The association between migraine and dementia - a national register-based matched cohort study.

OBJECTIVES: Migraine and dementia, two major public health challenges, are associated, but more knowledge is needed to understand their relationship. Objectives of this study were to investigate 1) the association between non-self-reported measures of migraine and dementia, and whether dementia was associated with 2) migraine without aura (MO) and with aura (MA) in combination with migraine medication use, and 3) migraine severity operationalized as the number of migraine prescriptions. STUDY DESIGN: Matched cohort study. METHODS: National register data were obtained from individuals born between 1934 and 1958. Migraine cases (aged 25-58 years) were identified by migraine diagnoses and redeemed migraine medication. Migraine cases were matched with non-cases (N = 340,850) and date of diagnosis or medication redemption was defined as index year. Dementia was identified by dementia diagnoses and redeemed dementia medication. RESULTS: We observed a 1.46 (95% CI: 1.26-1.69) times higher dementia rate in individuals with a migraine diagnosis and a 0.86 (95% CI: 0.76-0.97) times lower rate when using migraine medication. We found the highest dementia rate among individuals with MA, who also used migraine medication (HR = 2.23; 95% CI: 1.19-4.17), and the lowest rate among individuals with MO, who also used medication (HR = 1.25; 95% CI: 0.75-2.10). The number of migraine medication prescriptions was not associated with dementia. CONCLUSIONS: Being registered with a migraine diagnosis was associated with a higher dementia rate, while use of prescribed migraine medication was not. The differences in the dementia rate among migraine cases identified via diagnoses versus medications warrants further investigation.

More precise phenotyping of cluster headache using prospective attack reports.

BACKGROUND AND PURPOSE: The clinical characteristics of cluster headache (CH) are based mainly on retrospective attack descriptions of 'usual' attacks, but whether these reports are reliable is uncertain. The aim was to compare retrospective and prospective attack descriptions and describe the within- and between-patient variability of attacks. METHOD: Fifty-seven CH patients underwent a semi-structured interview obtaining a retrospective account of usual CH attacks. Patients thereafter prospectively recorded the clinical characteristics of up to 10 attacks per patient in a headache diary. Four different attack characteristics were investigated: (i) severity, (ii) duration, (iii) number of autonomic symptoms and (iv) number of migrainous symptoms. Retrospective and prospective data were compared. Within- and between-patient variability of attacks was assessed. RESULTS: Retrospective attack descriptions (n = 57) were significantly longer (P = 0.046) and more severe (P < 0.0001) for untreated attacks compared with prospective reports (n = 500). The number of autonomic symptoms was significantly higher in the retrospective reports compared to the prospective reports (P < 0.0001). Within-patient variability for attack duration, pain severity and number of autonomic and migrainous symptoms was low. Compared to men, more women reported longer (P = 0.026) and more severe (P = 0.028) attacks with more migrainous symptoms (P = 0.033). CONCLUSIONS: Important differences were found between prospectively and retrospectively reported attacks with duration and severity of untreated attacks overestimated in retrospective attack descriptions. CH attacks display low within-patient variability, but the presentation of CH attacks varies between patients. The high prevalence of symptoms typically associated with migraine should raise more diagnostic awareness for CH, especially in women who are more often misdiagnosed as having migraine.

Medical and non-medical predictors of initiating long-term use of proton pump inhibitors: a nationwide cohort study of first-time users during a 10-year period.

BACKGROUND: Studies of the increasing use of proton pump inhibitors (PPIs) have mainly focused on prevalent long-term use and associations with gastrointestinal morbidity and comedication. Little is known about non-medical characteristics of first-time users of PPI, and predictors of initiating long-term use of PPIs. AIMS: To describe medical and non-medical characteristics of first-time PPI users during a 10-year period and to analyse predictors of initiation of long-term use (>60 defined daily doses (DDDs) within 6 months) of PPIs. METHODS: A nationwide cohort study of first-time users of PPI. Data were collected from Danish national registers. Individuals redeeming their first prescription for a PPI (omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole) in 2001 and 2011 were identified. Redemption of more than 60 DDDs of PPI within 6 months defined long-term use. Logistic regression models were used to determine the associations between previous diagnoses, comedication and socio-economic characteristics and initiation of long-term use of PPIs in 2011. RESULTS: From 2001 to 2011 incidence of first-time users increased with an incidence rate ratio of 1.53 and mean quantity of PPI redeemed at first prescription increased by 44.6%. In 2011 a total of 37.6% redeemed >60 DDDs within 6 months, and 96% of the long-term users did not have a diagnosis registered which indicated treatment. New onset long-term use was significantly associated with low income and low educational level when adjusting for other predisposing variables. CONCLUSIONS: Proton pump inhibitor treatment is increasingly initiated with larger quantities prescribed for indications that are unidentifiable from the registers. Morbidity and comedication seem to be the strongest predictors of new onset long-term use of PPIs. However, there is also an independent social gradient.

