RSUME inhibits VHL and regulates its tumor suppressor function.

Somatic mutations or loss of von Hippel-Lindau (pVHL) happen in the majority of VHL disease tumors, which present a constitutively active Hypoxia Inducible Factor (HIF), essential for tumor growth. Recently described mechanisms for pVHL modulation shed light on the open question of the HIF/pVHL pathway regulation. The aim of the present study was to determine the molecular mechanism by which RSUME stabilizes HIFs, by studying RSUME effect on pVHL function and to determine the role of RSUME on pVHL-related tumor progression. We determined that RSUME sumoylates and physically interacts with pVHL and negatively regulates the assembly of the complex between pVHL, Elongins and Cullins (ECV), inhibiting HIF-1 and 2α ubiquitination and degradation. We found that RSUME is expressed in human VHL tumors (renal clear-cell carcinoma (RCC), pheochromocytoma and hemangioblastoma) and by overexpressing or silencing RSUME in a pVHL-HIF-oxygen-dependent degradation stability reporter assay, we determined that RSUME is necessary for the loss of function of type 2 pVHL mutants. The functional RSUME/pVHL interaction in VHL-related tumor progression was further confirmed using a xenograft assay in nude mice. RCC clones, in which RSUME was knocked down and express either pVHL wt or type 2 mutation, have an impaired tumor growth, as well as HIF-2α, vascular endothelial growth factor A and tumor vascularization diminution. This work shows a novel mechanism for VHL tumor progression and presents a new mechanism and factor for targeting tumor-related pathologies with pVHL/HIF altered function.

An open study of botulinum-A toxin treatment of trigeminal neuralgia.

Thirteen subjects with trigeminal neuralgia were treated with botulinum-A neurotoxin (BoNT/A) in an open-label pilot study. After BoNT/A, visual analog scale score, surface area of pain, and therapeutic coefficient were reduced in all patients and for all branch trigeminal nerves studied. Therefore, BoNT/A is an efficient treatment. There were no major side effects. A placebo-controlled clinical trial is needed to confirm these findings.

Fatigue in chronic migraine patients.

Fatigue is a common symptom frequently reported in many disorders including headaches, but little is known about its nature. The objective was to determine the prevalence of fatigue in chronic migraine (CM) patients, to define its subtypes and its relationship with other conditions comorbid with CM. Sixty-three CM patients were analysed. The Fatigue Severity Scale (FSS), the Chalder fatigue scale and the CDC diagnostic criteria for chronic fatigue syndrome (CFS) were used. Fifty-three (84.1%) patients had FSS scores greater than 27. Forty-two (66.7%) patients met the CDC criteria for CFS. Thirty-two patients (50.8%) met the modified CDC criteria (without headache). Beck depression scores correlated with FSS, mental and physical fatigue scores. Trait anxiety scores also correlated with fatigue scales. Women had higher FSS scores than men, P < 0.05. Physical fatigue was associated with fibromyalgia, P < 0.05. Fatigue as a symptom and CFS as a disorder are both common in CM patients. Therapeutic interventions include a graded aerobic exercise program, cognitive behavioural therapy and antidepressants. Identification of fatigue and its subtypes in headache disorders and recognition of headaches in CFS patients has implications for the pathophysiology, diagnosis and treatment of these disorders.

Hypothalamic involvement in chronic migraine.

OBJECTIVES: Chronic migraine (CM), previously called transformed migraine, is a frequent headache disorder that affects 2%-3% of the general population. Analgesic overuse, insomnia, depression, and anxiety are disorders that are often comorbid with CM. Hypothalamic dysfunction has been implicated in its pathogenesis, but it has never been studied in patients with CM. The aim was to analyze hypothalamic involvement in CM by measurement of melatonin, prolactin, growth hormone, and cortisol nocturnal secretion. METHODS: A total of 338 blood samples (13/patient) from 17 patients with CM and nine age and sex matched healthy volunteers were taken. Melatonin, prolactin, growth hormone, and cortisol concentrations were determined every hour for 12 hours. The presence of comorbid disorders was also evaluated. RESULTS: An abnormal pattern of hypothalamic hormonal secretion was found in CM. This included: (1) a decreased nocturnal prolactin peak, (2) increased cortisol concentrations, (3) a delayed nocturnal melatonin peak in patients with CM, and (4) lower melatonin concentrations in patients with CM with insomnia. Growth hormone secretion did not differ from controls. CONCLUSION: These results support hypothalamic involvement in CM, shown by a chronobiologic dysregulation, and a possible hyperdopaminergic state in patients with CM. Insomnia might be an important variable in the study findings.

