2 receptors. Cumulative concentration-response curves to NKA were performed in the presence of phosphoramidon to determine if the enhanced contractility to NKA following cytokine exposure was due to a reduction in endogenous neutral endopeptidase activity. To assess the calcium dependence of the hyperresponsiveness, cumulative concentration-responses to ACh were conducted in calcium-free Krebs'-Henseleit solution. RESULTS: Pre-incubation with TNF-alpha and IL-1beta caused a significant leftward shift, and an increase in the magnitude, of the concentration-response curves to both ACh and NKA. No difference in M3 and NK2 receptor antagonist affinity (pA2) values between the control and cytokine-treated tissue was observed. Neurokinin A contractility in the presence of phosphoramidon indicated that the enhanced contractility following cytokine exposure was not due to a reduction in endogenous neutral endopeptidase activity. Removal of extracellular calcium ions attenuated the contractile response to low concentrations of ACh in the control and cytokine-pretreated tissue. However, enhanced contractility following TNF-alpha and IL-1beta pretreatment was still present. CONCLUSION: Pro-inflammatory cytokines induce in vitro hyperresponsiveness in normal airway smooth muscle via a mechanism involving intracellular calcium mobilization.

Acetylcholine↗
PubMed2000

Outcome after surgery in patients with refractory temporal lobe epilepsy and normal MRI.

Our purpose is to determine predictors of outcome in patients with refractory temporal lobe epilepsy and normal high resolution magnetic resonance imaging (MRI) who undergo surgical therapy. We identified 23 patients who underwent temporal lobectomy and had normal pre-operative MRI, including surface coil phased array temporal lobe imaging. All were followed at least 2 years after surgery. We graded outcome as seizure-free, > 75% reduction in seizures, or < 75% reduction in seizures. We examined pre-operative interictal and ictal electroencephalographic (EEG) findings, age of onset, gender, duration of epilepsy, risk factors, family history, physical findings, age at operation, side of operation, and pathology of resected tissue in order to determine if any of these factors were associated with outcome. Overall, 48% (11/23) of patients were seizure-free, 39% (9/23) had > 75% reduction in seizures, while 13% (3/23) had < 75% reduction in seizures. Only the EEG findings were useful in predicting outcome. When ictal onsets arose from basal-temporal regions, 61% (11/18) of patients were seizure-free, while none (0/5) were seizure-free when seizures arose from mid-posterior temporal regions (P = 0.04). Interictally, if all epileptiform patterns were localized exclusively to one basal-temporal region, a finding that invariably correlated with ictal onsets, 78% (7/9) of patients were seizure-free, while only 29% (4/14) were seizure-free if discharges were bilateral or multifocal (P = 0.04). We conclude that surgery may be a reasonable treatment for some patients with intractable temporal lobe seizures and normal MRI. The best outcomes occur when seizure onsets and interictal epileptiform patterns are exclusive to one basal-temporal region. Unfavorable outcomes are most likely to occur when ictal origins are from mid-posterior temporal regions and when interictal discharges are bitemporal or multifocal in distribution.

Adolescent↗
PubMed2000

Unilateral diaphragmatic paralysis following bronchial artery embolization for hemoptysis.

Bronchial artery embolization is an effective treatment for patients with hemoptysis. Serious complications are rare, but may occur if the arterial supply to other structures is compromised. We present a case of unilateral diaphragmatic paralysis following bronchial artery embolization in a patient with cystic fibrosis. We believe that the diaphragmatic paralysis was due to the inadvertent obstruction of the left pericardiacophrenic artery during the embolization procedure, with compromise of the phrenic nerve blood supply. This resulted in a significant loss of lung function in our patient, who did not recover despite the subsequent return of diaphragmatic function.

Adult↗
PubMed1999

Dietary factors and the survival of women with breast carcinoma.

BACKGROUND: Little is known regarding how specific dietary factors affect the survival of women with breast carcinoma. METHODS: Female registered nurses were followed with biennial questionnaires in a prospective cohort with 18 years of follow-up. Participants were women with breast carcinoma (n = 1982) diagnosed between 1976-1990 who completed a food frequency questionnaire after diagnosis. The main outcome measure was time to death from any cause. Analysis was made by multivariate Cox proportional hazards models. RESULTS: In multivariate analyses of diet after diagnosis, no apparent association was found between fat intake and mortality. The relative risk (and 95% confidence interval) of mortality comparing the highest with the lowest quintile of protein intake was 0.65 (0.47-0.88). There was no association between red meat and mortality. These associations were similar in analyses with breast carcinoma death as the outcome. CONCLUSIONS: No survival advantage was found for a low fat diet after a diagnosis of breast carcinoma. However, increased survival was observed among women eating more protein, but not red meat. The findings suggest that differences in diet may affect survival after a diagnosis of breast carcinoma and should be examined in greater detail.

