Interrelationship of the rs7903146 TCF7L2 gene variant with measures of glucose metabolism and adiposity: The NEO study.

BACKGROUND AND AIMS: We investigated the interrelationship of rs7903146-T in TCF7L2 with measures of glucose metabolism and measures of adiposity. METHODS AND RESULTS: This cross-sectional analysis was conducted in 5744 middle-aged participants (mean (standard deviation [SD]) age is 55.9 (6.0) years) from the Netherlands Epidemiology of Obesity (NEO) Study. Associations between rs7903146-T and Type 2 diabetes mellitus (T2D) were assessed with logistic regression. Additive (per-allele) associations with measures of glucose metabolism (e.g., fasting insulin) and adiposity (e.g., body mass index [BMI]) were examined with multivariable linear regression. In the total study population, rs7903146-T was associated with a higher risk of T2D (additive odds ratio: 1.42; 95% confidence interval: 1.17; 1.72), and specifically with T2D treated with insulin analogs (2.31 [1.19; 4.46]). After exclusion of participants treated with glucose-lowering medication, rs7903146-T was associated with lower mean insulin concentration (additive mean difference: -0.07 SD [-0.14; 0.00]), but not with higher mean glucose concentration (0.03 SD [-0.01; 0.07]). Furthermore, rs7903146-T was associated with, among other measures of adiposity, a lower mean BMI (-0.04 SD [-0.09; -0.00]), and a lower mean total body fat (-0.04 SD [-0.08; -0.00]). The association between rs7903146-T and T2D increased after adjustment for BMI (odds ratio: 1.51 [1.24; 1.86]); the association between rs7903146-T and fasting insulin diminished after adjustment (-0.05 SD [-0.11; 0.02]). CONCLUSION: rs7903146-T is associated with a decreased insulin concentration and increased risk of T2D with opposing effects of adjustment for adiposity.

Presentation outside office hours does not negatively influence treatment times for reperfusion therapy for acute ischemic stroke.

BACKGROUND: Treatment outside office hours has been associated with increased workflow times for intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). Limited data suggest that this "off-hours effect" also exists for endovascular treatment (EVT). We investigated this phenomenon in a well-organized acute stroke care region in the Netherlands. METHODS: Retrospective, observational cohort study of consecutive patients with AIS who received reperfusion therapy in the Greater Amsterdam Area, consisting of 14 primary stroke centers and 1 comprehensive stroke center (IVT: 2009-2015, EVT: 2014-2017). Office hours were defined as presentation during weekdays between 8 AM and 5 PM, excluding National Festive days. Primary outcome was door-to-treatment time (door-to-needle [DNT] for IVT, door-to-groin [DGT] for EVT). For DGT, we used the door time of the first hospital. Other outcomes were in-hospital mortality, modified Rankin Scale (mRS) score at 90 days and symptomatic intracranial hemorrhage (sICH). We performed multivariable linear and logistic regression analyses and used multiple imputation to account for missing values. RESULTS: In total, 59% (2450/4161) and 61% (239/395) of patients treated with IVT and EVT, respectively, presented outside office hours. Median DNT was minimally longer outside office hours (32 vs. 30 min, p = 0.024, adjusted difference 2.5 min, 95% CI 0.7-4.2). Presentation outside office hours was not associated with a longer DGT (median 130 min for both groups, adjusted difference 7.0 min, 95% CI - 4.2 to 18.1). Clinical outcome and sICH rate also did not differ. CONCLUSION: Presentation outside office hours did not lead to clinically relevant treatment delays for reperfusion therapy in patients with AIS.

Antimigraine drug sumatriptan increases blood flow velocity in large cerebral arteries during migraine attacks.