General practice variation when initiating long-term prescribing of proton pump inhibitors: a nationwide cohort study.

BACKGROUND: Suggestions of overprescribing of proton pump inhibitors (PPIs) for long-term treatment in primary care have been raised. This study aims to analyse associations between general practice characteristics and initiating long-term treatment with PPIs. METHODS: A nationwide register-based cohort study of patients over 18 years redeeming first-time prescription for PPI issued by a general practitioner in Denmark in 2011. Patients redeeming more than 60 defined daily doses (DDDs) of PPI within six months were defined first-time long-term users. Detailed information on diagnoses, concomitant drug use and sociodemography of the cohort was extracted. Practice characteristics such as age and gender of the general practitioner (GP), number of GPs, number of patients per GP, geographical location and training practice status were linked to each PPI user. Logistic regression analysis was used to determine associations between practice characteristics and initiating long-term prescribing of PPIs. RESULTS: We identified 90 556 first-time users of PPI. A total of 30 963 (34.2 %) met criteria for long-term use at six months follow-up. GPs over 65 years had significantly higher odds of long-term prescribing (OR 1.32, CI 1.16-1.50), when compared to younger GPs (<45 years). Furthermore, female GPs were significantly less likely to prescribe long-term treatment with PPIs (OR 0.87, CI 0.81-0.93) compared to male GPs. CONCLUSIONS: Practice characteristics such as GP age and gender could explain some of the observed variation in prescribing patterns for PPIs. This variation may indicate a potential for enhancing rational prescribing of PPIs.

Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis.

Adrenergic stimulation adversely affects tumor growth and metastasis, but the underlying mechanisms are not well understood. Here, we uncovered a novel mechanism by which catecholamines induce inflammation by increasing prostaglandin E2 (PGE2) levels in ovarian cancer cells. Metabolic changes in tumors isolated from patients with depression and mice subjected to restraint stress showed elevated PGE2 levels. Increased metabolites, PTGS2 and PTGES protein levels were found in Skov3-ip1 and HeyA8 cells treated with norepinephrine (NE), and these changes were shown to be mediated by ADRB2 receptor signaling. Silencing PTGS2 resulted in significantly decreased migration and invasion in ovarian cancer cells in the presence of NE and decreased tumor burden and metastasis in restraint stress orthotopic models. In human ovarian cancer samples, concurrent increased ADRB2, PTGS2 and PTGES expression was associated with reduced overall and progression-free patient survival. In conclusion, increased adrenergic stimulation results in increased PGE2 synthesis via ADRB2-Nf-kB-PTGS2 axis, which drives tumor growth and metastasis.

Donor Kidney With Renal Cell Carcinoma Successfully Treated With Radiofrequency Ablation: A Case Report.

BACKGROUND: The risk of donor-transmitted cancer is evident. CASE REPORT: We report the case of a 69-year-old woman who was transplanted with a kidney from a deceased donor. Four days after transplantation a routine ultrasound scan revealed a 3-cm tumor in the middle-upper pole of the allograft. A biopsy showed the tumor to be papillary renal cell carcinoma. The patient was treated with radiofrequency ablation. This procedure was complicated by the development of a cutaneous fistula and open surgery was done with resection of an area of necrosis in the kidney and of the fistula. The maintenance immunosuppressive regimen was modified with a change in treatment to everolimus in combination with reduced dose mycophenolate and low-dose steroids. The patient was followed for 4.5 years and during that time she remained dialysis independent with an excellent allograft function (serum creatinine, 95 µmol/L [1.04 mg/dL]). CONCLUSIONS: To the best of our knowledge, this is the first case in which a donor-transmitted tumor was diagnosed in the renal allograft only 4 days after transplantation and subsequently treated successfully with radiofrequency ablation.

