Interaction affinity between cytokine receptor components on the cell surface.

The anti-common gamma chain (gammac) mAb CP.B8 is shown to inhibit interleukin 4 (IL-4)-dependent proliferation of phytohemagglutinin (PHA) activated T cells noncompetitively with respect to cytokine by blocking the IL-4-induced heterodimerization of IL-4Ralpha and gammac receptor chains. Affinities for the binding of IL-4 to Cos-7 cells transfected with huIL-4Ralpha, and to PHA blasts expressing both IL-4Ralpha and gammac, were used to estimate the affinity of the key interaction between gammac and the binary IL-4Ralpha.IL-4 complex on the cell surface. This affinity was defined in terms of the dimensionless ratio [IL-4Ralpha.IL-4.gammac]/[IL-4Ralpha.IL-4], which we designate KR. The results show that on PHA blasts this interaction is relatively weak; KR approximately 9, implying that approximately 10% of the limiting IL-4Ralpha chain remains free of gammac even at saturating concentrations of IL-4. This quantitative treatment establishes KR as a key measure of the coupling between ligand binding and receptor activation, providing a basis for functional distinctions between different receptors that are activated by ligand-induced receptor dimerization.

Molecular mapping with functional antibodies localizes critical sites on the human IL receptor common gamma (gamma c) chain.

The IL receptor common gamma (gamma c) chain is required for the formation of high affinity cytokine receptor complexes for IL-2, IL-4, IL-7, IL-9, and IL-15, and for signals regulating cell survival, growth, and differentiation. Our current understanding of how gamma c chain associates with multiple ligands and receptor subunits is drawn largely from its structural homology to the human growth hormone (hGH) receptor and known structure of the hGH/hGH receptor complex. These receptors share distinct features in their extracellular portions and are believed to function by a mechanism of ligand-induced association of receptor subunits. Here, we report the first directed mutational analysis of the human gamma c chain by alanine scanning conducted across seven regions likely to contain residues required for intermolecular contact. Functionally distinct, neutralizing anti-gamma c mAbs were employed to define critical residues. One particular mAb, CP.B8, unique in its ability to inhibit IL-2-, IL-4-, IL-7-, and IL-15-induced proliferation and high affinity cytokine binding of normal T cells as an intact mAb and as a Fab fragment, localized critical residues to four noncontinuous stretches, namely residues in loops AB and EF of domain 1, in the interdomain segment, and in loop FG of domain 2. Notably, these residues form a contiguous patch on the gamma c chain surface in a three-dimensional structural model. These results provide functional evidence for the location of contact points on gamma c chain required for its association with multiple ligands.

Short-lived head pains.

There are several short-lived paroxysmal head pain syndromes, many of which are responsive to indomethacin, and some of which are potentially ominous. Included in this article are icepick headache, hypnic headache syndrome, chronic paroxysmal hemicrania, cough headache syndrome, coital headache, and thunderclap headache.

Approach to the patient with migraine.

Women with migraine often experience a worsening of symptoms at menopause. Use of exogenous estrogens is not helpful and may even exacerbate the condition. Although initial pharmacologic management generally is focused on control of individual headaches, attempts to stabilize the underlying migraine mechanism through serotonin receptor downregulation are likely to provide a better outcome.

Headache.

Headache-prone patients have many highly effective therapeutic options open to them. Used only at the time of headache, sumatriptan succinate by mouth or injection and dihydroergotamine nasal spray are novel choices now or soon to be available. The original migraine therapy, ergotamine, is highly effective in its rectal suppository formulation, when used at a subnauseating dosage. Valproate sodium is the latest addition to the many therapies available for long-term stabilization.

Acute and prophylactic treatment of migraine: practical approaches and pharmacologic rationale.