Breast Neoplasms↗
PubMed1999

Association of dietary intake of fat and fatty acids with risk of breast cancer.

CONTEXT: High intakes of fat and specific fatty acids, including total, animal, saturated, polyunsaturated, and trans-unsaturated fats, have been postulated to increase breast cancer risk. OBJECTIVE: To determine whether intakes of fat and fatty acids are associated with breast cancer. DESIGN AND SETTING: Cohort study (Nurses' Health Study) conducted in the United States beginning in 1976. PARTICIPANTS: A total of 88795 women free of cancer in 1980 and followed up for 14 years. MAIN OUTCOME MEASURE: Relative risk (RR) of invasive breast cancer for an incremental increase of fat intake, ascertained by food frequency questionnaire in 1980, 1984, 1986, and 1990. RESULTS: A total of 2956 women were diagnosed as having breast cancer. Compared with women obtaining 30.1% to 35% of energy from fat, women consuming 20% or less had a multivariate RR of breast cancer of 1.15 (95% confidence interval [CI], 0.73-1.80). In multivariate models, the RR (95% CI) for a 5%-of-energy increase was 0.97 (0.94-1.00) for total fat, 0.98 (0.96-1.01) for animal fat, 0.97 (0.93-1.02) for vegetable fat, 0.94 (0.88-1.01) for saturated fat, 0.91 (0.79-1.04) for polyunsaturated fat, and 0.94 (0.88-1.00) for monounsaturated fat. For a 1% increase in energy from trans-unsaturated fat, the values were 0.92 (0.86-0.98), and for a 0.1% increase in energy from omega-3 fat from fish, the values were 1.09 (1.03-1.16). In a model including fat, protein, and energy, the RR for a 5% increase in total fat, which can be interpreted as the risk of substituting this amount of fat for an equal amount of energy from carbohydrate, was 0.96 (95% CI, 0.93-0.99). In similar models, no significant association of risk was evident with any major types of fat. CONCLUSION: We found no evidence that lower intake of total fat or specific major types of fat was associated with a decreased risk of breast cancer.

Adult↗
PubMed1999

Hippocampal or neocortical lesions on magnetic resonance imaging do not necessarily indicate site of ictal onsets in partial epilepsy.

Advances in neuroimaging techniques, particularly high-resolution magnetic resonance imaging (MRI), have proved invaluable in identifying structural brain lesions in patients with epilepsy. The assumption that such focal lesions invariably predict the site of seizure origin may not be correct, however. We report a series of 20 adults with medically intractable partial epilepsy, where high-resolution brain MRI disclosed a unilateral, focal, hippocampal, or neocortical lesion as the only abnormality in each case; nevertheless, based on electroencephalographic (EEG) recordings, ictal onsets arose from a completely different location than that of the MRI lesion. All patients underwent epilepsy surgery, with the operations based on ictal EEG findings, and all were followed at least 2 years after the resection. After the most recent follow-up examination, 50% (10/20) of the patients were completely seizure-free, 35% (7/20) had at least a 75% reduction in the number of seizures, and 15% (3/20) had less than a 75% reduction in the number of seizures. We conclude that the identification of a focal, structural, hippocampal, or neocortical lesion on brain MRI is not always indicative of the site of seizure origin in partial epilepsy. Furthermore, in cases of discordance between MRI and EEG data, a good outcome after epilepsy surgery is possible if EEG ictal onsets are definitive.

Adolescent↗
PubMed1999

Exercise-induced hypoxaemia in highly trained cyclists at 40% peak oxygen uptake.

