"Phobic postural vertigo". A further differentiation of psychogenic vertigo conditions seems necessary]

Due to the results of an interdisciplinary study on patients with vertigo as the chief symptom and on the background of psychodynamic theories concerning anxiety disorders the term of phobic postural vertigo (Brandt & Dieterich 1986) is discussed. It becomes obvious that phobic postural vertigo is a generalizing term which encompasses different forms of psychogenic vertigo. The authors plead for a more differentiated diagnosis and subgroup oriented classification of vertigo caused by psychiatric disorders.     

Prevalence and determinants of carotid atherosclerosis in healthy postmenopausal women

Fecal incontinence is an under-reported complication of scleroderma. Ten incontinent patients with scleroderma were evaluated through anorectal manometry and compared with 20 incontinent patients without scleroderma who were matched for age and sex as controls. The scleroderma patients had a higher voluntary external anal squeeze pressure, whereas the resting internal anal sphincter pressure was similar to that of the control group. The threshold for rectal sensation in the scleroderma group was significantly less than that in controls. Episodes of fecal incontinence, anal canal length, and maximal tolerable volume were not significantly different between the study groups. The rectoanal inhibitory response was abnormal in 80% of patients with systemic sclerosis but was normal in 70% of the controls. Stool consistency was significantly looser in the scleroderma patients. Treatment of fecal incontinence in scleroderma patients may be successful in many patients using a combination of dietary and pharmacologic manipulation because diarrhea is an important etiologic cofactor superimposed on reduced internal anal sphincter pressure.     

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer

Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical activity in glioma and melanoma. The purpose of this Phase I study is to characterize the toxicity, pharmacokinetics, and antitumor activity of TMZ administered on an oral 5-day schedule to patients with or without prior exposure to nitrosourea (NU). Thirty-six eligible patients received a total of 77 cycles of therapy with TMZ administered p.o. at doses ranging from 50 mg/m2/day to 250 mg/m2/day for 5 days, every 4 weeks. Separate dose escalations were carried out in patients, with or without prior exposure to NU. Pharmacokinetic studies were performed during the first cycle of treatment on days 1 and 5. Dose-limiting toxicity was thrombocytopenia, and the maximally tolerated doses for patients with and without prior exposure to NU were 150 mg/m2/day for 5 days (total dose, 750 mg/m2) and 250 mg/m2/day for 5 days (total dose, 1250 mg/m2), respectively. Significant (grade 3 or higher) thrombocytopenia was observed in six patients during cycle 1. The median times to nadir and recovery were 17 and 15 days, respectively. Nonhematological toxicity was generally manageable and consisted of fatigue, nausea, and vomiting. There were two complete responses (one glioma and one melanoma) in patients without prior NU. No objective responses were seen in patients with prior NU treatment. Pharmacokinetic studies showed rapid absorption with a mean time to peak concentration of 60 min and mean t1/2 of 109 min (range, 80-121 min). The area under the curve and the peak plasma concentrations were linear over the dose range of 50-250 mg/m2/day. The mean apparent oral clearances on day 1 for patients with and without prior NU exposure were 102+/- 27 and 115+/- 22 ml/min/m2, respectively. Apparent oral clearances on days 1 and 5 were found to differ with respect to NU exposure (P = 0.047). Renal clearance of the parent drug and its metabolism to 3-methyl-2, 3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid were minor pathways of TMZ elimination. We conclude that TMZ is well tolerated in this oral 5-day schedule with dose-limiting thrombocytopenia and that it has promising activity in glioma and melanoma. The recommended doses for Phase II studies in patients with and without prior NU are 125 mg/m2/day for 5 days and 225 mg/m2/day for 5 days, respectively.     