Fatal progressive multifocal leukoencephalopathy in a kidney transplant recipient 19 years after successful renal allograft transplantation.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare, demyelinating disease caused by viral infection of glial cells by JC polyomavirus (JCV) in immunocompromised patients. JCV is a member of the Polyomaviridae family. Infection is usually latent and reactivation only occurs in circumstances of extreme immunodeficiency. Development of fulminant PML is rare and treatment options are limited. CASE REPORT: We have presented a case of JCV reactivation resulting in PML 19 years after renal allograft transplantation and after recent conversion of immunosuppressive treatment. One year after conversion of immunosuppressive therapy owing to biopsy-proven acute humoral rejection, our patient presented with symptoms of deteriorating neurologic status. Cerebral computed tomography showed abnormal signals in the frontal lobe suspect for PML. Diagnosis was confirmed by qualitative polymerase chain reaction analysis of the cerebrospinal fluid. Owing to severe renal insufficiency, treatment options were limited to tapering of immunosuppressive treatment in hopes of achieving host clearance of the viral infection. Despite prompt termination of immunosuppressive treatment, the patient suffered rapid progressive neurologic decline and death rapidly ensued. CONCLUSION: Development of PML in transplant recipients remains rare. Despite advances in our understanding of JCV infection and PML, treatment options remain limited and prognosis is often poor.

Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation.

In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent.

Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare, dominantly inherited subtype of migraine with transient hemiplegia during the aura phase. Mutations in at least three different genes can produce the FHM phenotype. The mutated FHM genes code for ion transport proteins that animal and cellular studies have associated with disturbed ion homeostasis, altered cellular excitability, neurotransmitter release, and decreased threshold for cortical spreading depression. The common forms of migraine are characterized interictally by a habituation deficit of cortical and subcortical evoked responses that has been attributed to neuronal dysexcitability. FHM and the common forms of migraine are thought to belong to a spectrum of migraine phenotypes with similar pathophysiology, and we therefore examined whether an abnormal habituation pattern would also be found in FHM patients. METHODS: In a group of genotyped FHM patients (five FHM-1, four FHM-2), we measured habituation of visual evoked potentials (VEP), auditory evoked potentials including intensity dependence (IDAP), the nociception-specific blink reflex (nsBR) and compared the results to a group of healthy volunteers (HV). RESULTS: FHM patients had a more pronounced habituation during VEP (P=0.025) and nsBR recordings (P=0.023) than HV. There was no difference for IDAP, but the slope tended to be steeper in FHM. CONCLUSION: Contrary to the common forms of migraine, FHM patients are not characterized by a deficient, but rather by an increased habituation in cortical/brain stem evoked activities. These results suggest differences between FHM and the common forms of migraine, as far as central neuronal processing is concerned.

Identification of New Sources of Resistance in Winter Wheat to Multiple Strains of Xanthomonas translucens pv. undulosa.

Bacterial leaf streak (BLS), caused by Xanthomonas translucens pv. undulosa, has re-emerged as an important disease of wheat (Triticum aestivum) in the United States. Planting resistant varieties is the best approach to manage BLS in the absence of effective bactericides. However, most of the wheat varieties currently grown in the Upper Midwest of the United States appeared to be susceptible to BLS. From the core subset of the USDA National Small Grain Collection (NSGC), a set of 605 winter wheat accessions of diverse origin and improvement status were initially inoculated with a virulent strain BLSW16 of X. translucens pv. undulosa from Casselton, ND on the flag leaf of each plant in a greenhouse. Disease reactions were assessed between 7 and 10 days after infiltration using a 0 to 6 rating scale, where ≤2.0 was considered resistant and >2.1 was considered susceptible. Resistance varied with geographic origin and was significantly (P ≤ 0.05) more frequent in accessions from North America compared to accessions from northern, eastern, and southern Europe and from south-central Asia. About 8.3% of accessions tested were resistant, and accessions with an improvement status of "cultivar" were significantly more likely to be resistant than were accessions classified as either landraces or breeding lines. Forty-two of the accessions exhibiting resistance in response to the strain BLSW16 in the first screening test were retested utilizing each of the two additional strains (BLS Cr25 and BLS Lb74 of X. translucens pv. undulosa) collected from Carrington and Lisbon, respectively. Nonparametric data analysis revealed 35 accessions were resistant, one accession, PI 266860, was susceptible to both strains, and six accessions showed differential responses. The majority of the BLS-resistant accessions also were resistant to at least one other important wheat disease based on the Germplasm Resources Information Network (GRIN) data. These results suggest that diverse and novel sources of resistance to BLS identified in this study can be utilized in winter wheat breeding programs.

