Association of von Willebrand factor activity with ACE I/D and MTHFR C677T polymorphisms in migraine.

Angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms are linked to endothelial dysfunction and to cerebral white matter lesions. Objectives of this study were to determine if ACE and MTHFR gene polymorphisms are associated with von Willebrand factor (vWF) activity, an endothelial dysfunction marker, and with a distinct headache phenotype. We enrolled 64 women (18-50 years old) with International Classification of Headache Disorders, 2nd edn migraine without aura (MoA) and 61 with aura (MA). Genotypic frequencies: ACE DD 35%, ID 42%, II 23%, and MTHFR TT 17%, CT 40%, CC 43%. Those with ACE DD genotype had higher levels of vWF activity (152%) compared with ID and II genotypes. Levels were highest (179%) with combined ACE DD and MTHFR TT genotypes. ACE DD was associated with higher headache frequency, and MTHFR TT was associated with MA. In migraine, vWF activity may be a marker of endothelial-mediated genetic risk for ischaemic conditions.

Whites and African-Americans in headache specialty clinics respond equally well to treatment.

This study sought to determine if Whites and African-Americans respond similarly to headache treatment administered in 'real-world' headache specialty treatment clinics. Using a naturalistic, longitudinal design, 284 patients receiving treatment for headache disorders completed 30-day daily diaries that assessed headache frequency and severity at pretreatment and 6-month follow-up and also provided data on their headache disability and quality of life at pretreatment and 1-, 2- and 6-month follow-up. Controlling for socioeconomic status and psychiatric comorbidity, hierarchical linear models found that African-Americans and Whites reported significant reductions in headache frequency and disability and improvements in life quality over the 6-month treatment period. African-Americans, unlike Whites, also reported significant decreases in headache severity. Nevertheless, Africans-Americans had significantly more frequent and disabling headaches and lower quality of life after treatment relative to Whites. Although Whites and African Americans responded favourably to headache treatments, more efficacious treatments are needed given the elevated level of headache frequency that remained in both racial groups following treatment.

History of childhood maltreatment is associated with comorbid depression in women with migraine.

BACKGROUND: A bidirectional relationship between migraine and depression suggests a neurobiological link. Adverse experiences, particularly childhood maltreatment, may alter neurobiological systems, and predispose to a multiplicity of adult chronic disorders. Our objective is to determine, within a headache clinic population of women, if depression moderates the abuse-migraine relationship. METHODS: At six headache specialty clinics, women with migraine were diagnosed using ICHD-II criteria, and frequency was recorded. A questionnaire regarding maltreatment history, headache characteristics, current depression, and somatic symptoms was completed. RESULTS: A total of 949 women with migraine completed the survey: 40% had chronic headache (> or =15 headache days/month) and 72% had "very severe" headache-related disability. Major depression was recorded in 18%. Physical or sexual abuse was reported in 38%, and 12% reported both physical and sexual abuse in the past. Migraineurs with current major depression reported physical (p < 0.001) and sexual (p < 0.001) abuse in higher frequencies compared to those without depression. Women with major depression were more likely to report sexual abuse occurring before age 12 years (OR = 2.30, 95% CI: 1.14 to 4.77), and the relationship was stronger when abuse occurred both before and after age 12 years (OR = 5.08, 95% CI: 2.15 to 11.99). Women with major depression were also twice as likely to report multiple types of maltreatment (OR = 2.07, 95% CI: 1.27 to 3.35) compared to those without depression. CONCLUSIONS: Childhood maltreatment was more common in women with migraine and concomitant major depression than in those with migraine alone. The association of childhood sexual abuse with migraine and depression is amplified if abuse also occurs at a later age.

High prevalence of somatic symptoms and depression in women with disabling chronic headache.

OBJECTIVE: To better define, in women with headache, the relationship of depression and somatic symptoms to headache, characterized by diagnoses, frequency, and disability. METHODS: At six headache specialty clinics, women with headache were classified using ICHD-II criteria, and frequency was recorded. A questionnaire addressing demographics, age at onset of headache, headache-related disability, somatic symptom, and depression severity was completed. Logistic regression was performed to measure the associations of headache frequency and headache-related disability with somatic symptom and depression severity. RESULTS: A total of 1,032 women with headache completed the survey, 593 with episodic (96% with migraine) and 439 with chronic headache (87% with migraine). Low education and household income was more common in chronic headache sufferers and in persons with severe headache disability. Somatic symptom prevalence and severity was greater in persons with chronic headache and with severe headache-related disability. Significant correlation was observed between PHQ-9 and PHQ-15 scores (r = 0.62). Chronic headache, severe disability, and high somatic symptom severity were associated with major depressive disorder (OR = 25.1, 95% CI: 10.9 to 57.9), and this relationship was stronger in the subgroup with a diagnosis of migraine (OR = 31.8, 95% CI: 12.9 to 78.5). CONCLUSIONS: High somatic symptom severity is prevalent in women with chronic and severely disabling headaches. Synergistic relationship to major depression exists for high somatic symptom severity, chronic headache, and disabling headache, suggesting a psychobiological underpinning of these associations.