Identification of a unique ligand which has high affinity for all four bombesin receptor subtypes

Four subtypes of bombesin receptors are identified (gastrin-releasing peptide receptor, neuromedin B receptor, the orphan receptor bombesin receptor subtype 3 (BB3 or BRS-3) and bombesin receptor subtype 4 (BB4)), however, only the pharmacology of the gastrin-releasing peptide receptor has been well studied. This lack of data is due in part to the absence of a general ligand. Recently we have discovered a ligand, 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) that binds to BRS-3 receptors. In this study we investigate its ability to interact with all four bombesin receptor subtypes. In rat pancreatic acini containing only gastrin-releasing peptide receptor and in BB4 transfected BALB cells, this ligand and 125I-[Tyr4]bombesin, the conventional gastrin-releasing peptide receptor ligand, gave similar results for receptor number, affinity for bombesin and affinity for the unlabeled ligand. In neuromedin B receptor transfected BALB cells, this ligand and 125I-[D-Tyr0]neuromedin B, the generally used neuromedin B receptor ligand, gave similar results for receptor number, neuromedin B affinity or the unlabeled ligand affinity. Lastly, in BRS-3 transfected BALB cells, only this ligand had high affinity. For all four bombesin receptors this ligand had an affinity of 1-8 nM and was equal or greater in affinity than any other specific ligands for any receptor. The unlabeled ligand is specific for gastrin-releasing peptide receptors on rat pancreatic acini and did not inhibit binding of 125I-cholecystokinin octapeptide (125I-CCK-8), 125I-vasoactive intestinal peptide (125I-VIP) or 125I-endothelin to their receptors. The unlabeled ligand was an agonist only at the gastrin-releasing peptide receptor in rat acini and did not interact with CCK(A) receptors or muscarinic M3 acetylcholine receptors to increase [3H]inositol phosphates. These results demonstrate 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) is a unique ligand with high affinity for all subtypes of bombesin receptors. Because of the specificity for bombesin receptors, this ligand will be a valuable addition for such pharmacological studies as screening for bombesin receptor agonists or antagonists and, in particular, for investigating BRS-3 cell biology, a receptor for which no ligand currently exists.     

Surgical and nonsurgical management of primary and metastatic liver tumors

The medical records of 267 patients who had liver tumors, primary and metastatic, from 1988 to 1995 were retrospectively reviewed. Two hundred thirteen patients (80%) had metastatic disease, and 54 patients (20%) had primary liver disease. Their clinical manifestations and laboratory values were evaluated as factors predictive of diagnosis and survival. There was a significant increase in the occurrence of upper abdominal pain, weight loss, extrahepatic symptoms due to the metastatic origin, and hepatomegaly. Metastases from colorectal primary lesions were synchronous in 34 patients and metachronous in 31 patients. Stomach, lung, and pancreatic primaries were more commonly synchronous. Breast metastases were more commonly metachronous. Elevated serum glutamic-oxaloecetic transaminase and alkaline phosphatase and decreased albumin were the most common liver test abnormalities at diagnosis. Carcinoembryonic antigen values were elevated in the majority of colon cancer patients. Eighty-one percent of patients with primary liver cancer had elevated levels of alpha-fetoprotein, 40 per cent were seropositive for hepatitis B, and 23 per cent were seropositive for hepatitis C. Seventy-nine patients (30%) underwent surgery for their cancer, 37 (47%) had resections, 38 (48%) were unresectable, and 4 (5%) underwent liver transplantation. The patients who underwent surgery had a 32 per cent 5-year survival rate compared to a 0 per cent 5-year survival in the patients who did not have surgery (p = 0.0001). The patients who had resections had a better survival rate than those deemed unresectable at surgery (62% versus 0% at 5-years with p = 0.0008). The perioperative morbidity rate was 16 per cent, with lobectomies having the best rate and trisegmentectomies having the worst. Perioperative mortality rate was zero for all liver resections. Hepatic resection and, in selected patients, liver transplantation are the only two available therapeutic modalities that produce long-term survival with a possible cure in patients with primary and metastatic liver tumor.     