Sumatriptan, a novel selective 5-hydroxytryptamine1d (5-HT1d) receptor agonist, which is highly effective in the acute treatment of migraine attacks, blocks dural neurogenic plasma extravasation and constricts cranial blood vessels in animal experiments. We measured intra- and extracranial blood flow velocities (BFV) with a transcranial Doppler device in 67 patients during a spontaneous migraine attack, before and after treatment with 3 mg or 6 mg subcutaneous sumatriptan or placebo. Sumatriptan, but not placebo, significantly increased BFV (cm/sec) in the internal carotid and middle cerebral arteries on both sides, without detectably changing the BFV in the common and external carotid arteries. The rise in BFV increased with the dose of sumatriptan, parallel to an increase in proportion of patients improved. There were no significant changes in heart rate, blood pressure, or respiratory frequency after treatment with sumatriptan. The increase in BFV probably reflects vasoconstriction of the large basal intracranial arteries, which may be a mechanism for the antimigraine action of sumatriptan.

Adult adrenoleukodystrophy: the clinical spectrum in a large Dutch family.

A large family with adrenoleukodystrophy is described and the case histories of two clinically symptomatic and related male patients are presented. Clinical, biochemical and genetic screening of their family demonstrated two clinically affected males, one biochemically affected male and five carrier females. Two women were symptomatic; one suffered an acute exacerbation. One female was diagnosed as a carrier, based on genetic analysis and the family history only. Endocrinological screening was performed in the five affected males, demonstrating an elevated adrenocorticotrophic hormone level and a normal cortisol level in two, as evidence of compensated adrenocortical failure.

Cytogenetic effects of fractionated or unfractionated X-ray exposures to mouse spermatogonia.

The induction of chromosomal aberrations in mouse spermatogonia was studied, after single (50 and 100 rad) and fractionated doses (50 / 50 rad spaced 24 h apart), a short time after irradiation, by analysis of mitotic stages. From 17 to 21 h after the second fraction of the dose, the recorded frequencies of chromosomal deletions and exchanges were fully additive when compared with single "control" doses. Thus there was no suggestion of any sensitization effect of the first exposure. Possible reasons for this are discussed.

Delay in diagnosis of X-linked adrenoleukodystrophy.

In 16 consecutive patients with clinically suspected and biochemically proven X-linked adrenoleukodystrophy (X-ALD), total delay (interval between onset of symptoms and diagnosis) and specialist delay (interval between referral to a specialist and diagnosis) were determined. All patients previously were unaware of the existence of X-ALD in their families. From the time of onset of symptoms attributable to this disease until diagnosis, mean total delay was 9.9 (range 1-33) years and mean specialist delay was 8.4 (range 0-33) years. Three patients who presented with adrenocortical insufficiency had mean total and specialist delays of 17.3 (range 9-33) years. Five patients with an initial diagnosis of multiple sclerosis had mean total and specialist delays of 12.8 (range 5-25) and 11.2 (range 1-23) years, respectively. In 12 patients with adrenomyeloneuropathy--the second most frequent phenotype of X-ALD--mean total delay was 11.0 (range 2-33) years and mean specialist delay 9.1 (range 0-33) years. Since 1981 X-ALD can be reliably diagnosed on the basis of elevated levels of very long chain fatty acids in plasma and/or cultured fibroblasts. The delays therefore must have been due to the unfamiliarity with the clinical manifestations and diagnostic possibilities of this disease. Once X-ALD is diagnosed, dietary treatment and/or bone marrow transplantation may be considered. Genetic counseling should be performed, and screening of other family members is essential for the early identification of affected relatives.

Lack of asymmetry of middle cerebral artery blood velocity in unilateral migraine.

BACKGROUND AND PURPOSE: A recent transcranial Doppler study found reduced blood velocity in seven patients during migraine attacks in the middle cerebral artery at the headache side. This would implicate vasodilation of the middle cerebral artery in the pathogenesis of headache in migraine. We attempted to confirm this finding. METHODS: We determined blood velocity with transcranial Doppler ultrasonography in the middle cerebral arteries of 51 migraine patients with unilateral headache (5 with aura, 46 without aura) and of 14 patients with bilateral headache, during and outside attacks. During attacks, median time from onset of attack to transcranial Doppler examination was 6 hours (range, 1 to 35 hours). RESULTS: We found no difference between blood velocity at the headache and nonheadache sides nor between blood velocity during and outside attacks. Similar results were obtained in a subgroup of 11 patients who were investigated in the first 4 hours of an attack. There were also no differences between attacks with unilateral or bilateral headache. CONCLUSIONS: We cannot support the hypothesis that migraine is associated with vasodilation of the middle cerebral artery ipsilateral to the headache.