A group of 15 competitive male cyclists [mean peak oxygen uptake, VO2peak 68.5 (SEM 1.5 ml x kg(-1) x min(-1))] exercised on a cycle ergometer in a protocol which began at an intensity of 150 W and was increased by 25 W every 2 min until the subject was exhausted. Blood samples were taken from the radial artery at the end of each exercise intensity to determine the partial pressures of blood gases and oxyhaemoglobin saturation (SaO2), with all values corrected for rectal temperature. The SaO2 was also monitored continuously by ear oximetry. A significant decrease in the partial pressure of oxygen in arterial blood (PaO2) was seen at the first exercise intensity (150 W, about 40% VO2peak). A further significant decrease in PaO2 occurred at 200 W, whereafter it remained stable but still significantly below the values at rest, with the lowest value being measured at 350 W [87.0 (SEM 1.9) mmHg]. The partial pressure of carbon dioxide in arterial blood (PaCO2) was unchanged up to an exercise intensity of 250 W whereafter it exhibited a significant downward trend to reach its lowest value at an exercise intensity of 375 W [34.5 (SEM 0.5) mmHg]. During both the first (150 W) and final exercise intensities (VO2peak) PaO2 was correlated significantly with both partial pressure of oxygen in alveolar gas (P(A)O2, r = 0.81 and r = 0.70, respectively) and alveolar-arterial difference in oxygen partial pressure (P(A-a)O2, r = 0.63 and r = 0.86, respectively) but not with PaCO2. At VO2peak PaO2 was significantly correlated with the ventilatory equivalents for both oxygen uptake and carbon dioxide output (r = 0.58 and r = 0.53, respectively). When both P(A)O2 and P(A-a)O2 were combined in a multiple linear regression model, at least 95% of the variance in PaO2 could be explained at both 150 W and VO2peak. A significant downward trend in SaO2 was seen with increasing exercise intensity with the lowest value at 375 W [94.6 (SEM 0.3)%]. Oximetry estimates of SaO2 were significantly higher than blood measurements at all times throughout exercise and no significant decrease from rest was seen until 350 W. The significant correlations between PaO2 and P(A)O2 with the first exercise intensity and at VO2peak led to the conclusion that inadequate hyperventilation is a major contributor to exercise-induced hypoxaemia.

Adult↗
PubMed1999

Predicting outcome following reoperation for medically intractable epilepsy.

The purpose of this study was to determine predictors of probable outcome following reoperation for medically intractable partial epilepsy. We reviewed outcome at least 1 year after reoperation in 21 patients with intractable seizures, for whom an earlier operation had failed. We examined age of onset of epilepsy, duration of seizures, gender, details of the history and clinical examination, pre-operative magnetic resonance (MRI) findings, electroencephalographic (EEG) studies obtained before and after the failed surgery, presence or absence of lateralizing neuro-psychological deficits, sites of operation and pathology of resected tissue to identify the factors associated with outcome. We found two factors that were significantly related to outcome: (1) no individual with a history of central nervous system (CNS) infection which predated the onset of epilepsy had a seizure-free outcome after reoperation (P = 0.04). (2) Reoperations that extended previous resections, based on new ictal EEG recordings that were concordant with both EEG ictal onsets and MRI findings obtained before the first, failed surgery resulted in a seizure-free outcome or >95% reduction in seizures for 100% (7/7) of such patients. This compares to 29% (4/14) of the remaining individuals without such concordance who had a similar outcome (P = 0.009). Site of operation (temporal or extratemporal) did not, in and of itself, predict outcome. A portion of patients who fail surgery for intractable partial seizures will achieve significant improvement following reoperation. Furthermore, we may be able to identify those individuals most likely to have an excellent result from a second operation.

Adolescent↗
PubMed1999

Valproate therapy for prevention of posttraumatic seizures: a randomized trial.

OBJECT: Seizures frequently accompany moderate to severe traumatic brain injury. Phenytoin and carbamazepine are effective in preventing early, but not late, posttraumatic seizures. In this study the authors compare the safety and effectiveness of valproate with those of short-term phenytoin for prevention of seizures following traumatic brain injury. METHODS: The study was a randomized, double-blind, single-center, parallel-group clinical trial. Treatment began within 24 hours of injury. One hundred thirty-two patients at high risk for seizures were assigned to receive a 1-week course of phenytoin, 120 were assigned to receive a 1-month course of valproate, and 127 were assigned to receive a 6-month course of valproate. The cases were followed for up to 2 years. The rates of early seizures were low and similar when using either valproate or phenytoin (1.5% in the phenytoin treatment group and 4.5% in the valproate arms of the study; p = 0.14, relative risk [RR] = 2.9, 95% confidence interval [CI] 0.7-13.3). The rates of late seizures did not differ among treatment groups (15% in patients receiving the 1-week course of phenytoin, 16% in patients receiving the 1-month course of valproate, and 24% in those receiving the 6-month course of valproate; p = 0.19, RR = 1.4, 95% CI 0.8-2.4). The rates of mortality were not significantly different between treatment groups, but there was a trend toward a higher mortality rate in patients treated with valproate (7.2% in patients receiving phenytoin and 13.4% in those receiving valproate; p = 0.07, RR = 2.0, 95% CI 0.9-4.1). The incidence of serious adverse events, including coagulation problems and liver abnormalities, was similar in phenytoin- and valproate-treated patients. CONCLUSIONS: Valproate therapy shows no benefit over short-term phenytoin therapy for prevention of early seizures and neither treatment prevents late seizures. There was a trend toward a higher mortality rate among valproate-treated patients. The lack of additional benefit and the potentially higher mortality rate suggest that valproate should not be routinely used for the prevention of posttraumatic seizures.