The antimigraine efficacy of many drugs may be mediated less through their primary modes of action than through the common pathway of serotonergic transmission stabilization. Migraine treatment may be symptomatic, acute/abortive, or prophylactic. Because oral drug absorption is impaired during attacks, parenteral agents are more appropriate for acute therapy. Acute agents include ergots and ergotamine derivatives, narcotics, and sumatriptan succinate. Agents that activate the 5-HT3 receptors must be administered with an antiemetic. Sumatriptan succinate, a specific 5-HT1 receptor agonist, does not necessitate adjunctive antiemetics. Stabilization regimens, such as those using valproate, may favorably alter the natural history of migraine. Sumatriptan succinate is appropriate both for acute attacks and for symptomatic management during stabilization. beta-Blockers, tricyclic antidepressants, and calcium antagonists may be used prophylactically.

Thoracic surgery in the AIDS patient.

AIDS is a syndrome caused by HIV. The virus is spread by homosexual or heterosexual transmission and by infected blood or certain body fluids. Respiratory infections are the commonest cause of death, and diagnosis may be difficult. The fiberoptic bronchoscope (FOB) plays an essential role in diagnosing respiratory infections in AIDS and is important in minimizing the need for open lung biopsies. Various problems require thoracic surgical consultation and treatment. We do not consider it ethical to deny these patients help. There can be no "double standard" in the care of patients in the hospital or in the operating room since any of our patients may have HIV without our knowledge.

Modern pharmacotherapy of migraine.

Rectal ergotamine and naproxen are the major candidates for the ad hoc treatment of migraine attacks; for particularly dramatic episodes, intravenous DHE with prochlorperazine is the author's preference. For long-term stabilization, after simpler measures fail, valproate appears to be a major addition to migraine therapy.

Antimigraine treatment for slit ventricle syndrome.

Slit ventricle syndrome is characterized by chronic or recurring headaches associated with subnormal ventricular volume in patients who have undergone shunt treatment for hydrocephalus. There appear to be at least three pathophysiological mechanisms that cause this syndrome: 1) intermittent shunt malfunction; 2) intracranial hypotension; and 3) paroxysms of increased intracranial pressure in the presence of normal shunt function. To treat seven patients with slit ventricle syndrome caused by paroxysms of elevated intracranial pressure, we successfully used antimigraine therapy rather than standard calvarial expansion procedures. None of these patients has required shunt revision or calvarial expansion during a mean follow-up period of 2 years. The symptoms of slit ventricle syndrome may be a form of "acquired" migraine in shunt patients. We suggest that, in clinically stable patients with normal shunt function, treatment against migraine may stabilize symptoms resulting from paroxysms of increased intracranial pressure. Such treatment may prevent unnecessary shunt revisions and/or calvarial expansion procedures.

Lumbar puncture headache: a review.

August Bier, the father of spinal anesthesia, suffered and reported the first lumbar puncture (LP) headache. On August 24, 1898 his assistant, a Dr. Hildebrandt, attempted to administer a spinal anesthetic to Dr. Bier; it was never completed because the syringe did not fit the already implanted spinal needle. Bier himself suggested that continued leakage of cerebrospinal fluid (CSF) through the dural puncture site was the cause of headache, a theory that has been embraced by the medical community; however, the mechanism is probably more complex. Nearly 50 years ago, J. Lawrence Pool, using an endoscopic technique to visualize the surface of the spinal cord and the cauda equina, frequently observed large collections of epidural fluid two to four days following lumbar puncture in patients without headache. Evidence that will be presented below suggests that CSF volume alterations may be the signal closest to the headache mechanism.

Treatment of status migrainosus: the American experience.

Dependence upon a variety of drugs--ergotamine, analgesics, benzodiazepines, corticosteroids--is a major reason for patients to enter an intractable phase of their migrainous disorders. Repeated dosing of dihydroergotamine has proven to be remarkably effective in stabilizing the mechanism of migraine, allowing these patients to make the transition to a more reasonable as well as more specific form of therapy.

Pharmacology of migraine.