Occurrence of a putative SCF ubiquitin ligase complex in Drosophila.

Many proteins are targeted to proteasome degradation by a family of E3 ubiquitin ligases, termed SCF complexes, that link substrate proteins to an E2 ubiquitin-conjugating enzyme. SCFs are composed of three core proteins-Skp1, Cdc53/Cull, Rbx1/Hrt1-and a substrate specific F-box protein. We have identified in Drosophila melanogaster the closest homologues to the human components of the SCF(betaTrCP) complex and the E2 ubiquitin-conjugating enzyme UbcH5. We show that putative Drosophila SCF core subunits dSkpA and dRbx1 both interact directly with dCu11 and the F-box protein Slmb. We also describe the direct interaction of the UbcH5 related protein UbcD1 with dCul1 and Slmb. In addition, a functional complementation test performed on a Saccharomyces cerevisiae Hrt1p-deficient mutant showed that Drosophila Rbx1 is able to restore the yeast cells viability. Our results suggest that dRbx1, dSkpA, dCullin1, and Slimb proteins are components of a Drosophila SCF complex that functions in combination with the ubiquitin conjugating enzyme UbcD1.

Tension-type headaches.

Tension-type headache is the term designated by the International Headache Society to describe what was previously called tension headache, muscle contraction headache, psychomyogenic headache, stress headache, ordinary headache, and psychogenic headache. The International Headache Society defines tension-type headache more precisely, distinguishes between the episodic and the chronic varieties, and divides them into two groups, those associated with a disorder of the pericranial muscles and those not associated with this type of disorder. Most clinic-based studies of tension-type headache suffer from selection bias, as they include patients with more severe headaches, patients with concomitant migraine, and patients with chronic daily headache. Traditionally, episodic tension-type headache and migraine have been considered distinct disorders, and the International Headache Society continues the separation. Some believe that both migraine and tension-type headache are recurring benign headaches. Chronic tension-type headache used to be called chronic daily headache, but they are not identical. Chronic tension-type headache must be distinguished from chronic daily headache even though the International Headache Society has not done this. Chronic daily headache is a syndrome consisting of a group of disorders and can be subclassified into primary and secondary types. The primary chronic daily headache disorders include transformed migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Secondary causes of chronic daily headache include post-traumatic headache, cervical spine disorders, and headache associated with vascular disorders and nonvascular intracranial disorders. Patients with frequent headaches are prone to overuse analgesics, ergotamine, or both. Most patients with chronic daily headache overuse symptomatic medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin (5-HT) and migraine.

Serotonin, or 5-hydroxytryptamine [5-HT], is a biogenic amine implicated in controlling feeding behavior, thermoregulation, sexual behavior, and sleep. 5-HT receptors recognize at least three types of molecular structures: G protein coupled receptors, ligand gated ion channels, and transporters. It is now believed that there are at least seven different families of receptors, many of which have subtypes. The nervous system can be compared to a group of well-modulated neural networks functioning in parallel. The serotonergic system may modulate these networks rather than actually mediate individual responses. Circumstantial evidence suggests a link between 5-HT and migraine. Platelet HT decreases during an attack, and in some cases increased levels of metabolites are found. Many antimigraine drugs interact with 5-HT and its receptors.

The forgotten lumbar puncture.

Lumbar puncture is crucial in two distinct clinical situations in the diagnosis of the headache patient. The first is the patient who is suspected of having a symptomatic headache; the second is the patient with a chronic intractable or atypical headache disorder. This review discusses the usefulness of the lumbar puncture in the diagnosis of headache secondary to subarachnoid hemorrhage, meningitis, and intracranial hypotension and hypertension. The value of lumbar puncture in the presence of a normal CT/MRI scan is discussed.

