A patient with Wegener''s granulomatosis presenting with a subarachnoid hemorrhage: case report and review of CNS disease associated with Wegener''s granulomatosis

1. Travellers to high altitude often complain of paroxysmal cough, which has not been previously investigated. We recorded overnight cough frequency and cough-receptor sensitivity to inhaled citric acid in a group of climbers travelling to 5300 m or higher. 2. Cough frequency, monitored in ten subjects, increased from a median of 0 coughs at sea level (range 0-1) to 5 coughs at 5000 m (range 0-13) and to over 60 coughs in subjects ascending to 7000 m. Citric acid cough threshold, measured in 42 subjects, was unchanged on arrival at 5300 m compared with sea level (geometric mean difference 1.26, 95% confidence intervals 0.84-1.89, P = 0.25), but was significantly reduced after 6 days, or more, at altitude compared with sea level (geometric mean difference 2.2, 95% confidence intervals 1.54-3.15, P = 0.0002). Cough threshold was not related to symptoms of acute mountain sickness, oxygen saturation, carbon dioxide tension or lung function. 3. These results indicate an increase in cough and cough-receptor sensitivity after some days at altitude. This may be due to respiratory tract damage from breathing cold dry air at increased ventilatory rates. Other explanations, such as sub-clinical pulmonary oedema or an effect on the cough centre of acclimatization to altitude, cannot be excluded.     

Vaccination for experimental gliomas using GM-CSF-transduced glioma cells

Within the pituitary, folliculostellate (FS) cells are considered to regulate the intercellular communication between endocrine cells by paracrine mechanisms. One of the possible paracrine factors involved, could be interleukin-6 (IL-6) which is produced by these cells. Since IL-6 has been shown to be a growth factor of pituitary cells, we have determined whether IL-6 can also influence FS cell proliferation. To test this, a FS cell-like mouse pituitary cell line (TtT/GF cells) was used that exhibits most characteristics of normal FS cells. Under serum-free conditions the proliferation of TtT/GF cells is critically dependent on the initial seeding density: cells seeded at low density do not grow at all whereas cells seeded at high density proliferate with maximal doubling times of 34 hrs. Mouse IL-6 (mIL-6) stimulated only low density cell cultures in a dose and time dependent manner. For cells seeded at high density, exogenously added IL-6 may have failed to stimulate growth because of endogenously produced mIL-6. Conditioned medium from TtT/GF cells, in which mIL-6 concentrations up to 1017 pg/ml were measured, stimulated the proliferation of TtT/GF cells, indicating an autocrine growth stimulatory mechanism. A neutralizing mIL-6 antibody partially suppressed the growth of TtT/GF cells seeded at high density and partially reduced the growth stimulatory activity of TtT/GF conditioned medium. Thus, IL-6 is one but not the only factor that is involved in the autocrine growth stimulatory loop. The relevance of this mechanism for normal FS cells and its physiological consequence needs to be elucidated.     

Lymphocytes mediate TNF-alpha-induced endothelial cell adhesion molecule expression: studies on SCID and RAG-1 mutant mice

TNF-alpha is known to elicit a rapid increase in the expression of specific endothelial cell adhesion molecules (ECAMs) within different vascular beds. The aim of this study was to determine whether lymphocytes contribute to the increased ECAM expression elicited by TNF-alpha. A dual radiolabeled mAb technique was used to quantify constitutive and TNF-alpha-induced expression of ICAM-1, VCAM-1, E-selectin, and P-selectin in different vascular beds (lung, heart, stomach, mesentery, small intestine, large intestine, and muscle) in wild-type and SCID mice. In reconstitution experiments, either whole splenocytes, T cell-enriched splenocytes, or B cell-enriched splenocytes were injected into SCID mice 48 h before TNF-alpha administration. Although the constitutive expression of ECAMs differed only slightly between wild-type and SCID mice, TNF-alpha-induced ECAM expression was markedly blunted in SCID mice compared with wild-type mice. This blunted response to TNF-alpha was also demonstrated for VCAM-1 in recombination activating gene (RAG)-1 mutant mice. Reconstitution studies revealed that administration of 50 x 10(6) splenocytes in SCID mice at 48 h before cytokine treatment restored the TNF-alpha-induced expression of VCAM-1 to levels normally observed in wild-type mice. Reconstitution with T cell- but not B cell-enriched splenocytes, also restored the TNF-alpha-induced expression of VCAM-1 in SCID mice to wild-type levels. These results implicate circulating T lymphocytes as modulators of the increased ECAM expression elicited by TNF-alpha.     