Identification of distinct metabolic pools of aggrecan and their relationship to type VI collagen in the chondrons of mature bovine articular cartilage explants

The metabolism and distribution of newly synthesized aggrecan present in the extracellular matrix of intact explant cultures of mature articular cartilage was investigated with respect to type VI collagen-stained chondrons. Using biochemical, autoradiographical and novel confocal immunohistochemical techniques it was shown that aggrecan exists as a number of distinct pools that are located within the extracellular matrix of the tissue. The first was identified as a pool of high specific radioactivity, much of which appeared in the medium one day after incubation with radiolabeled sulfate. Of the radiolabeled aggrecan remaining within the extracellular matrix, three pools were differentiated on the basis of time and location within the extracellular matrix. One pool was resident within the pericellular microenvironment associated with the chondron, one migrated into the territorial matrix adjacent to the chondron and one was sequestered long term in the interterritorial matrix. Analysis of the kinetics of loss of radiolabeled aggrecan macromolecules present in the region of matrix defined by the chondron suggests that this pool rapidly turns over and is a precursor to the pools of aggrecan present in the territorial and interterritorial matrix. There were marked differences in the distribution of newly synthesized aggrecan present in these regions of the extracellular matrix in explant cultures maintained with or without fetal calf serum. In the absence of serum, more of the newly synthesized aggrecan moved into the territorial and interterritorial matrix indicating that the presence of serum in the culture medium influenced the tissue distribution of aggrecan. This work indicates that the pericellular microenvironment of the chondron plays an important role in the retention and maturation of aggrecan prior to the sequestration of aggrecan complexes into the functional load bearing matrices of adult articular cartilage.     

Late-onset chronic inflammatory encephalopathy in immune-competent and severe combined immune-deficient (SCID) mice with astrocyte-targeted expression of tumor necrosis factor

To examine the role of tumor necrosis factor (TNF)-alpha in the pathogenesis of degenerative disorders of the central nervous system (CNS), transgenic mice were developed in which expression of murine TNF-alpha was targeted to astrocytes using a glial fibrillary acidic protein (GFAP)-TNF-alpha fusion gene. In two independent GFAP-TNFalpha transgenic lines (termed GT-8 or GT-2) adult (>4 months of age) animals developed a progressive ataxia (GT-8) or total paralysis affecting the lower body (GT-2). Symptomatic mice had prominent meningoencephalitis (GT-8) or encephalomyelitis (GT-2) in which large numbers of B cells and CD4+ and CD8+ T cells accumulated at predominantly perivascular sites. The majority of these lymphocytes displayed a memory cell phenotype (CD44high, CD62Llow, CD25-) and expressed an early activation marker (CD69). Parenchymal lesions contained mostly CD45+ high, MHC class II+, and Mac-1+ cells of the macrophage microglial lineage with lower numbers of neutrophils and few CD4+ and CD8+ T cells. Cerebral expression of the cellular adhesion molecules ICAM-1, VCAM-1, and MAdCAM as well as a number of alpha- and beta-chemokines was induced or upregulated and preceded the development of inflammation, suggesting an important signaling role for these molecules in the CNS leukocyte migration. Degenerative changes in the CNS of the GFAP-TNFalpha mice paralleled the development of the inflammatory lesions and included primary and secondary demyelination and neurodegeneration. Disease exacerbation with more extensive inflammatory lesions that contained activated cells of the macrophage/microglial lineage occurred in GFAP-TNFalpha mice with severe combined immune deficiency. Thus, persistent astrocyte expression of murine TNF-alpha in the CNS induces a late-onset chronic inflammatory encephalopathy in which macrophage/microglial cells but not lymphocytes play a central role in mediating injury.     

Cognitive activity and physiological arousal: processes that mediate mood-congruent memory

This research proposes that the cognitive activity associated with the experience of an emotional state mediates the occurrence of mood-congruent processing. Two experiments examined the role of cognitive activity in selective processing of words in a mood congruence paradigm. Four induction procedures were used: a depressed-mood induction, a schema induction organized around the theme of writing a paper, an arousal induction, and a control neutral-mood induction. The memory task consisted of recalling a word list composed of negatively associated and thematically organized words. Selective processing was demonstrated in conjunction with the depressed-mood and organizational-schema induction procedures. In contrast, the arousal and neutral induction procedures did not produce selective processing of words from the list. The findings support the thesis that cognitive activity mediates the selective processing typical of mood congruence as distinct from arousal processes per se. The findings are discussed with respect to the resource allocation model and semantic network theory.     