Orthotopic heart transplantation with bicaval and pulmonary venous anastomoses.

We present our experience with an alternative technique for orthotopic heart transplantation. It consists of total excision of the recipient's atria, with the donor's heart implantation performed using bicaval end-to-end anastomoses as well as pulmonary venous anastomoses. Forty consecutive patients receiving transplants in this fashion were compared with 64 patients who underwent orthotopic transplantation with the standard technique. The incidence of postoperative tricuspid regurgitation was reduced in patients receiving transplants with the new surgical approach (p = 0.003). In addition, the need for pacemaker implantation for severe bradyarrhythmia in the early (0 to 6 weeks) posttransplantation period (p = 0.003) was eliminated. Although not statistically significant, there was a trend in the reduction of postoperative mitral regurgitation in patients who received transplants by the modified technique. Based on this experience, we believe this modified technique for orthotopic heart transplantation has an anatomic and physiologic advantage that may improve long-term hemodynamic results.

Combined heart and kidney transplantation with allografts from the same donor.

We present the cases of 3 patients who underwent simultaneous heart and kidney transplantation using allografts from the same donor. This combined approach offers a reasonable option for patients with coexisting end-stage heart and kidney disease. A review of all previously reported cases suggests that survival is similar to that of single-organ transplantation. In addition, there appears to be a low incidence of rejection when multiple allografts from the same donor are used. The heart and kidney can and frequently do reject asynchronously, so rejection monitoring and surveillance should be carried out separately for each transplanted organ.

Motivational orientation and span of apprehension in children with mental retardation.

Children diagnosed as mildly mentally retarded were examined with respect to performance on Estes's (1965) span-of-apprehension task. Based on their scores on the Simplified Version of the Intellectual Achievement Responsibility scale, we divided subjects into a "learned-helpless" group and a "mastery-oriented" group. Motivational orientation had a significant effect on performance, with the mastery-oriented subjects demonstrating higher detection accuracies than the learned-helpless subjects. These results have implications regarding not only centrally mediated attentional functioning in children with mental retardation, but also interpretation of certain previous findings with the span-of-apprehension task.

Span of apprehension in mentally retarded children: an initial investigation.

The present investigation is the first to apply Estes' (1965) span of apprehension task to the study of attentional functioning in mentally retarded persons. Detection accuracies of 25 children diagnosed as mildly mentally retarded and 25 non-retarded children were compared under conditions of 100-ms exposure duration, and either two, four, six or eight distractor letters. Significant main effects of subject group and distractor number were found, with no interaction. These results provide converging evidence in support of previous positions that posit a structural deficit in mentally retarded individuals with respect to centrally mediated processing.

Bradyarrhythmias requiring pacemaker implantation after orthotopic heart transplantation: association with rejection.

Patients with severe sinus-node dysfunction that required pacemaker implantation after orthotopic heart transplantation were reviewed. During a 21-month period, 42 transplantations were performed in 41 patients. Five patients (12.2%) required a permanent pacemaker because of severe dysrhythmias. Three patients had moderate-to-severe cellular and/or humoral (vascular) rejection, and two of the five patients (40%) died. In the remaining two patients, bradyarrhythmias were due most likely to trauma to the sinus node during harvesting of the donor heart, and these patients have shown no evidence of significant rejection on repeated biopsies. A strong relationship was found between moderate or severe rejection and the development of significant bradyarrhythmias that required the placement of a permanent pacemaker. The development of severe dysrhythmias during the early or late posttransplantation period should be considered a manifestation of an ongoing rejection episode until proven otherwise. In our experience this evidence of rejection may imply a poor prognostic sign because it is associated with high mortality rates.

Mechanism of conversion of human apo- to holomethionine synthase by various forms of cobalamin.