Actinomyces species: A danish survey on human infections and microbiological characteristics.

This study compared phenotypic and genotypic identification of Actinomyces strains, tested susceptibility to antibiotics and evaluated their clinical importance. Thirty-four Actinomyces strains were examined; sixteen type strains, and 18 clinical strains from different hospitals in Denmark from the period 2003-2005. Partial 16S rDNA sequencing using a stretch of 526 bases was used for genotypic identification. Susceptibility testing was done by E-test. The antibiotics examined were: benzylpenicillin, piperacillin with tazobactam, ceftriaxone, meropenem, erythromycin, clindamycin, linezolid, moxifloxacin, tetracycline and tigecycline. Clinical parameters were obtained by reviewing patient records. There was poor agreement between the phenotypic and genotypic identification. Phenotypic tests were helpful in identifying strains closely related by DNA sequences. The strains were sensitive to the examined antibiotics except for moxifloxacin to which most strains were resistant, and a few strains were resistant to meropenem and tetracycline. The clinical strains were from many different types of infections and locations. None of the patients was described as having typical actinomycetic lesions, and an apparently good outcome was obtained with different treatment regimens.

Laparoscopically assisted total daVinci aorto bifemoral graft bypass with a unique system of graft delivery.

We report the first known example of a fully robotic aortobifemoral graft and aortic endarterectomy using the daVinci Surgical System and a unique method for graft delivery using the Endo-Vein Harvester.

Sumatriptan does not affect arteriovenous oxygen differences in jugular and cubital veins in normal human subjects.

Arteriovenous anastomoses (AVAs) may open up during migraine attacks. In studies with anaesthetized and bilaterally vagosympatectomized pigs, triptans reduce AVA blood flow and increase the arteriovenous O2 difference (AVDO2). To investigate whether subcutaneous sumatriptan 6 mg could induce changes in the AVDO2, we measured the AVDO2 in the external jugular vein in healthy subjects. We also measured the AVDO2 in the internal jugular and cubital veins. There were no changes in AVDO2 after subcutaneous sumatriptan, probably because AVA blood flow is limited in humans with an intact sympathetic nervous system.

Familial hemiplegic migraine type 1 shows no hypersensitivity to nitric oxide.

Familial hemiplegic migraine type 1 (FHM-1) is a dominantly inherited subtype of migraine with aura and transient hemiplegia associated with mutations in the CACNA1A gene. FHM-1 shares many phenotypical similarities with common types of migraine, indicating common neurobiological pathways. Experimental studies have established that activation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that CACNA1A mutations in patients with FHM-1 are associated with hypersensitivity to NO-cGMP pathway. We included eight FHM-1 patients with R583Q and C1369Y mutations and nine healthy controls, who received intravenous infusions of 0.5 microg kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by Dermascan. One patient reported migraine without aura 5 h after start of the GTN infusion. No aura was reported. The AUC(headache) in the immediate phase was more pronounced in patients than in controls (P = 0.01). In the 14 h following GTN infusion, there was no difference in the AUC(headache) between patients and controls (P = 0.17). We found no difference in the AUC(VmeanMCA) (P = 0.12) or AUC(STA) (P = 0.71) between FHM-1 patients and controls. None of the control persons reported migraine-like headache. FHM-1 patients do not show hypersensitivity of the NO-cGMP pathway, as characteristically seen in migraine patients with and without aura. This indicates that the pathophysiological pathways underlying migraine headache in FHM-1 may be different from the common types of migraine.

Familial hemiplegic migraine type 2 does not share hypersensitivity to nitric oxide with common types of migraine.

