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Biomedical subjects

K M A Welch

Publications and source records attributed to K M A Welch.

17 recordsLinked to original sources
PubMed2006

High-dose atorvastatin after stroke or transient ischemic attack.

BACKGROUND: Statins reduce the incidence of strokes among patients at increased risk for cardiovascular disease; whether they reduce the risk of stroke after a recent stroke or transient ischemic attack (TIA) remains to be established. METHODS: We randomly assigned 4731 patients who had had a stroke or TIA within one to six months before study entry, had low-density lipoprotein (LDL) cholesterol levels of 100 to 190 mg per deciliter (2.6 to 4.9 mmol per liter), and had no known coronary heart disease to double-blind treatment with 80 mg of atorvastatin per day or placebo. The primary end point was a first nonfatal or fatal stroke. RESULTS: The mean LDL cholesterol level during the trial was 73 mg per deciliter (1.9 mmol per liter) among patients receiving atorvastatin and 129 mg per deciliter (3.3 mmol per liter) among patients receiving placebo. During a median follow-up of 4.9 years, 265 patients (11.2 percent) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 percent; adjusted hazard ratio, 0.84; 95 percent confidence interval, 0.71 to 0.99; P=0.03; unadjusted P=0.05). The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. The five-year absolute reduction in the risk of major cardiovascular events was 3.5 percent (hazard ratio, 0.80; 95 percent confidence interval, 0.69 to 0.92; P=0.002). The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P=0.98), as were the rates of serious adverse events. Elevated liver enzyme values were more common in patients taking atorvastatin. CONCLUSIONS: In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke. (ClinicalTrials.gov number, NCT00147602 [ClinicalTrials.gov].).

Adult↗
PubMed2006

Mismatch in how oestrogen modulates molecular and neuronal function may explain menstrual migraine.

This paper is designed to provide concepts and stimulate directions for further investigation of menstrual migraine. On the basis of experimental studies and literature review, we propose that abnormalities in how estrogen modulates neuronal function in migraine are due to a mismatch between its gene-regulation and membrane effects. In the interictal phase when estrogen levels peak, increased neuronal excitability is balanced by homeostatic gene regulation in brain cortex, and nociceptive systems. When levels fall at menses, mismatch in homeostatic gene regulation by estrogen unmasks non-nuclear mitogen-activated hyperexcitability of cell membranes, sensitizing neurons to triggers that activate migraine attacks. At the trough of estrogen levels, the down-regulating effect on inflammatory genes is lost and peptide modulated central sensitization is increased as is pain and disability of the migraine attack.

Dysmenorrhea↗
PubMed2006

Effects of oestrogen on trigeminal ganglia in culture: implications for hormonal effects on migraine.

Although migraine is more common in women than men and often linked to the menstrual cycle, few studies have investigated the biological basis of hormonal influences on the trigeminovascular system. In the present study we investigated the effect of physiological levels (10(-9) m) oestrogen on female rat trigeminal ganglia in vitro. Immunocytochemical analysis demonstrated the presence of oestrogen receptor-alpha in a predominantly cytoplasmic location and in neurites. Microarray analysis demonstrated that oestrogen treatment regulates several genes with potential relevance to menstrual migraine. The genes that were upregulated included synapsin-2, endothelin receptor type B, activity and neurotransmitter-induced early gene 7 (ania-7), phosphoserine aminotransferase, MHC-1b, and ERK-1. Down-regulated genes included IL-R1, bradykinin B2 receptor, N-tropomodulin, CCL20, GABA transporter protein, fetal intestinal lactase-phlorizin hydrolase, carcinoembryonic antigen-related protein, zinc finger protein 36, epsin 1 and cysteine string protein. Protein activity assays demonstrated that exposure of the cultured neurons to oestrogen leads to activation of ERK, which has been linked to inflammatory pain. Immunocytochemistry demonstrated that activated ERK was present in neurons containing peripherin, a marker of nociceptive neurons. Several of the genes in the present study may provide potential targets for understanding the association of oestrogen with migraine and other hormone-related orofacial pain.