Methionine synthase catalyzes the conversion of N5-methyltetrahydrofolate and homocysteine to tetrahydrofolate and methionine. Methylcobalamin (Me-Cbl) is tightly bound to methionine synthase and is required for enzymatic activity. When added to crude tissue homogenates, Me-Cbl stimulates methionine synthase but similar stimulation is observed with hydroxocobalamin, cyanocobalamin (CN-Cbl), and adenosyl-Cbl, although the mechanisms involved are unknown. We prepared human apomethionine synthase and studied its activation in the presence of [14C]CN-Cbl and [14CH3]Me-Cbl with concentrations of 2-mercaptoethanol ranging from 0.15 to 100 mM. We observed that the removal of the labeled upper axial ligands from CN-Cbl and Me-Cbl both paralleled the activation of human apomethionine synthase. Spectral studies employing CN-Cbl and Me-Cbl showed that both forms of Cbl must be converted to Cob(II)alamin before they can bind to human apomethionine synthase and convert it to its activated holoenzyme form. Studies with 14 different Cbl analogues with alterations in various portions of the corrin ring and the nucleotide showed that all of the analogues were able to fully activate human methionine synthase when they were reduced with 2-mercaptoethanol. Full activation occurred at lower concentrations of many of the Cbl analogues than occurred with Cbl itself. We conclude that Me-Cbl and other forms of Cob(III)alamin do not bind to human apomethionine synthase and that all must first be reduced to Cob(II)alamin before such binding can occur. The fact that human methionine synthase shows little absolute specificity for alterations in various portions of the Cbl molecule suggests that the potent inhibition of mammalian methionine synthase activity observed in vivo with various Cbl analogues is due to inhibition of intracellular Cbl transport or to inhibition of the enzymatic formation of Cob(II)alamin rather than to direct inhibition of mammalian methionine synthase itself.

Morbidity and mortality after coronary artery bypass in octogenarians.

One hundred fifty seven consecutive octogenarians (mean age +/- standard deviation, 82.4 +/- 1.9 years) underwent coronary artery bypass grafting with hypothermia (mean temperature, 21.8 degrees +/- 1.8 degrees C), hyperkalemic cardioplegia, and cardiopulmonary bypass in a 9-year period. Sixty-six percent were male. Preoperatively, 115 patients (73%) were in New York Heart Association functional class IV, with the remainder being in either class III (23%) or class II (4%). Twenty percent of the patients had major complications including postoperative hemorrhage (15), sepsis (9), cerebrovascular accident (6), third-degree heart block (5), renal failure requiring dialysis (1), and pulmonary embolism (1). The 30-day or in-hospital mortality rate was 7.0%. Mean total hospital stay was 26.1 +/- 17.9 days. One-year and 5-year actuarial survival rates were 85% and 62%, respectively. Higher mortality was seen to be associated with New York Heart Association class IV, left ventricular ejection fraction less than 0.40, and lesser values for cardiac output and cardiac index. At the 6-month postoperative follow-up, 73% of the survivors reported that their general health had improved as compared with before operation. This experience demonstrates that for select octogenarians with unmanageable angina pectoris, coronary artery bypass grafting is an effective therapeutic option.

Early-onset Alzheimer's disease: clinical predictors of institutionalization and death.

Follow-up observations were made of 92 white patients with early-onset Alzheimer's disease to determine the demographic, clinical, and neuropsychological factors predictive of institutionalization or death. The cumulative mortality rate 5 years after entry into the study was 23.9%, compared with an expected rate of 9.5%. The 5-year cumulative rate of admission to nursing homes was 62.8%. The language ability of the patients on entry to the study, their scores on a brief screening test of cognitive function, and their overall ratings of clinical dementia were found to be predictors of subsequent institutional care and death. The age of the patients had a significant modifying effect on these predictive factors, resulting in a greater risk of institutionalization and death in younger patients with severe cognitive impairment as compared with older individuals with the same degree of dysfunction.

Failure of long term high-dose lecithin to retard progression of early-onset Alzheimer's disease.