Familial hemiplegic migraine type 2 (FHM-2) and common types of migraine show phenotypic similarities which may indicate a common neurobiological background. The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that ATP1A2 mutations in patients with FHM-2 are associated with hypersensitivity to NO-cGMP pathway. Eight FHM-2 patients with R202Q, R763C, V138A and L764P mutations and nine healthy controls received intravenous infusions of 0.5 mug kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded the following variables: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by ultrasound. The primary end-points were differences in incidence of migraine headache and area under the curve (AUC) for headache score during an immediate phase (0-120 min) and a delayed phase (2-14 h) after start of infusion. We found no difference in the incidence of reported migraine between FHM-2 patients, 25% (two out of eight), and controls, 0% (0 out of nine) (95% confidence interval -0.06, 0.56) (P = 0.21). The AUC(headache) in the immediate (P = 0.37) and delayed (P = 0.09) phase was not different between patients and controls. The GTN infusion resulted in a biphasic response in patients. During the immediate phase, the median peak headache occurred at 30 min and tended to be higher in patients, 1 (0, 3.8), than in controls, 0 (0, 1) (P = 0.056). During the delayed phase, the median peak headache occurred 4 h after the start of the infusion and was significantly higher in patients, 2.5 (0, 3), than in controls, 0 (0, 0) (P = 0.046). We found no difference in the AUC(VmeanMCA) (P = 0.77) or AUC(STA) (P = 0.53) between FHM-2 patients and controls. GTN infusion failed to induce more migraine in FHM-2 patients than in controls. The pathophysiological pathways underlying migraine headache in FHM-2 may be different from the common types of migraine.

Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine.

We hypothesized that intravenous infusion of the parasympathetic transmitter, vasoactive intestinal peptide (VIP), might induce migraine attacks in migraineurs. Twelve patients with migraine without aura were allocated to receive 8 pmol kg(-1) min(-1) VIP or placebo in a randomized, double-blind crossover study. Headache was scored on a verbal rating scale (VRS), mean blood flow velocity in the middle cerebral artery (V(mean MCA)) was measured by transcranial Doppler ultrasonography, and diameter of the superficial temporal artery (STA) by high-frequency ultrasound. None of the subjects reported a migraine attack after VIP infusion. VIP induced a mild immediate headache (maximum 2 on VRS) compared with placebo (P = 0.005). Three patients reported delayed headache (3-11 h after infusion) after VIP and two after placebo (P = 0.89). V(mean MCA) decreased (16.3 +/- 5.9%) and diameter of STA increased significantly after VIP (45.9 +/- 13.9%). VIP mediates a marked dilation of cranial arteries, but does not trigger migraine attacks in migraineurs. These data provide further evidence against a purely vascular origin of migraine.

The validity of a symptom diary in ratings of dyspepsia measured against a detailed interview: do patients and clinicians agree in their assessment of symptoms?

BACKGROUND: Patients' self-assessment of symptoms is central in drug treatment trials of functional dyspepsia. The validity of such ratings is important. AIM: To validate a diary for monitoring severity and duration of dyspepsia. METHOD: We compared the diary-cards with two clinicians' ratings of the patient's open-ended responses to the same questions administered by interview. Agreements were evaluated by estimation of the overall agreement and weighted kappa values (Kw). RESULTS: Forty-six patients were evaluated. The Kw between the two clinicians rating severity and duration of symptoms were 0.59 and 0.86, respectively. Overall agreement between patients' diary rating and clinicians' consensus rating of severity were 52%, and a moderate agreement with Kw of 0.49 was found. For duration of symptoms the overall agreement and Kw were 67% and 0.59, respectively. Qualitative data revealed useful insight in the possible causes of suboptimal agreement between patients and clinicians. CONCLUSIONS: We found a moderate to good agreement between patient and observer ratings, indicating that patients to a reasonable extent interpret severity and duration of dyspeptic symptoms in the same way as do investigators. A ceiling effect of the duration scale indicates suboptimal response categories, which should be adjusted before further use.

Magnetic resonance angiography shows dilatation of the middle cerebral artery after infusion of glyceryl trinitrate in healthy volunteers.

Previous studies have reported dilatation of the middle cerebral artery (MCA) during acute glyceryl trinitrate (GTN)-induced headache, using imaging techniques such as transcranial Doppler (TCD), positron emission tomography (PET) and single photon emission computerized tomography (SPECT). In the present study we aimed to evaluate whether magnetic resonance angiography (MRA) may be used to examine the effect of GTN on the MCA, with respect to changes in diameter and cross-sectional area in healthy volunteers. In addition, we wanted to determine the intra- and inter-observer variation of the method. In a randomized, double blind, crossover study 12 healthy volunteers received intravenous infusion of GTN (0.5 microg/kg/min for 20 min) or placebo. Using 1.5 Tesla MRA, we recorded changes in the diameter and cross-sectional area of MCA before, during and after infusion of GTN. The MRA images were evaluated by two blinded, independent observers/neuroradiologists. The primary endpoints were the differences in the AUC for diameter and cross-sectional area of the MCA between the two experimental conditions and the intra- and inter-observer variation. The areas under the curve (AUC) of the MCA diameter and cross-sectional area were significantly greater after GTN than after placebo (P < 0.05). The intra-observer variation (day-to-day) at baseline was 8.3% and 10.9% for the two observers. The mean inter-observer variation of the cross-sectional MCA area was 15.5% and for the diameter measurements 8%. The present study shows that the MRA method gives a reliable semi-quantitative index of the vascular changes in the intra-cerebral arteries after infusion of GTN and may be useful for headache research.