Animals↗
PubMed2006

Factors determining headache at onset of acute ischemic stroke.

Headache is a frequent accompaniment of acute ischaemic stroke. The predisposing factors and underlying mechanisms are currently incompletely defined. We analysed prospectively collected data relevant to headache occurring at ischaemic stroke onset in consecutive patients included in the Henry Ford Hospital Stroke Data Bank. Patients with headache (HA+) and without headache (HA-) were compared for demographic factors, medical history, medications, examination findings, laboratory findings, and stroke localization and subtype. Group comparisons for categorical data were performed with chi(2) test, and for continuous variables with two-sample t-tests. Stepwise logistic regression analysis, including all variables with P<0.25, was used to define the independent predictors of onset headache. Three hundred and seventy-five patients had complete headache and clinical datasets and were included in the analysis (HA+, N=118; HA-, N=257). Multivariate analysis revealed that the independent predictors of HA+ were: infarct in the distribution of the posterior circulation [P=0.0076, odds ratio (OR) 2.15, 95% confidence interval (CI) 1.23, 3.77], absence of history of hypertension (P=0.0106, OR 0.48, 95% CI 0.27, 0.84), and treatment with warfarin at the time of the index stroke (P=0.0135, OR 4.89, 95% CI 1.39, 17.21). The occurrence of headache at onset of ischaemic stroke is determined by posterior circulation distribution of the ischaemic event, absence of history of hypertension and treatment with warfarin at the time of the index stroke. These results suggest that preserved elasticity and maintenance of the intracranial vasculature in a relaxed state, in combination with coagulation system derangements, and activation of dense perivascular afferent nerves, play a role in the pathogenesis of onset headache.

Acute Disease↗
PubMed2006

C-reactive protein may be increased in migraine patients who present with complex clinical features.

OBJECTIVES: Stroke risk is increased in migraine, the basis of which remains to be established. C-reactive protein (CRP) is a marker of cerebrovascular disease, suggesting in part an inflammatory mechanism. Because attacks of migraine may involve repeated sterile vascular inflammation, we measured CRP in migraine patients. METHODS: Retrospective review was conducted of 60 randomly sampled charts of patients with the diagnosis of migraine without aura (MwoA, n = 29) and migraine with aura (MwA, n = 31), in which CRP was recorded as part of the differential diagnostic evaluation. CRP was measured by standard commercial laboratory methods; high sensitivity CRP (hs-CRP) values above 3mg/L were considered abnormal. RESULTS: Elevated hs-CRP was found in 43% of all patients (26 of 60). In MwoA, of 29 subjects, abnormal hs-CRP was recorded in 16; in 10 no other conditions were found to explain the abnormality. In MwA, of 31 subjects, abnormal CRP was recorded in 10; in 5 no other condition could explain the abnormality. No associations were found between other demographic or clinical features. CONCLUSIONS: CRP may be abnormal in MwoA and MwA patients who present with atypical, severe, or complex clinical features that require extensive differential diagnostic investigation.

Adult↗
PubMed2003

Contemporary concepts of migraine pathogenesis.

The pathogenesis of migraine is incompletely understood. Recent discoveries have shed light on the neuronal events mediating both the aura and the headache phases of migraine, identifying a cerebral cortical origin of migraine aura, susceptibility to attacks based on cortical hyperexcitability, and headache originating in the trigeminovascular system and its central projections. Abnormal modulation of brain nociceptive systems, at first transient but becoming permanent with continuing illness and, predisposing to central sensitization, may explain the prolonged headache of the migraine attack and the shift of the migraine phenotype from episodic to chronic headache. Migraine attacks might also originate in abnormal nociceptive neuromodulator centers in the brainstem.

Animals↗
PubMed2003

Comorbidity of migraine and depression: investigating potential etiology and prognosis.