Stabilization of serotonergic neurotransmission by depressing the activity of serotonergic neurons may be the common mode of action of drugs effective in migraine. By serotonin receptor agonism, by prolonging the biologic half-life of serotonin in the synaptic cleft (through blockade of its re-uptake or metabolic degradation), by an increase in its synthesis, by inhibiting the release of serotonin, or by activation of cyclic AMP (fig), a unitary expression for the action of these drugs can be formulated which is corroborated, for many of the drugs, by direct measurement of serotonergic neuronal firing rates. However, there are at least three serotonin receptor sites in brain at which drugs would be effective, as assessed by differential responsiveness to agonists and antagonists and by different types of postsynaptic responses: presynaptically, postsynaptically, and at the autoreceptor itself. The locus of action for the antimigraine drugs may be primarily at the raphe, upon the serotonin neurons per se, but it will probably prove to be more complex as more data are generated.

Adenosine diphosphate ribosyl transferase responses to a standardized dose of hydrogen peroxide in the mononuclear leukocytes of patients with a diagnosis of cancer.

Mononuclear leukocytes from 151 patients with cancer of various organs and from 467 apparently cancer-free individuals were exposed, in vitro, to H2O2 (100 microM) and the effects of the exposure on the activity of adenosine diphosphate ribosyl transferase (ADPRT) were determined. First, the reproducibility of this test procedure was established as satisfactory, by comparing the results of assays performed independently by two investigators, and by measuring ADPRT in cells from two individuals over a 9-week period. The test data were analyzed by multiple linear regression, and the correlation of cancer diagnosis, age, sex and smoking habits with ADPRT values was determined. The strongest correlate was cancer diagnosis. We considered categorizing ADPRT values as high and low, with a cut-off value that would substantially distinguish cancer from cancer-free individuals. When a cut-off value of 1200 c.p.m. TCA ppt [3H]NAD+/5 x 10(5) cells was applied to the complete test material, it was found that ADPRT values from cancer patients were more frequently below the cut-off than values from disease-free individuals: the relative risk estimate (odds ratio) was 13.8. When a similar analysis was done on values from lung cancer patients and smoking disease-free individuals, the odds ratio was 73.5. However, a cut-off value of 2000 c.p.m. TCA ppt [3H]NAD+/5 x 10(5) cells was most effective in distinguishing lung cancer patients (the largest cancer group, n = 96) from smoking non-cancer individuals: that value provided better sensitivity (85%) and specificity (81%) than other cut-off values tested in the range 1200-2000 c.p.m. Further, in the case of lung cancer, possible effects of anatomical site, and of staging and pathology on ADPRT values was analyzed by the chi-squared test: no significant associations were found. These data support the value of the ADPRT test in detecting early stage lung cancer regardless of location or pathological type.

Brain metastases in malignant pleural mesothelioma. Case report and review of the literature.

Recent advances in pleural malignant mesothelioma include the sequential use of palliative surgery, perioperative radiation therapy, and systemic chemotherapy. Radical treatments may not only palliate but also improve survival in some patients. The latter may be associated with the appearance of metastases in unusual sites including the central nervous system. In malignant mesothelioma, brain metastases were previously reported in 19 patients at autopsy and in only 1 patient antemortem. We detail the clinical presentation in the second patient with pleural malignant mesothelioma thus far reported to develop brain metastases. The difficulties in diagnosis, the role of immunoperoxidase stains in malignant mesothelioma, excellent tolerance of different modalities of treatment, and a review of the literature of brain metastases in mesothelioma are discussed. Based on our report, the possibility of brain metastases should be investigated by careful clinical examination prior to a radical treatment in patients with progressive refractory mesothelioma.

Chest wall stabilization using plate fixation.

Large defects of the chest wall require stabilization of the remaining thorax to prevent paradoxical movement. A technique of fixation using rib grafts and compression plates is presented.