Homonucleotide tracts, short repeats and CpG/CpNpG motifs are frequent sites for heterogeneous mutations in the neurofibromatosis type 1 (NF1) tumour-suppressor gene

Glutamatergic synaptic potentials induced by micromolar concentrations of the potassium conductance blocker 4-aminopyridine (4-AP) were recorded intracellularly from rat neostriatal neurons in the presence of 10 microM bicuculline (BIC). These synaptic potentials originate from neostriatal cortical and thalamic afferents and were completely blocked by 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) plus 100 microM D-2-amino-5-phosphonovaleric acid (2-APV). Their inter-event time intervals could be fitted to exponential distributions, suggesting that they are induced randomly. Their amplitude distributions had most counts around 1 mV and fewer counts with values up to 5 mV. Since input resistance of the recorded neurons is about 40 M omega, the amplitudes agree to quantal size measurements in mammalian central neurons. The action of a D2 agonist, quinpirole, was studied on the frequency of these events. Mean amplitude of synaptic potentials was preserved in the presence of 2-10 microM quinpirole, but the frequency of 4-AP-induced glutamatergic synaptic potentials was reduced in 35% of cases. The effect was blocked by the D2 antagonist sulpiride (10 microM). Input resistance, membrane potential, or firing threshold did not change during quinpirole effect, suggesting a presynaptic site of action for quinpirole in some but not all glutamatergic afferents that make contact on a single cell. The present experiments show that dopaminergic presynaptic modulation of glutamatergic transmission in the neostriatum does not affect all stimulated afferents, suggesting that it is selective towards some of them. This may control the quality and quantity of afferent flow upon neostriatal neurons.     

Bioactive fragment of human IL-1beta [163-171] modulates the immune response to synthetic peptides of HIV

The activation of T helper cells specific for viral antigens is critical for antibody production and the generation of cytotoxic T cells during retroviral infection. In this study, we examined the effect of linking HIV peptides with a bioactive fragment of human interleukin-1beta (IL-1beta) (163-171) on the induction of immune response to the peptides. A panel of highly purified synthetic peptides representing defined regions of gp41, Gag and gp120 were used as antigens. Mouse spleen cells primed with the peptide conjugates produced greater proliferation on in vitro stimulation than spleen cells primed with peptide alone. In addition, antibody production as assessed by ELISA was observed after immunization with conjugated peptides but not with peptide alone, indicating B-cell activation. We also found that a high level of IgG2a antibody production correlated with a high level of IFN-gamma production. These findings favor the notion that IL-1beta plays an important role in immune responses. These observations support the formulation and design of synthetic vaccines against HIV using synthetic HIV peptides conjugated with immunomodulators. Such an approach may provide an effective vaccination against other infectious agents.     

Extracorporeal photochemotherapy (photopheresis) induces apoptosis in lymphocytes: a possible mechanism of action of PUVA therapy

The mechanism of action of psoralen plus UVA (PUVA) and photopheresis is not entirely understood. These therapies are assumed to be immunomodulating partly by gradually decreasing leukocyte viability. We investigated whether this delayed form of cell death was due to apoptosis. Untreated and treated (PUVA exposed) leukocytes obtained from six patients with systemic sclerosis and (untreated) leukocytes from healthy control individuals were studied. Qualitative gel electrophoresis and quantitative in situ nick translation analysis of DNA fragmentation was performed. Apoptosis of the treated cells did occur (gel electrophoresis) after 24 h. At t = 0 h, immediately after exposure to PUVA, there was no evidence of DNA fragmentation in the treated cells. The percentage of treated cells undergoing apoptosis was 20-55% at t = 24 h (in situ nick translation). The untreated leukocytes of the patients and the healthy individuals showed no distinctive rise in apoptotic cells. Apoptosis of the leukocytes after PUVA or photopheresis treatment might be a mechanism of action and might explain the therapeutic response.     