BACKGROUND: An association between migraine and major depression has been observed in clinical and community samples. The factors that contribute to this association and their implications remain unclear. OBJECTIVE: To determine the factors contributing to the association of migraine and major depression. METHODS: A cohort study of persons aged 25 to 55 years with migraine (n = 496) or with other headaches of comparable severity (n = 151) and control subjects with no history of severe headaches (n = 539) randomly selected from the general community were interviewed first in 1997 and then reinterviewed in 1999. RESULTS: Major depression at baseline predicted the first-onset migraine during the 2-year follow-up period (odds ratio [OR] = 3.4; 95% CI = 1.4, 8.7) but not other severe headaches (OR = 0.6; 95% CI = 0.1, 4.6). Migraine at baseline predicted the first-onset major depression during follow-up (OR = 5.8; 95% CI = 2.7, 12.3); the prospective association from severe headaches to major depression was not significant (OR = 2.7; 95% CI = 0.9, 8.1). Comorbid major depression did not influence the frequency of migraine attacks, their persistence, or the progression of migraine-related disability over time. CONCLUSIONS: Major depression increased the risk for migraine, and migraine increased the risk for major depression. This bidirectional association, with each disorder increasing the risk for first onset of the other, was not observed in relation to other severe headaches. With respect to other severe headaches, there was no increased risk associated with pre-existing major depression, although the possibility of an influence in the reverse direction (i.e., from severe headaches to depression) cannot be securely ruled out.

Adult↗
PubMed2003

Concepts of migraine headache pathogenesis: insights into mechanisms of chronicity and new drug targets.

The pathophysiology of migraine is incompletely understood. Neurobiological and gene regulation studies and advanced brain imaging are providing new insights into migraine pathogenesis. Recent discoveries have shed light on the neuronal events mediating both the aura and the headache phases of migraine, identifying a cerebral cortical origin of migraine aura, susceptibility to attacks based on cortical hyperexcitability, and the trigeminovascular system and its central projections as the origin of headache. This review focuses on abnormal modulation of brain nociceptive systems leading to central sensitization that may explain prolonged headache of the migraine attack and shift of the migraine phenotype from episodic to chronic headache.

Concept Formation↗
PubMed2003

The threshold for phosphenes is lower in migraine.

We have reported a preliminary study confirming hyperexicitability of occipital cortex in migraine with aura (MwA) using transcranial magnetic stimulation (TMS). We have now completed a blinded study to investigate the occipital cortex in MwA and without aura (MwoA) compared with normal controls (NC) using TMS. TMS was performed using the Caldwell MES-10 stimulator. A circular coil 9.5 cm diameter was applied to the occipital scalp (7 cm above the inion). Stimulator intensity was increased in 10% increments until subjects reported visual phenomena or 100% intensity was reached. Stimulation intensity was then fine tuned to determine the threshold at which phosphenes were seen. Fisher's exact t-test and logrank test were used for statistical comparisons. Ten subjects with MwA and MwoA were compared to 10 NC. The difference in the proportion of subjects with phosphene generation was statistically significant (MwA 100%, MwoA 60% and NC 30%) [P = 0.003]. The difference in threshold levels for phosphenes was also significant for MwA 42.8%, and controls 57.3% [P = 0.0001]. There is a difference in threshold for excitability of occipital cortex in MwA and MwoA compared to NC. This is a direct neurophysiological correlate for clinical observations, which have inferred hyperexicitability of the occipital cortex in migraineurs.

Adult↗
PubMed2002

Functional MRI-BOLD of brainstem structures during visually triggered migraine.