Adult↗
PubMed1998

High-resolution inter-ictal SPET and phased-array MRI in partial epilepsy: an imaging comparison with video/EEG and outcome correlation.

To assess the clinical utility of high-resolution inter-ictal single photon emission tomography (SPET) of regional cerebral perfusion and high-resolution magnetic resonance imaging (MRI) of the brain with a phased-array temporal lobe coil, 35 patients with presumed partial epilepsy were evaluated prospectively by these techniques in addition to prolonged video/electroencephalographic (EEG) monitoring. Twenty of these patients had surgical treatment of partial epilepsy with outcome determinations spanning from 12 months to 3 years at follow-up. There were four categories of imaging findings as compared to scalp/sphenoidal EEG localization. Category I included 12 patients (34% of total) in whom there was complete imaging and EEG concordance. Category II included 4 patients (11%) in whom MRI and EEG were concordant but SPET was divergent or normal. Category III included 13 patients (37%) in whom SPET and EEG were concordant but MRI was divergent or normal. Category IV included 4 patients (11%) in whom neither SPET nor MRI was concordant with EEG. In this study, the relative sensitivities of SPET and MRI for localization of partial epilepsy based on prolonged scalp/sphenoidal video/EEG recordings were 76% and 49%, respectively. We conclude that these neuroimaging techniques (phased-array MRI and inter-ictal cerebral perfusion SPET) are complementary and useful in the pre-operative evaluation of patients with partial epilepsy.

Adolescent↗
PubMed1998

What is the significance of subjective events recorded during long-term EEG video monitoring?

PURPOSE: Purely subjective events, identified as "seizures" by patients but not accompanied by any clinical or EEG changes, commonly occur during evaluation of patients for intractable epilepsy. We wished to determine the significance of such events. METHODS: We analyzed the frequency of subjective episodes in 379 adults who underwent EEG video monitoring as part of their evaluation for intractable epilepsy and the relationship of these experiences to epileptic and psychogenic nonepileptic (NES) seizures. We examined the results of tests of mental ability and of emotional, psychosocial, and quality of life (QOL) adjustment to determine if individuals with subjective events alone could be distinguished from those with epileptic seizures only, NES only, or no events, by these measures. RESULTS: We noted subjective events in 39% (147 of 379) of the patients. Of patients with subjective episodes, 52% also had epileptic seizures, 7% had NES, 1% had both epileptic seizures and NES, and 40% had subjective events alone. As a group, patients with subjective events alone were slightly more intelligent and less impaired neuropsychologically than people in the other groups, but they performed more poorly on several important measures of adjustment. CONCLUSIONS: The identification of persons with purely subjective episodes apart from all other episodes is important both phenomenologically and from a practical viewpoint.

Adolescent↗
PubMed1998

Is partial epilepsy progressive? Ten-year follow-up of EEG and neuropsychological changes in adults with partial seizures.

PURPOSE: This study was undertaken to determine what changes, if any, occur in the electroencephalogram (EEG) and in neuropsychological test findings of adults with medically intractable complex partial epilepsy over a 10-year period. METHODS: We studied 35 adults, with a mean age of 32 years (range, 16-59 years) at time of initial testing. We compared the distribution of epileptiform patterns documented on the initial pair of waking and sleeping EEGs to those observed on another pair obtained 10 years later. During this same 10-year period, we also examined changes in the Wechsler Adult Intelligence Scale (WAIS) and on the tests from the Neuropsychological Battery for Epilepsy. RESULTS: The EEGs of 28 (80%) of patients at the tenth year were identical to those seen initially. Five (14%) of patients demonstrated EEGs after 10 years with either no discharges or only unilateral discharges, where bilateral discharges were seen a decade earlier. Only two (6%) of patients had EEGs at the tenth year that showed bilateral discharges where only unilateral discharges were seen originally. We found no general change in intelligence or neuropsychological functioning after 10 years, although a few subtle losses were noted on several neuropsychological measures. CONCLUSIONS: For most adults with medically intractable complex partial epilepsy, the EEG and neuropsychological test scores remain reasonably stable over a decade.