Transient loss of speech followed by dysarthria after removal of posterior fossa tumour.

The authors report three children who suffered transient loss of speech during six to eight weeks following removal of a large midline cerebellar tumour. None manifested speech difficulties immediately after surgery, but all developed mutism within 24 to 48 hours. The speech of all children slowly but completely recovered, after a period of severe dysarthria. The re-organization of speech functions is discussed in relation to the functioning of musculature.

Blood flow velocity changes in migraine attacks--a transcranial Doppler study.

A pulsed Doppler device was used to measure blood flow velocities in the common carotid artery, the extracranial part of the internal carotid artery, the external carotid artery, the middle cerebral artery, and the anterior cerebral artery in 31 migraineurs without aura (n = 27) and with aura (n = 4), both during and outside an attack. The aims were to compare blood flow velocity during and between migraine attacks and to study asymmetries of the blood flow velocity. Compared with blood flow velocity values obtained in the attack-free interval, blood flow velocity was lower during attacks without aura in both common carotid arteries, but not in the other extra- and intracranial vessels which were examined. However, during attacks of migraine with aura, blood flow velocity tended to be lower in all examined vessels. There were no asymmetries of the blood flow velocity. We suggest that during migraine attacks without aura there is a dissociation in blood flow regulation in the common carotid and middle cerebral arteries.

Familial occurrence of tumours of the choroid plexus.

The case histories of two children of consanguineous parents with papillomas of the choroid plexus are presented. Although exogenic factors in the genesis of these neoplasms can not be excluded, autosomal recessive inheritance is proposed.

Vascular reactivity during migraine attacks: a transcranial Doppler study.

We measured vascular reactivity--expressed i) as decrease in blood flow velocity (cm/sec) per vol% CO2 decrease due to voluntary hyperventilation and ii) as increase of blood flow velocity during the first minute after resuming normal ventilation, per vol% CO2 increase--in the middle cerebral and basilar artery of 48 migraineurs with attacks without aura, and 17 normal controls. We found no differences for both determinants of vascular reactivity between migraineurs during and outside an attack, and between migraineurs and healthy volunteers. We conclude that the vasomotor reactivity is normal during migraine attacks without aura.

Holoprosencephaly: variation of expression in face and brain in three sibs.

A family is described containing three sibs with holoprosencephaly. They showed a striking diversity of both cerebral and facial abnormalities. Autosomal recessive inheritance seems most likely. Because of the great variety in expression of this disorder, it is of importance for genetic counselling to examine both sibs and parents.

Blood flow velocities in the vertebrobasilar system during migraine attacks--a transcranial Doppler study.

In this study, blood flow velocity in the basilar artery and both vertebral and middle cerebral arteries was measured with a transcranial Doppler device in 23 migraineurs during and outside a migraine attack. The aim of the study was to compare blood flow velocities during and outside an attack and to examine vascular reactivity to voluntary hyperventilation during both conditions. No differences in blood flow velocity were found. Although blood pressure was increased and end-expiratory CO2 decreased during the attack, this exerted no influence on blood flow velocity. Neither was a difference in vascular reactivity to voluntary hyperventilation detected between the two conditions. These findings support the notion of functional integrity of the examined large arteries during migraine attacks without aura.

Cranial nerve palsy as the presenting feature of secondary plasma cell leukemia.

A patient with IgA lambda multiple myeloma (MM) developed plasma cell leukemia (PCL), presenting as oculomotor nerve palsy. The cerebrospinal fluid (CSF) contained plasma cells, which double stained with fluoresceinated anti-IgA and anti-lambda antisera. The palsy was most probably due to meningeal myelomatosis. The neurologic disorder appeared to be refractory to the therapy used, although plasma cells disappeared from the peripheral blood. Secondary plasma cell leukemia is a rare complication of MM, usually occurring in the terminal stage of the disease. Those patients may be eligible for central nervous system (CNS) prophylaxis, as is commonly performed in patients with other types of leukemia.