BACKGROUND: Previously, hyperoxia and blood volume increase were reported in the red nucleus and substantia nigra during spontaneous migraine with aura. OBJECTIVE: To further understand the pathophysiologic role of these centers, activation of brainstem structures was investigated in patients with visually triggered migraine. METHODS: Twenty-six patients with migraine (23 with aura and 3 without aura), and 10 normal control subjects were studied with blood oxygen level-dependent (BOLD) fMRI during repeated checkerboard visual stimulation. Three axial image sections, which covered the occipital cortex and brainstem, were acquired 224 times with a temporal resolution of 3.5 seconds. RESULTS: Repetitive visual stimulation triggered symptoms in 12 patients; four who had migraine with aura developed both visual symptoms and headaches, and six who had migraine with aura and two who had migraine without aura had headaches only. Four patients who had migraine with aura experienced the onset of their usual aura or onset of their typical headache either during the experiment or immediately after. In the remaining 10 patients with migraine, and all control subjects, visual stimulation failed to trigger symptoms at any time. In 75% of the patients who developed symptoms during stimulation, baseline T2*-weighted MR signal intensities increased in the red nucleus and substantia nigra before occipital cortex signal elevation or the onset of visually triggered symptoms. CONCLUSION: Activation (hyperoxia and blood volume increase) of the red nucleus and substantia nigra in association with visually triggered symptoms of migraine suggest that these brainstem structures are a part of a neuronal network activated during an attack.

Adult↗
PubMed2002

Contrasts in cortical magnesium, phospholipid and energy metabolism between migraine syndromes.

BACKGROUND: Previous single voxel (31)P MRS pilot studies of migraine patients have suggested that disordered energy metabolism or Mg(2+) deficiencies may be responsible for hyperexcitability of neuronal tissue in migraine patients. These studies were extended to include multiple brain regions and larger numbers of patients by multislice (31)P MR spectroscopic imaging. METHODS: Migraine with aura (MWA), migraine without aura (MwoA), and hemiplegic migraine patients were studied between attacks by (31)P MRS imaging using a 3-T scanner. RESULTS: Results were compared with those in healthy control subjects without headache. In MwoA, consistent increases in phosphodiester concentration [PDE] were measured in most brain regions, with a trend toward increase in [Mg(2+)] in posterior brain. In MWA, phosphocreatine concentration ([PCr]) was decreased to a minor degree in anterior brain regions and a trend toward decreased [Mg(2+)] was observed in posterior slice 1, but no consistent changes were found in phosphomonoester concentration [PME], [PDE], inorganic phosphate concentration ([Pi]), or pH. In hemiplegic migraine patients, [PCr] had a tendency to be lower, and [Mg(2+)] was significantly lower than in the posterior brain regions of control subjects. Trend analysis showed a significant decrease of brain [Mg(2+)] and [PDE] in posterior brain regions with increasing severity of neurologic symptoms. CONCLUSIONS: Overall, the results support no substantial or consistent abnormalities of energy metabolism, but it is hypothesized that disturbances in magnesium ion homeostasis may contribute to brain cortex hyperexcitability and the pathogenesis of migraine syndromes associated with neurologic symptoms. In contrast, migraine patients without a neurologic aura may exhibit compensatory changes in [Mg(2+)] and membrane phospholipids that counteract cortical excitability.

Adult↗
PubMed2002

Cortical spreading depression and gene regulation: relevance to migraine.

Cortical spreading depression (CSD) may be the underlying mechanism of migraine aura. The role of CSD in initiating a migraine headache remains to be determined, but it might involve specific changes in gene expression in the brain. To examine these changes, four episodes of CSD at 5-minute intervals were induced in the mouse brain by application of 300mM KCl, and gene expression was examined 2 hours later using cDNA array and reverse transcriptase-polymerase chain reaction. Controls consisted of groups that received anesthesia only, attachment of recording electrodes only, and application of 0.9% NaCl. Of the over 1,180 genes examined in our experiments, those consistently regulated by CSD included vasoactive peptides; the vasodilator atrial natriuretic peptide was induced by CSD, while the vasoconstrictor neuropeptide Y was downregulated. Other genes specifically regulated by CSD were involved in oxidative stress responses (major prion protein, glutathione-S-transferase-5, and apolipoprotein E). L-type calcium channel mRNA was upregulated. In summary, CSD regulates genes that are intrinsic to its propagation, that identify accompanying vascular responses as a potential source of pain, and that protect against its potential pathological consequences. We believe these observations have strong relevance to the mechanisms of migraine and its outcomes.

Anesthetics↗