Better postural balance in elderly women receiving estrogens

OBJECTIVE: The amount of bone mass and the tendency to fall are main risk factors for hip fractures and both deteriorate with advancing age. The dynamics between estrogen exposure and fracture protection seem too rapid to be explained by an effect on bone mass only. Postural balance function may be another potential mechanism for the fracture-protecting effect of estrogens. STUDY DESIGN: We examined 16 long-term users of 17 beta-estradiol implants (20 mg) (mean age 67.9 years and mean duration of treatment 17.3 years [3.3 to 34 years]) and 16 age-matched (+/-2 years) nonusers (mean age 68.3 years). Postural balance (sway velocity) was measured by static posturography before and after blindfolding and application of vibration stimulus (20 to 100 Hz) to the calf muscles to disturb the proprioception and to induce imbalance. RESULTS: Sway velocities were significantly lower in estrogen users than in nonusers (p = 0.0067) and similar to those in young premenopausal women. The differences were accentuated after provocation by blindfolding and by increasing frequencies of vibration stimulus to the calf muscle. Serum levels of estradiol and estradiol/sex hormone-binding globulin were negatively and follicle-stimulating hormone levels positively associated with sway velocity (p = 0.0194, p = 0.0036, and p = 0.0052, respectively) and independent of age (p = 0.02 to 0.005), supporting causality between estrogen exposure and postural balance. CONCLUSIONS: These data indicate that postural balance function is better preserved in long-term estrogen users than in nonusers. Effects on postural balance function may be one mechanism explaining the rapid increase in distal forearm fractures early after menopause and the rapid dynamics between estrogen exposure and hip fracture protection and may potentially reduce the fracture risk in elderly women starting estrogen replacement therapy in spite of marginal increases in bone mass.     

Epidermal growth factor and neurotensin induce microvillus hypertrophy following massive enterectomy

OBJECTIVE: To describe the relative risk for venous thrombosis (VT) associated with antiphospholipid antibodies (aPL) in systemic lupus erythematosus (SLE). DESIGN: Systematic review and meta-analysis of 26 articles that examined the association between aPL and VT in SLE. SETTING: Mostly secondary and tertiary referral centres. PATIENTS: 2249 patients with SLE, 1120 tested for LA (lupus anticoagulant) and 1563 tested for aCL (anticardiolipin antibodies). MAIN OUTCOME MEASURES: A summary of study characteristics and a critical appraisal of study quality were done. Two statistical combinations of 18 primary studies that examined the association of VT and LA and of 14 studies that examined the association of VT and aCL were performed to estimate the risk for VT associated with aPL. RESULTS: The odds ratios of the risk of VT related to the LA summarized from 18 studies were 5.61 [95% CI; 3.80-8.27] overall, 6.32 [CI; 3.71-10.78] for deep venous thrombosis and pulmonary embolism, 11.6 [3.65-36.91] for recurrent venous thrombosis after the first event. The odds ratios of the risk of VT related to aCL summarized from 14 studies were 2.17 [95% CI; 1.51-3.11] overall, 2.50 [CI; 1.51-4.14] for deep venous thrombosis and pulmonary embolism, 3.91 [1.14-13.38] for recurrent venous thrombosis after the first event. CONCLUSIONS: Patients with SLE and LA are at approximately six times greater risk for VT than patients without LA, whereas patients with SLE and aCL are approximately two times greater risk for VT than patients without aCL. We have identified important methodologic limitations and differences in study characteristics. Other risk factors for VT have not been thoroughly evaluated in these studies. Further studies are needed that provide an accurate estimate of the absolute risk for aPL related VT.