Adolescent↗
PubMed1998

Can behavioral risk factors explain the difference in body mass index between African-American and European-American women?

African-American women are heavier than European-American women; the reasons are unknown. The purpose of this study was to examine potentially modifiable reasons for the weight difference among 86,326 female nurses. The determinants of body mass index (BMI) were modelled using the method of linear regression. The findings included the following: mean BMI (kg/m2) was 9.0% (95% CI, 7.8-10.1%) higher among African American (27.3) than among European-American women (25.1) (P<0.0001). However, recalled BMI at age 18 was equal in the two groups (21.4, P=0.98). Multivariate determinants of BMI include age, age 18 BMI, alcohol and calorie intake, exercise, marital status, parity, race, recent intentional weight loss, smoking, and television watching. Even after controlling for these factors, African-American women still had an 8.6% (95% CI, 7.7-9.5%) higher BMI than European-American women. Correction for error in measurement of physical activity attenuated this difference to 6.4% (95% CI, 5.0-7.8%). In conclusion, in this single occupation group, African-American women had a significantly higher BMI than European-American women. Age and measured behavioral factors did not explain this difference. However, imprecision in the measurement of diet and activity may explain this difference in part. Better measurement may help quantify the differences that are as yet unexplained.

Adolescent↗
PubMed1997

Tachykinins contribute to the acute airways response to allergen in sheep actively sensitized to Ascaris suum.

Tachykinins, found in sensory nerves, have effects in the airways which suggest that they may contribute to the pathogenesis of asthma. We aimed to find evidence for tachykinin involvement in the immediate airway response to allergen in a sheep model of experimental asthma. Twenty-four sheep were actively sensitized to Ascaris suum, then challenged with nebulized Ascaris extract in a dose-response fashion. Change in lung resistance (RL) in response to challenge was measured. Responder sheep (those with an increase in RL of > or = 100% over baseline) that had reproducible responses over three challenges were identified (n = 4 sheep) and a PC100 (number of breaths of extract required to induce a 100% increase in RL) was determined. The effect of the neutral endopeptidase inhibitor phosphoramidon, the NK-1 receptor-specific antagonist CP 96, 345 and capsaicin desensitization on the RL response to Ascaris challenge was then assessed. Administration of phosphoramidon before Ascaris decreased the PC100 to 31 +/- 7% of the PC100 seen with Ascaris alone (P < 0.05), whereas CP 96,345 and capsaicin desensitization increased the PC100 to 285 +/- 41% and 555 +/- 93% respectively (P < 0.05 for both). These findings suggest that endogenous tachykinins are released in response to allergen challenge and that they contribute to the immediate increase in RL.

Allergens↗
PubMed1997

Outcome following surgery in patients with bitemporal interictal epileptiform patterns.

We reviewed outcome at least 1 year after temporal lobectomy in 44 patients with bitemporal, independent, interictal epileptiform patterns on EEG. All 44 underwent preoperative intracranial monitoring. Twenty-two (50%) were seizure-free, 14 (32%) had at a least 75% reduction in seizures, and eight (18%) had less than a 75% reduction in seizures. We analyzed age of seizure onset, duration of epilepsy, gender, side of operation, history and clinical findings, findings on MRI, results of intracranial EEG-video monitoring, presence or absence of lateralizing neuropsychological deficits, and pathology of resected tissue to identify factors associated with outcome. Three factors emerged as independently associated with a good outcome: concordance of MRI abnormality and side of operation (p = 0.01), history of febrile seizures (p = 0.04), and 100% lateralization of intracranially recorded ictal onsets to the side of operation (p = 0.05). A seizure-free outcome was much more likely to occur if more than one of these factors was present: with at least two factors co-existing, 83% (15/18) of patients were seizure-free, while only 35% (7/20) were seizure-free with a single factor present (p = 0.0009). Of the six patients without any of the three factors, none were seizure-free. We conclude that it is possible to predict reasonably which patients with bitemporal epileptiform abnormalities will have a good outcome after surgery.

Adolescent↗