Epidemiology of migraine.

Migraine epidemiology presents methodological challenges, partially simplified by the use of the new International Headache Society (IHS) Classification. Most previously published migraine studies were clinic-based, which introduces bias since less than 5% of migraineurs consult specialists. A series of population-based studies of migraine prevalence and incidence, based on the new operational IHS criteria, are now available and are reviewed, along with the migraine personality, comorbid psychiatric conditions and neuropsychological impairment. Migraine headaches are now divided into those with aura (classic migraine) and those without aura (common migraine). Headache occurs in about 91% of men and 96% of women, migraine occurs in about 6% of men and 18% of women (one-year prevalence). Migraine is most common in the third decade of life and in lower socioeconomic groups. It is associated with an increased prevalence of depression and panic attacks.

The treatment of cluster headache with repetitive intravenous dihydroergotamine.

We reviewed our experience with 54 cluster headache patients (23 episodic, 31 chronic) admitted to our headache center 64 tines over the past five years and treated with repetitive intravenous dihydroergotamine (IV DHE). DHE therapy was initiated on admission and prophylactic medication regimens were started or adjusted. All 54 patients had complete relief of their cluster headache, usually within two days. Most (82.8%) had no side effects. The average length of hospitalization was 6.7 days. At the three month followup, 92.9% of the episodic cluster patients were headache-free and 7.1% had a 50-74% improvement; at six months, all were headache-free. Of the chronic cluster patients, 44.4% were headache-free at three months and 52.8% had at least 50% improvement. At six months, 75% were headache-free and 22.2% were at least 75% improved, probably as a result of continued prophylactic medication. Repetitive IV DHE safely, rapidly, and effectively controls cluster headache.

Review article: migraine and pregnancy.

A 27-year-old woman with no family or personal history of migraine presented with headache associated with unilateral paresthesias and blurred vision. This was her first, and so far only, attack of migraine with aura and led to the diagnosis of her pregnancy and to this review. Migraine can begin for the first time with pregnancy, particularly in the first trimester. Cases of migraine with aura are the most commonly reported. Preexisting migraine usually improves with pregnancy, particularly if it was associated with menstrual migraine. Headache occurs frequently in the post-partum period, particularly in known migraineurs. Migraineurs have no increased risk of complications during pregnancy and their children have no increased incidence of birth defects.

Estrogens, progestins, and headache.

PIP: Migraine headaches appear to be linked to the menstrual cycle and the use of oral contraceptives (OCs). Migraine attacks occur during menses in 60% of women and appear to be related to the withdrawal of estrogen. The fluctuations in estrogen levels associated with migraine headaches produce biochemical changes in prostaglandin production, prolactin release, and opoid regulation. Treatment seeks to interrupt the pathophysiological sequence of menstrual-related migraine through the administration of nonsteroidal anti-inflammatory drugs, ergotamine, or, in refractory cases, hormonal agents. The frequency of migraine decreases with age, but tends either to regress or worsen during menopause. In some cases, estrogen replacement therapy for menopausal symptoms produces headache and it may be necessary to reduce the estrogen dose or change from conjugated estrogen to pure estradiol or estrone. The incidence and severity of migraines are also affected by OC use. OCs may trigger migraine episodes and exacerbate or alleviate pre-existing headache. This variable response seems to be a result of individual differences in intrinsic estrogen neuronal response. Although migraine itself may be a risk factor in stroke, there is no evidence that this risk is increased in migrainers who use OCs.^ieng

Idiopathic intracranial hypertension without papilledema.

We describe 10 patients with idiopathic intracranial hypertension who did not have papilledema. Idiopathic intracranial hypertension without papilledema, although rarely reported, may well be a clinically important headache syndrome. Historical and demographic features of patients with idiopathic intracranial hypertension without papilledema are similar to those of patients with papilledema. Obese women with chronic daily headache and symptoms of increased intracranial pressure, pulsatile tinnitus, history of head trauma or meningitis, an empty sella on imaging studies, or a headache that is unrelieved by standard therapy should have a diagnostic lumbar puncture. Findings from laboratory and neurologic investigations are normal in most patients with idiopathic intracranial hypertension without papilledema. Initial management should include removal of possible inciting agents, weight loss if applicable, and standard headache therapy. Lumbar puncture and diuretic therapy should precede a trial of corticosteroids. Surgery (lumboperitoneal or ventriculoperitoneal shunt or perhaps optic nerve sheath fenestration) may be indicated for prolonged incapacitating headache that is not responsive to medical management or lumbar puncture.

