Discovery and characterization of dietary antigens in oral tolerance.

Food antigens elicit immune tolerance through the action of regulatory T cells (Tregs) in the intestine. Although antigens that trigger common food allergies are known, the epitopes that mediate tolerance to most foods have not been described. Here, we identified murine T cell receptors specific for maize, wheat, and soy, and used expression cloning to de-orphan their cognate epitopes. All of the epitopes derive from seed storage proteins that are resistant to degradation and abundant in the edible portion of the plant. Multiple unrelated T cell clones were specific for an epitope at the C-terminus of 19 kDa alpha-zein, a protein from maize kernel. An MHC tetramer loaded with this antigen revealed that zein-specific T cells are predominantly Tregs localized to the intestine. These cells, which develop concurrently with weaning, constitute up to 2% of the peripheral Treg pool. Bulk and single-cell RNA sequencing revealed that these cells express higher levels of immunosuppressive markers and chemokines compared to other Tregs. These data suggest that immune tolerance to plant-derived foods is focused on a specific class of antigens with common features, and they reveal the functional properties of naturally occurring food-specific Tregs.

Overview of tension-type headache.

Tension-type headache (TTH) is the most prevalent form of headache. Although it is not the most severe form of headache, it has a significant impact on society. In spite of this, little is known about its pathophysiology. Current International Headache Society classification has been called into question, and new classification approaches have been suggested. With reference to chronic TTH, the issue of analgesic rebound may confound the diagnosis. Transformed migraine and new persistent daily headaches are clarified and differentiated from chronic TTHs (CTTHs). The best documented abnormality found in TTHs is the presence of pericranial tenderness. It is generally believed that pain is initiated by a peripheral mechanism, most likely increased input from the myofascial nociceptors. In CTTH, there may be an impaired supraspinal modulation of the incoming stimuli. Whether there is an overlap in the continuum between TTH and migraine is controversial. Abortive and prophylactic treatments are discussed and wellness and adjunct therapy are also emphasized. Lastly, special attention is paid to the doctor-patient relationship in patients with difficult headaches.

Effectiveness of sumatriptan in reducing productivity loss due to migraine: results of a randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVE: To determine the effect of sumatriptan on migraine-related workplace productivity loss. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled, parallel-group trial, adult migraineurs self-injected 6 mg of sumatriptan or matching placebo to treat a moderate or severe migraine within the first 4 hours of a minimum of an 8-hour work shift. Outcome measures included productivity loss and number of patients returning to normal work performance 2 hours after injection and across the work shift, time to return to normal work performance, and time to headache relief. RESULTS: A total of 206 patients underwent screening, 140 (safety population) of whom returned for clinic treatment. Of these 140 patients, 119 received migraine treatment in the workplace (intent-to-treat population), 116 of whom comprised the study population. Of these 116 patients, 76 self-administered sumatriptan, and 40 self-administered placebo. Sumatriptan treatment tended to reduce median productivity loss 2 hours after injection compared with placebo (25.2 vs 29.9 minutes, respectively; P = .14). Significant reductions in productivity loss were obtained across the work shift after sumatriptan treatment compared with placebo (36.8 vs 72.6 minutes, respectively; P = .001). Significantly more sumatriptan-treated patients vs placebo-treated patients experienced shorter return to normal work performance at 2 hours (53/76 [70%] vs 12/40 [30%], respectively) and across the work shift (64/76 [84%] vs 23/40 [58%], respectively; P < .001). Significantly more sumatriptan-treated patients experienced headache relief 1 hour after injection compared with placebo-treated patients (48/76 [63%] vs 13/40 [33%], respectively; P = .004). CONCLUSION: Across an 8-hour work shift, sumatriptan was superior to placebo in reducing productivity loss due to migraine.

Symptomatic and prophylactic treatment of migraine and tension-type headache.