Clinical evaluation of mastalgia

OBJECTIVE: To describe an accurate and reproducible method to quantify a patient's subjective experience of breast pain. DESIGN: Prospective diary study. SETTING: Military tertiary care hospital. PATIENTS: Thirty female military health care beneficiaries from the Walter Reed Army Medical Center, Washington, DC, gynecology and general surgery clinics. MAIN OUTCOME MEASURES: Daily mastalgia was recorded using a visual analog scale and menstrual symptoms were measured using a daily questionnaire. These measures were correlated with results of a screening questionnaire completed prior to study entry. RESULTS: Patients identified as having cyclical mastalgia based on the screening questionnaire (n= 15) were found to have higher peak perimenstrual mastalgia according to their daily diaries than patients who did not meet diagnostic criteria (n=15) (5.3+/-0.7 vs 3.5+/-0.5, P<.001). Applying the same criteria used in the screening questionnaire to the diary data, 17 of 30 patients met diagnostic criteria for cyclical mastalgia. The ability of the screening questionnaire to predict the results of the prospective diary data was calculated, and positive and negative predictive values were 73% and 60%, respectively. Most patients with cyclical mastalgia also have other perimenstrual psychological and somatic complaints, although a subset of patients has high levels of mastalgia with minimal associated symptoms. CONCLUSIONS: Accurate assessment of mastalgia cannot be done with a retrospective questionnaire and requires prospective diary evaluation, owing to the variable and subjective nature of symptoms and recall bias. A daily visual analog scale provides reproducible results and is easy for patients to use.     

Reproductive sequelae in female rats after in utero and neonatal exposure to the phytoestrogen genistein

OBJECTIVE: To determine reproductive sequelae in female rats after in utero and lactational dietary exposure to genistein. DESIGN: Experimental animal study. SETTING: University laboratory. ANIMAL(S): Sprague Dawley rats. INTERVENTION(S): Pregnant rats were fed control rat chow or rat chow incorporated with genistein (approximately 50 microg/d) beginning on day 17 of gestation and continuing until the end of lactation (postpartum day 21). Genistein-exposed female pups were divided into two groups on day 21. One group continued to receive a genistein-added diet (G70); the other group was changed to a control diet (Ex-G). At necropsy (days 21 and 70), blood and reproductive tissues were collected. MAIN OUTCOME MEASURE(S): Serum levels of gonadotropins and gonadal steroids and histopathologic examination of the ovaries. RESULT(S): The weight of the ovaries and uterus and serum levels of E2 and progesterone in genistein-exposed rats on day 21 (G21) were significantly reduced compared with control rats. On day 70, serum levels of E2, progesterone, LH, and FSH were similar in all groups. Atretic follicles and secondary interstitial glands were more common in G70 and Ex-G rats compared with control rats. Cystic rete ovarii was observed in some G70 and Ex-G rats. CONCLUSION(S): Our data indicate that in utero and lactational exposure to dietary genistein adversely affects reproductive processes in the adult female rat.     

Premenstrual syndrome: diagnosis and intervention

Premenstrual syndrome (PMS) is a recurrent disorder that occurs in the luteal phase of the menstrual cycle. It is characterized by intense physical, psychologic, and behavioral changes that interrupt interpersonal relationships and disrupt the lives of affected women. Up to 40% of women of childbearing age have some form of PMS, and up to 10% have severe signs and symptoms. There are at least four types of PMS, each with its own constellation of signs and symptoms. Related illnesses or illnesses that need to be ruled out include diabetes mellitus, thyroid dysfunction, hypoglycemia, and primary and secondary dysmenorrhea. Difficulty in identifying the exact etiology of the disorder is documented. Diagnostic issues include confusion over exact signs and symptoms, differential diagnoses, pertinent laboratory data, careful history taking, and the importance of women recording a menstrual cycle history on a calendar. Recommended first-line treatments include a diet low in salt, fat, caffeine, and sugar; an aerobic exercise regimen; and stress reduction via changes in lifestyle.