Isolation and characterization of a dimeric cAMP-dependent protein kinase from the fungus Saccobolus platensis.

A cAMP-dependent protein kinase from mycelia of Saccobolus platensis was characterized. The holoenzyme seems to be a dimer (i.e., regulatory subunit--catalytic subunit) of 78,000 Da, slightly activated by cAMP but susceptible to dissociation into its subunits by cAMP, or by kemptide and protamine, the best substrates for Saccobolus protein kinase. The regulatory subunit was purified to homogeneity by affinity chromatography. It is highly specific for cAMP and has two types of binding sites but failed to inhibit the phosphotransferase activity of the homologous or the heterologous (bovine heart) catalytic components. The activity of the catalytic subunit was completely abolished by the regulatory component of the bovine heart protein kinase as well as by a synthetic peptide corresponding to the active site of the mammalian protein kinase inhibitor. The data suggest that interaction between the subunits of the S. platensis protein kinase is different than that found in cAMP-dependent protein kinases from other sources. Similarities and differences between the Saccobolus protein kinase and enzymes from low eucaryotes and mammalian tissues are discussed.

Repetitive intravenous DHE in the treatment of refractory headache.

We analyzed retrospectively the data for 300 patients with refractory headache who were treated with dihydroergotamine (DHE) at the Comprehensive Headache Center at Germantown Hospital. The patients had either chronic daily headache (with drug rebound -216, without rebound -42), short-duration headache (18), or cluster headache (24). Treatment consisted of withdrawal of overused medications (usually analgesics and ergots), repetitive IV administration of DHE, and use of metoclopramide and prophylactic medications, together with educational and psychological support. Overall, 91% (range, 86% to 100%) of the patients became headache-free, usually within 2 to 3 days. The average duration of hospitalization was 7.4 days. Side effects, reported in 157 (52%) of the patients, consisted primarily of nausea (32%), tightness and burning (8%), leg cramps (7%), vomiting (6%), and increased blood pressure (5%). The side effects generally resolved spontaneously or with adjustment of the DHE dose and/or adjunct medication, and necessitated withdrawal of therapy in only 2 patients (1 with drug-related claudication; 1 with somatic complaints of uncertain origin). We conclude that a regimen of repetitive intravenous DHE and metoclopramide can provide rapid relief of chronic intractable headache, and can ameliorate the effects of analgesic and ergot withdrawal in patients with chronic daily headache and rebound associated with overuse of these drugs.

Spontaneous low cerebrospinal fluid pressure headache.

A 69 year old man presented with headache on arising and relieved with recumbency. His clinical presentation, laboratory data, response to treatment and radiographic evaluation were consistent with spontaneous low cerebrospinal fluid pressure from CSF hyperabsorption. Cisternography showed rapid accumulation in the kidneys and urinary bladder, without evidence of CSF leak. His headache was eventually controlled with two blood patches and oral caffeine.

A radioactive method for the measurement of trypsin and trypsin-like activities.

A simple and highly sensitive method for the assay of trypsin has been developed by making use of the phosphorylated synthetic peptide Leu-Arg-Arg-Ala-Ser-(32P)-Leu-Gly as substrate. The technique has been adapted from the phosphocellulose method of R. Roskoski, Jr. (in Methods in Enzymology (Corbin, J., and Hardman, J., Eds.), Vol. 99, pp. 3-6, Academic Press, New York) used for measuring of protein kinases. In addition to measuring the activity of trypsin at the microgram level, the 32P-labeled peptide method can be used for measuring other trypsin-like enzymes. It has been successfully utilized for the identification of a new peptidase from the fungus Saccobolus platensis.