Pharmacotherapy is the mainstay for patients with persistent headaches. When simple analgesics can no longer be used, combination analgesics are prescribed. Symptomatic medications also include antiemetics, ergot derivatives, corticosteroids, neuroleptics, and narcotics. Nonsteroidal anti-inflammatory drugs are commonly used both symptomatically and prophylactically, and are the treatment of choice for menstrual migraine. Exertional migraine, benign orgasmic cephalalgia, chronic paroxysmal hemicrania, cough headache, and "ice-pick" headache are treated with indomethacin. Ergotamine tartrate is often recommended when simple or combination analgesics do not relieve headaches. Dihydroergotamine (DHE) is effective for treating intractable headache; because it has fewer side effects than ergotamine, it is tolerated by patients unable to tolerate other ergotamine preparations. DHE is administered IM and, for occasional use, patients can be taught self-injection. Repetitive IV DHE therapy for chronic severe headaches requires hospitalization; most patients become headache-free within 3 days. Patients who refuse hospitalization, do not respond to the drug, or are not suitable candidates for DHE therapy may receive a short course of a corticosteroid, a neuroleptic or, rarely, a narcotic. For frequent headaches, prophylactic treatment usually begins with a tricyclic antidepressant or a beta blocker.

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.

An unusual angiographic picture in status migrainosus.

Arteriographic findings suggestive of inflammation are described in a 26-year-old woman presenting with headache and syncope. There were no clinical findings of angitis, and a diagnosis of status migrainosus was eventually made. We present her case, as well as a review of previous cases of arterial changes in patients with headache. Most previous cases report arterial narrowing, felt to reflect spasm, whereas our patient demonstrated segmental stenoses and dilatations, perhaps implicating inflammation. The inflammatory process has been postulated as the pathogenesis of migraine pain. As most migraineurs do not undergo arteriography, the incidence of arterial change in these patients is unknown. This finding has therapeutic implications for selecting the optimal anti-migraine agent.

Claudication: an unusual side effect of DHE administration.

DHE is effective in the treatment of acute and chronic migraine. The side effects most commonly observed are abdominal discomfort, muscle pain, diarrhea and anxiety. DHE is a dehydrogenated amino acid ergot alkaloid and, as such, causes only limited vasoconstriction; indeed, its overall effects include peripheral vasodilation. The literature is replete with reports of clinical vasospasm and claudication occurring with therapeutic doses of ergotamine. There has not been any previous description of claudication caused by DHE. This paper describes pulselessness in two patients during relatively short courses of DHE. Treatment consisted of calcium channel blockers and discontinuation of DHE. Recovery was complete.

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.

Cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol and norepinephrine levels in alcohol withdrawal. Correlations with clinical signs.

Cerebrospinal fluid (CSF) and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were significantly elevated in patients during the alcohol withdrawal syndrome. When CSF MHPG was corrected using a formula proposed to determine CSF MHPG levels of central origin, these values were still significantly elevated when compared with control values. The MHPG concentrations in CSF also showed significant positive correlations with heart rate, systolic and diastolic blood pressures, tremor, anorexia, and sweating. The results of this study indicate increased presynaptic release of norepinephrine during alcohol withdrawal.

Intractable seizures: long-term follow-up after prolonged inpatient treatment in an epilepsy unit.

Seventy-four patients with intractable seizures were followed up 6 to 57 months (mean 25 months) after intensive monitoring. At discharge from the hospital, 59% of the patients had at least a 50% reduction in seizure frequency and 63% had decreased antiepileptic drug toxicity. The findings at follow-up compared with those at admission showed reduced seizure frequency in 55% of the patients, diminished medication toxicity in 54%, and improved social adjustment in 38%. A change in the seizure diagnosis was the best predictor of a favorable outcome. Patients with impaired mental status were not less likely to improve. The relationship between seizure type and outcome was not significant, although patients with complex partial seizures tended to be less likely to improve. Intensive monitoring can lead to significant long-lasting improvement of patients with severe epilepsy.

CSF levels of norepinephrine during alcohol withdrawal.

Cerebrospinal fluid norepinephrine (NE) levels were determined by radioenzymatic assay in 21 patients with a variety of neurological diseases and 49 patients in acute alcohol withdrawal. A second determination was made in 19 patients who had recovered from the alcohol withdrawal syndrome. Cerebrospinal fluid NE concentration was higher in the patients during alcohol withdrawal (192.3 plus or minus 22.3 pg/mL) and decreased during recovery to 137.8 plus or minus 15.9 pg/mL. The CSF NE level was higher in both groups than in patients with other neurological disorders. This may help explain the adrenergic signs observed during alcohol withdrawal.