Vasoactive intestinal polypeptide evokes only a minimal headache in healthy volunteers.

The role of the parasympathetic nervous system in the pathogenesis of migraine is disputed. The headache-eliciting effect of the parasympathetic neurotransmitter, vasoactive intestinal polypeptide (VIP), and its effect on cerebral arteries and brain haemodynamics has not been systematically studied in man. We hypothesized that infusion of VIP might induce headache in healthy subjects and cause changes in cerebral haemodynamics. VIP (8 pmol/kg per min) or placebo (0.9% saline) was infused for 25 min into 12 healthy young volunteers in a crossover, double-blind design. Headache was scored on a verbal rating scale from 0 to 10, regional cerebral blood flow (rCBF) was measured with single-photon emission computed tomography and (133)Xe inhalation and mean flow velocity in the middle cerebral artery (V(meanMCA)) was measured with transcranial Doppler ultrasonography. The headache was very mild with a maximum score of 2 and described as a pressing or throbbing sensation. Five participants developed headache during VIP and one during placebo. During the infusion, a significant drop in V(meanMCA) was seen for VIP compared with placebo (P < 0.001), but the effect quickly waned and no difference was found when comparing the time between 30 and 120 min. In addition, no significant difference in the diameter of the MCA could be found during the infusion. No significant differences in rCBF (P = 0.10) were found between VIP and placebo. A marked dilation of the superficial temporal artery was seen (P = 0.04) after VIP in the first 30 min but no difference was found when comparing the time between 30 and 120 min. We found no difference in mean arterial blood pressure between VIP and placebo days but the heart rate increased significantly on a VIP day compared with a placebo day (AUC(0-30 min), P < 0.001). Plasma VIP was significantly higher on a VIP day compared with placebo (AUC(0-80 min), P < 0.001). These results show that VIP causes a decrease in V(meanMCA) without affecting rCBF. In spite of a marked vasodilator effect in the extracranial vessels and increased plasma VIP, healthy subjects developed only a very mild headache.

Glutathione depletion modulates methanol, formaldehyde and formate toxicity in cultured rat conceptuses.

The proposed use of methanol (H3COH) as an alternative to fossil fuels has prompted concern about potential health risks resulting from widespread environmental exposure. Methanol is teratogenic in rodents and, although the exact toxic species is not known, teratogenesis may result from the enzymatic biotransformation of H3COH to formaldehyde (CH2O) and formic acid causing increased biological reactivity and toxicity. A protective role for the antioxidant glutathione (GSH) has been described for H3COH, CH2O and formic acid toxicity in various biological systems but has yet to be evaluated in the developing conceptus. Whole embryo culture studies were conducted using GD 10-11 rat conceptuses to elucidate the relationship between H3COH and its metabolites and GSH status. Methanol exposure produced a decrease in normal growth parameters and a dose-dependent loss of viability. CH2O had deleterious effects on embryo growth and viability. Sodium formate (HCOONa) exposure resulted in a high mortality rate but viable embryos did not manifest any abnormalities. Methanol, CH2O, and HCOONa all produced a significant depletion of GSH in both embryo and VYS. Inhibition of GSH synthesis by L-buthionine-S,R-sulfoximine (BSO) treatment exacerbated H3COH, CH2O and HCOONa embryotoxicity. Interestingly, only H3COH/BSO and CH2O/BSO co-treatments caused increased malformation, while embryos treated with HCOONa/BSO did not produce any developmental deformities. These results implicate CH2O as the most embryotoxic H3COH metabolite, on a molar basis, in terms of causing dysmorphogenesis, alterations of normal growth parameters and embryolethality. HCOONa was selectively embryolethal and did not produce dysmorphogenesis. CH2O toxicity is potentiated by GSH depletion, indicating that GSH may be more directly involved in its detoxication in the embryo.