We conducted a six-month, randomized, double-blind trial of lecithin therapy in early-onset Alzheimer's disease. We hypothesized that such therapy would retard the progression of the clinical and neuropsychological manifestations of this illness. Of the 73 referred patients, 37 met strict requirements for diagnosis and compliance. The 21 placebo and 16 lecithin-treated patients (mean age 63 years) had a comparable degree of severity of dementia (mean Clinical Dementia Rating 1.6). Lecithin therapy produced an increase in mean plasma choline levels from a baseline of 15.9 to 28.8 nmol/ml. Patients were evaluated by the physician using clinical assessments (CDR, Lawton ADL and other rating scales) and by the neuropsychologist who determined the outcome of therapy on a battery of tests (Mini Mental State Examination, Wepman Aphasia Screen, Verbal Fluency Test, Verbal Selective Reminding Test and Spatial Memory Test). Only 6 (37.5%) of the 16 lecithin-treated patients were considered by the neurologist to be clinically stable or improved as compared to 12 (57.1%) of the 21 patients given placebo (difference -19.6%, 95% confidence limits of -51% to 12%). The neuropsychologic scores showed no differences in the stability of the dementing process over time between the lecithin-treated (50.0%) and placebo (47.6%) groups. On the basis of these clinical and neuropsychological findings, it appears that lecithin alone has no important therapeutic effect in early-onset Alzheimer's disease.

Comparison of amaurosis fugax and transient cerebral ischemia: a prospective clinical and arteriographic study.

We compared the clinical associations, arteriographic findings, and long-term outcome of 93 patients with amaurosis fugax and 212 patients with focal cerebral ischemia (transient ischemic attacks [TIAs]). The group of patients with cerebral TIAs included a significantly larger proportion of blacks and had a higher prevalence of hypertension than the group with amaurosis. Operable atherosclerotic lesions of the carotid arteries were more often associated with amaurosis (66%) than with cerebral TIAs (51%). The seven-year cumulative rate of cerebral infarction, however, was less in patients with amaurosis (14%) than in those with cerebral TIAs (27%; p less than 0.02). This difference in outcome persisted after adjustment for race, hypertension, and type of therapy. There were no significant differences, however, in the cumulative rates either of recurrent TIAs or of myocardial infarction or sudden death in the two groups of patients.

Isolation and characterization of methionine synthetase from human placenta.

The cobalamin-dependent enzyme, methionine synthetase, has been purified approximately 1000-fold to apparent homogeneity from human placenta with a 19% recovery. The final two steps of the purification utilized two different affinity columns. The first was a N5-methyltetrahydrofolate-cystamine-agarose column, and the second was a S-adenosylhomocysteine-agarose column. The enzyme was eluted from the first affinity column by buffer containing reducing agent which released the folate and the enzyme while elution from the second affinity column was accomplished with buffer containing 0.5 M sodium chloride. Criteria for purity were the observations that single peaks of enzyme activity, protein, and cobalamin with an apparent molecular weight of 160,000 were obtained by gel filtration and that holomethionine synthetase contained 1 mol of cobalamin/mol of protein. Furthermore, analysis by high performance liquid chromatography using a molecular weight sizing column demonstrated a single peak of protein with a corresponding cobalamin peak. This single peak of protein was progressively converted to a second protein peak that was enzymatically inactive, and this conversion was associated with a directly proportional loss of enzyme activity and cobalamin from the first peak. Methionine synthetase appeared to have a molecular weight of 160,000 on unreduced sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis and subunits of Mr 90,000, 45,000, and 35,000 on reduced sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis.

Risk of ischemic heart disease in patients with TIA.

A prospective study was made of the morbidity and mortality from ischemic heart disease in 390 patients with focal TIA caused by atherosclerotic vascular disease. The 5-year cumulative rate of myocardial infarction or sudden death in these patients was 21.0%, a rate only slightly less than that of fatal or nonfatal cerebral infarction (22.7%). Risk factors including diabetes, angina, and ECG abnormalities were associated with an increase in morbidity and mortality from ischemic heart disease. A major factor associated with these cardiac events was the presence of atherosclerotic obstructive or ulcerative lesions in the carotid arteries. These observations indicate that focal TIA caused by carotid atherosclerosis is a predictor not only of cerebral infarction, but also of serious cardiac disease and death.

Cranial nerve paralysis following carotid endarterectomy.

During the past seven years 347 patients have been entered into a data bank at the Duke University Medical Center for evaluation of transient neurologic ischemia. One hundred fifty eight of these patients had carotid endarterectomies of whom 24 (15.1%) developed 26 (16.4%) peripheral cranial nerve palsies. Injury to the peripheral portion of the hypoglossal nerve was noted in 13 patients, to the cervical branch of the facial nerve in five and to the recurrent laryngeal nerve branch of the vagus in eight. Complete recovery of nerve function usually occurred within four months but residual deficit was present at one year in two patients with facial nerve and four with hypoglossal nerve involvement. Even though these complications of carotid endarterectomy are generally benign and transient, the frequency of occurrence can be reduced if careful attention is given to anatomic localization of the cranial nerves during surgery.